Elicit: Pharmacokinetics and Pharmacodynamics of Emicizumab in Hemophilia A

Skip to main content

Pharmacokinetics and Pharmacodynamics of Emicizumab in Hemophilia A

Research reportView only

Create alertChat

May 5, 2026

Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A

Emicizumab exhibits predictable, dose-proportional pharmacokinetics with sustained plasma concentrations that produce FVIII-equivalent hemostatic activity and reduce bleeding rates by 94% through an exposure-response relationship plateauing above 30 µg/mL.

Abstract

Emicizumab demonstrates dose-proportional, predictable pharmacokinetics across diverse hemophilia A populations, with subcutaneous administration achieving sustained trough concentrations of 42-66 µg/mL during maintenance dosing across weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), and every-4-weeks (6 mg/kg) regimens. The median elimination half-life is 23-30 days, with time to steady-state of 12 weeks with loading doses and 24 weeks without. Interindividual variability in trough concentrations is moderate (32%), influenced primarily by body weight, age, albumin levels, and rarely by neutralizing antibodies. Infants achieve higher concentrations (60-65 µg/mL) than older individuals with identical dosing, while bioavailability decreases after age 65. Pharmacodynamically, emicizumab maintains FVIII-equivalent activity of 17-25 IU/dL, thrombin generation >100 nM, and normalized aPTT without affecting FIX, FX, or coagulation activation markers.

Exposure-response modeling establishes that bleeding control plateaus above emicizumab concentrations of 30 µg/mL (IC50 3.58 µg/mL), explaining equivalent efficacy across dosing regimens that achieve mean concentrations of 53.5 µg/mL and produce a 94% reduction in annualized bleeding rates. Clinical studies demonstrate annualized bleeding rates for treated bleeds of 0.4-2.4, with 54-78% of patients achieving zero treated bleeds. The safety profile is favorable, with injection site reactions as the most common adverse event (16-22%), no thromboembolic events when used alone, and minimal immunogenicity. These pharmacokinetic and pharmacodynamic characteristics support body weight-based dosing without routine therapeutic drug monitoring, with potential for individualized dosing in patients maintaining concentrations substantially above the 30 µg/mL efficacy threshold.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods

Records from Elicit search

n = 200

Papers screened using: Population - Hemophilia A, Intervention - Emicizumab, Outcome - PK/PD Data, Study Population - Human Subjects, Study Design, Intervention Specificity, Population Specificity, Data Relevance

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

Press enter or space to select a node.You can then use the arrow keys to move the node around. Press delete to remove it and escape to cancel.

Press enter or space to select an edge. You can then press delete to remove it or escape to cancel.

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A”

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

Extract patient demographics and clinical characteristics relevant to emicizumab pharmacokinetics/pharmacodynamics in hemophilia A, including:

Extract all details about emicizumab dosing and administration for PK/PD assessment, including:

Extract pharmacokinetic parameters and characteristics of emicizumab in hemophilia A patients, including:

Extract pharmacodynamic outcomes and biomarkers for emicizumab in hemophilia A, including:

Extract any analyses of exposure-response or concentration-effect relationships for emicizumab in hemophilia A, including:

Extract safety and immunogenicity data relevant to emicizumab PK/PD in hemophilia A, including:

Extract factors identified as affecting emicizumab pharmacokinetics or pharmacodynamics in hemophilia A patients, including:

Extract methodological details relevant to PK/PD assessment of emicizumab in hemophilia A, including:

Results

Characteristics of Included Studies

The review included 10 sources examining emicizumab pharmacokinetics and pharmacodynamics in hemophilia A, comprising clinical trial reports, a systematic review, and an exposure-response modeling study. The studies varied in design from Phase I dose-escalation trials to Phase III pivotal studies and represented diverse patient populations.

Study

Full text retrieved?

Study Type

Population

Sample Size (PK/PD)

Study Design

C. Schmitt et al., 2020

Yes

Primary study (Phase III)

Adults/adolescents (12-75 years) with severe HA and FVIII inhibitors; multicenter (14 countries)

112

Open-label, multicenter, randomized

A. Kiialainen et al., 2023

No (abstract only)

Pooled analysis

HAVEN 1-4 participants

Not specified

Phase III trials

M. Shima et al., 2016

No (abstract only)

Primary study (Phase I)

Japanese adults with severe HA with/without inhibitors

18

Open-label, non-randomized, dose-escalation

M. Shima et al., 2017

Yes

Primary study (Phase I/II extension)

Japanese adults (12-58 years) with severe HA with/without inhibitors

18

Open-label, long-term extension

S. Pipe et al., 2022

No (abstract only)

Primary study (Phase IIIb interim)

Infants ≤12 months with severe HA without inhibitors

52

Multi-center, open-label (HAVEN 7)

Qianqian Mao et al., 2025

No (abstract only)

Primary study (retrospective)

Chinese pediatric patients (0.93-16.25 years) with HA

46

Retrospective single-center

S. Pipe et al., 2023

No (abstract only)

Primary study (Phase IIIb primary)

Infants ≤12 months with severe HA without inhibitors

55

Multi-center, open-label (HAVEN 7)

A. Donners et al., 2021

Yes

Systematic review

Adults and children (0 to ≥12 years) with HA with/without inhibitors

469 PwHA, 140 volunteers

Systematic review of 15 studies

S. Pipe et al., 2019

No (abstract only)

Primary study (Phase III)

Adults/adolescents (≥12 years) with severe HA with/without inhibitors from 6 countries

41 (expansion cohort)

Multi-center, open-label, two-stage (HAVEN 4)

F. Jonsson et al., 2021

Yes

Modeling study

445 PwHA with/without inhibitors (age 1-77 years)

385 emicizumab-treated

Exposure-response modeling of pooled Phase III data

toof

Pageof

The populations spanned a wide age range from infants (9 days old) to adults (up to 77 years), including specialized studies in infants ≤12 months and Chinese pediatric patients. Most studies included patients with severe hemophilia A, with variable inhibitor status across studies. Prior treatment history varied, with several studies including previously untreated or minimally treated patients.

Dosing Regimens and Administration

Emicizumab was administered subcutaneously across all studies, with various loading and maintenance regimens tested to optimize pharmacokinetic profiles.

Study

Loading Dose

Maintenance Dose

Dosing Frequency

Duration

C. Schmitt et al., 2020

3 mg/kg weekly for 4 weeks

1.5 mg/kg

Once weekly

Median 60.5 weeks (range 3.3-94.2)

A. Kiialainen et al., 2023

3 mg/kg weekly for 4 weeks

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Weekly, Q2W, or Q4W

Not specified

M. Shima et al., 2016

None mentioned

0.3, 1.0, or 3.0 mg/kg

Weekly

12 weeks

M. Shima et al., 2017

1 mg/kg (cohort 1), 3 mg/kg (cohort 2)

0.3, 1.0, or 3.0 mg/kg

Once weekly

Up to 33.3 months

S. Pipe et al., 2022

3 mg/kg weekly for 4 weeks

3 mg/kg

Every 2 weeks for 52 weeks

≥52 weeks with 7-year follow-up

Qianqian Mao et al., 2025

Median 2.85 mg/kg per week (range 2.14-3.90)

Median 5.21 mg/kg (range 2.54-6.46)

Loading: weekly; Maintenance: every 28 days

December 2023-July 2025

S. Pipe et al., 2023

3 mg/kg weekly for 4 weeks

3 mg/kg, 1.5 mg/kg, or 6 mg/kg

Q2W for 52 weeks; then weekly or Q4W options

≥52 weeks with 7-year follow-up

A. Donners et al., 2021

Not mentioned

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Weekly (75%), Q2W (11%), Q4W (14%)

≥16 weeks

S. Pipe et al., 2019

3 mg/kg weekly for 4 weeks

6 mg/kg

Every 4 weeks

≥24 weeks

F. Jonsson et al., 2021

3 mg/kg weekly for 4 weeks

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Once weekly, Q2W, or Q4W

365.25 days for ABR calculation

toof

Pageof

The standard loading regimen across recent studies was 3 mg/kg weekly for 4 weeks, designed to rapidly achieve therapeutic concentrations. Maintenance dosing flexibility allowed for once-weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), or every-4-weeks (6 mg/kg) administration. Dose adjustments were permitted in some studies, with up-titration to 3 mg/kg weekly allowed for suboptimal efficacy after 6 months and individualized dose modifications implemented based on efficacy and safety committee review. In the HAVEN 7 study, one participant required dose up-titration from biweekly to weekly due to decreasing emicizumab levels.

Pharmacokinetic Parameters

Emicizumab demonstrated predictable, dose-proportional pharmacokinetics across diverse patient populations.

Plasma Concentrations

Study

Steady-State Trough Concentrations

Peak/Loading Concentrations

Time to Steady-State

C. Schmitt et al., 2020

≥50 µg/mL maintained; mean 54.1 µg/mL after loading, sustained >50 µg/mL

Not specified

Not specified

A. Kiialainen et al., 2023

42.1-52.3 µg/mL with maintenance dosing

Mean 52.9 µg/mL (SD 13.6) at week 5

Not specified

M. Shima et al., 2016

Increased in dose-dependent manner

Not specified

Not specified

M. Shima et al., 2017

10.3 mg/mL (cohort 1), 29.9 mg/mL (cohort 2), 120 mg/mL (cohort 3)

Not specified

~12 weeks with loading, 24 weeks without

S. Pipe et al., 2022

60-65 µg/mL maintained

Mean 63.2 µg/mL (95% CI: 59.5-66.8) at Week 5

Not specified

Qianqian Mao et al., 2025

Maintenance: median 50.6 µg/mL (range 17.3-81.7)

Loading: median 57.7 µg/mL (range 31.8-79.9)

Not specified

S. Pipe et al., 2023

Sustained at 57-66 µg/mL

Mean 62.0 µg/mL (95% CI: 58.3-65.6) at Week 5

Not specified

A. Donners et al., 2021

Moderate interindividual variability (32%)

Not specified

Not specified

S. Pipe et al., 2019

Not specified

Not specified

Not specified

F. Jonsson et al., 2021

~50 µg/mL across regimens; trough: 28.4 (QW), 24.9 (Q2W), 17.7 (Q4W) µg/mL

Not specified

Not specified

toof

Pageof

Trough concentrations increased during the loading phase, reaching mean values of 52.9-63.2 µg/mL by week 5, and were sustained at 42.1-66 µg/mL with maintenance dosing. The Chinese pediatric study reported somewhat lower median trough concentrations during maintenance (50.6 µg/mL). Dose-proportional increases in steady-state trough levels were observed across dose cohorts in the Phase I/II extension, with levels of 10.3, 29.9, and 120 mg/mL for 0.3, 1.0, and 3.0 mg/kg weekly dosing, respectively. Plasma concentrations increased in a dose-dependent manner across all dose escalation studies.

A notable finding was higher emicizumab concentrations in infants compared to older populations. In HAVEN 7, infant concentrations (60-65 µg/mL) were higher than those observed with the same dosing regimen in HAVEN 1-4 studies of older patients (46.7 ± 14.9 µg/mL) and HAVEN 2-3 studies (46-48 µg/mL).

Pharmacokinetic Model Parameters

The Chinese pediatric study provided detailed estimates using the published population PK model. Median clearance (CL/F) was 0.0637 L/day (range 0.0421-0.1578), volume of distribution (V/F) was 2.1543 L (range 1.2629-6.2103), and elimination half-life was 23.44 days (range 20.79-27.28). The earlier Phase I study reported a longer half-life of 4-5 weeks, while another source cited approximately 30 days. The systematic review noted that clearance was comparable to other therapeutic IgG4-based monoclonal antibodies (0.2-0.5 L/day), but emicizumab demonstrated increased distribution volumes (10 vs. 6 L) and a longer half-life. Time to steady-state was approximately 12 weeks with a loading dose and 24 weeks without loading.

Pharmacokinetic Variability

Interindividual variability in trough concentrations was moderate at 32% and remained consistent across various subgroups including FVIII inhibitor status, age group, and dosing interval. Total PK interindividual variability was approximately 60%, influenced by body weight, neutralizing antidrug antibodies, age, and albumin levels. Children showed slightly less variability than adults and adolescents. The long half-life was expected to result in minimal variation in peak/trough plasma concentrations, supporting stable pharmacokinetics with minimal peak-trough fluctuation.

Emicizumab demonstrated high subcutaneous bioavailability, with bioavailability decreasing with age, particularly after 65 years. The dose-linear pharmacokinetics supported body weight-based dosing, although individualized monitoring may allow for more cost-effective dosing.

Pharmacodynamic Outcomes

FVIII-Equivalent Activity and Coagulation Parameters

Study

FVIII-Equivalent Activity (IU/dL)

aPTT Response

Thrombin Generation (nM)

Other Coagulation Parameters

C. Schmitt et al., 2020

Remained above 20 U/dL

Normalized at subtherapeutic concentrations

Peak height above 100 nM

FIX, FX, fibrinogen, PT, D-dimer, PF1.2 not significantly affected

A. Kiialainen et al., 2023

25.2 IU/dL at week 5, sustained 17-23 IU/dL

Shortened following first dose

115.2 nM at week 5, sustained >116 nM

Not mentioned

M. Shima et al., 2016

Not mentioned

Remained short throughout

Not mentioned

No clinically relevant coagulation abnormalities

M. Shima et al., 2017

Not mentioned

Remained short, within or shorter than reference range

Promotion of FXIa-triggered thrombin generation

Not mentioned

S. Pipe et al., 2022

21 U/dL during loading, sustained

Normalized by Week 3

Increased to 100 nM from Week 17 onwards

FIX and FX unaffected

Qianqian Mao et al., 2025

Loading: 14.6 IU/dL (range 7.4-39.2); Maintenance: 20.2 IU/dL (range 8.9-39.6)

Not mentioned

Not mentioned

Not mentioned

S. Pipe et al., 2023

Not mentioned

Not mentioned

Not mentioned

Not mentioned

A. Donners et al., 2021

Not mentioned

Not mentioned

Not mentioned

Not mentioned

S. Pipe et al., 2019

Not mentioned

Not mentioned

Not mentioned

Not mentioned

F. Jonsson et al., 2021

Not mentioned

Not mentioned

Not mentioned

Not mentioned

toof

Pageof

FVIII-like activity increased during the loading period to 21-25.2 IU/dL and was sustained at 17-23 IU/dL with maintenance dosing, remaining consistently above 20 U/dL. The Chinese pediatric study reported median FVIII-equivalent activity of 14.6 IU/dL during loading and 20.2 IU/dL during maintenance. These levels theoretically convert patients with severe hemophilia A to a mild disease phenotype.

Thrombin generation peak height increased during loading, reaching 100-115.2 nM by week 5-17, and was sustained above 100-116 nM thereafter. Activated partial thromboplastin time (aPTT) was normalized at subtherapeutic concentrations of emicizumab, shortened following the first dose, normalized by Week 3 in most participants, and remained short throughout studies.

Importantly, emicizumab did not significantly affect plasma concentrations of target antigens FIX and FX, nor did it affect fibrinogen, prothrombin time (international normalized ratio), D-dimer, or prothrombin fragment 1.2 levels, indicating no induction of consumptive coagulopathy or coagulation activation.

Bleeding Outcomes

Study

Treated Bleeds ABR (95% CI)

All Bleeds ABR (95% CI)

Treated Joint Bleeds ABR (95% CI)

Zero Treated Bleeds (%)

C. Schmitt et al., 2020

87% reduction vs. no prophylaxis

Not specified

Not specified

62.9%

M. Shima et al., 2016

Cohort 1: 32.5→4.4; Cohort 2: 18.3→0.0; Cohort 3: 15.2→0.0

Not specified

Not specified

73% (with inhibitors), 71% (without)

M. Shima et al., 2017

Median: Cohort 1: 1.4; Cohort 2: 0.2; Cohort 3: 0

Not specified

Not specified

8/18 patients (44%)

S. Pipe et al., 2022

0.4 (0.23-0.65)

1.9 (1.35-2.68)

0.1 (0.01-0.22)

77.8%

Qianqian Mao et al., 2025

Median ABR: 0

Not specified

Not specified

Not specified

S. Pipe et al., 2023

0.4 (0.30-0.63)

2.0 (1.49-2.66)

0.0 (0.01-0.09)

54.5%

A. Donners et al., 2021

At 30 µg/mL: 2.4; At 50 µg/mL: 1.9

Not specified

At 30 µg/mL: 1.1; At 50 µg/mL: 1.0

70.8%→80.2% after 1 year

S. Pipe et al., 2019

2.4 (1.4-4.3)

4.5 (3.1-6.6)

1.7 (0.8-3.7)

56.1% (39.7-71.5)

F. Jonsson et al., 2021

Predicted mean: 1.28 at 53.5 µg/mL (94% reduction from baseline)

Not specified

Not specified

Not specified

toof

Pageof

Emicizumab prophylaxis demonstrated substantial efficacy in reducing bleeding rates across all studies. In the infant population (HAVEN 7), the model-based ABR for treated bleeds was 0.4 (95% CI: 0.23-0.65 in interim analysis and 0.30-0.63 in primary analysis), with ABR for all bleeds of 1.9-2.0 and treated joint bleeds of 0.0-0.1. No intracranial hemorrhage occurred in this vulnerable population. The proportion of patients achieving zero treated bleeds ranged from 54.5% to 77.8% in the HAVEN 7 analyses.

In the Phase I dose-escalation study, median ABRs decreased from baseline values of 18.3-32.5 to 0.0-4.4 across cohorts receiving 0.3-3.0 mg/kg weekly, with 71-73% of patients experiencing no bleeding. The long-term extension showed median ABRs remaining low at 0.0-1.4.

The HAVEN 4 study examining every-4-weeks dosing reported an ABR of 2.4 (95% CI: 1.4-4.3) for treated bleeds, with 56.1% of patients reporting no treated bleeds. The Chinese pediatric study achieved a median ABR of 0. Overall, the systematic review found that 70.8% of patients had no treated bleeds initially, increasing to 80.2% after 1 year of treatment.

The majority of bleeds were traumatic (87.9% in HAVEN 7), with breakthrough bleeding episodes successfully treated with episodic FVIII or bypassing agents when needed. The episodic use of clotting factors to control bleeding was reduced.

Exposure-Response Relationships

Several studies characterized the relationship between emicizumab concentrations and clinical outcomes, demonstrating clear concentration-dependent effects on both pharmacodynamic biomarkers and bleeding control.

Concentration-Biomarker Correlations

FVIII-like activity and thrombin generation peak height correlated with emicizumab concentrations. The Chinese pediatric study quantified this relationship, finding a positive correlation between emicizumab concentration and FVIII-equivalent activity by linear regression (Y = 0.9569·X + 33.24, R² = 0.37, p < 0.01) and Spearman correlation (ρ = 0.56, p < 0.01). The relationship between emicizumab plasma concentration and aPTT was well described by an inhibitory Emax model.

In the infant population, sustained FVIII-like activity and normalization of aPTT suggested a concentration-effect relationship, with higher emicizumab concentrations in infants compared to older individuals contributing to excellent bleeding control.

Concentration-Efficacy Relationships

The systematic review by Donners et al. performed detailed exposure-response modeling using an Emax model relating trough plasma concentrations to annualized bleeding rates. The EC50 for treated bleeds was 1.47 µg/mL with an Emax of 0.96, while for treated joint bleeds the EC50 was 1.09 µg/mL with an Emax of 0.98. Critically, the control of bleeds did not improve above emicizumab concentrations of 30 µg/mL, establishing an effectiveness plateau. At 30 µg/mL, the expected ABR was 2.4 for treated bleeds and 1.1 for treated joint bleeds, while at 50 µg/mL these values were 1.9 and 1.0, respectively.

The comprehensive exposure-response analysis by Jonsson et al. using a generalized Poisson distribution and inhibitory Emax relationship found that emicizumab concentrations were inversely related to bleeding rates, with higher concentrations leading to reduced bleeding. The IC50 was estimated at 3.58 µg/mL, indicating the concentration required for half-maximal effect. Importantly, concentrations above 30 µg/mL provided clinically meaningful control of bleeding. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate was 1.28, corresponding to a 94.0% reduction from baseline. Simulations demonstrated that the three dosing regimens (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W) maintain concentrations near the plateau of effect.

Visual predictive checks from the exposure-response model showed adequate prediction of bleeding onset over time, supporting the model’s validity. The PK profile of once-weekly emicizumab provided sustained therapeutic plasma levels consistent with population PK models.

Factors Affecting Pharmacokinetics and Pharmacodynamics

Body Weight and Size Effects

Body weight was a significant covariate affecting emicizumab pharmacokinetics across multiple studies. Dosing regimens were universally based on body weight (mg/kg), and including body weight in population PK models significantly reduced interindividual variability in both clearance (CL/F) and volume of distribution (V/F). Body weight also affected apparent clearance and distribution volume in the exposure-response model. The Chinese pediatric study documented body size characteristics, with median weight of 14.5 kg (range 8.5-41.8 kg) and median BMI of 16.8 kg/m² (range 13.8-21.5 kg/m²).

Plasma concentrations of emicizumab increased in a dose-dependent manner, and steady-state trough levels increased in a dose-proportional manner, supporting body weight-based dosing strategies. However, the systematic review suggested that individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

Age Effects

Age emerged as an important covariate affecting emicizumab pharmacokinetics and potentially pharmacodynamics. Bioavailability decreased with age, particularly after 65 years. Conversely, infants demonstrated higher emicizumab concentrations compared to older individuals with the same dosing regimen, with concentrations of 60-65 µg/mL in HAVEN 7 versus 46.7 ± 14.9 µg/mL in older HAVEN 1-4 participants and 46-48 µg/mL in HAVEN 2-3.

The Chinese pediatric study population had a median age at enrollment of 3.52 years (range 0.93-16.25 years) and a median age at emicizumab initiation of 1.40 years, with height (median 92.0 cm) also documented. The HAVEN 7 studies focused specifically on infants ≤12 months of age, demonstrating feasibility and efficacy in this youngest population. Studies in adults included participants from age 12 to 75 years.

Inhibitor Status and Prior Treatment History

FVIII inhibitor status did not significantly affect emicizumab PK variability or efficacy. Emicizumab was effective in patients with FVIII inhibitors as well as those without, with no significant difference in bleeding control between the two groups.

Prior treatment history varied across studies and was considered as a potential covariate. Several studies included previously untreated or minimally treated patients (PUPs/MTPs). The Chinese pediatric study reported that 15 patients were previously untreated or minimally treated, and 9 had a history of inhibitors. In the exposure-response analysis, prior prophylaxis with FVIII significantly reduced bleeding hazard by 44.7%, representing the most clinically significant covariate effect identified.

Other Covariates

Albumin levels affected pharmacokinetics, with low albumin levels associated with decreased exposure and albumin affecting apparent clearance. The Chinese pediatric study documented median albumin levels of 46.1 g/L (range 41.4-49.6 g/L).

Ethnic differences were observed, with African race mentioned as a factor affecting PK variability and ethnicity affecting distribution volume in population PK models. The Chinese pediatric study specifically noted that ethnic and developmental factors—such as body size, nutritional status, and earlier treatment initiation—may influence drug exposure and clinical response.

Neutralizing antidrug antibodies represented a primary source of interindividual PK variability, though their actual occurrence was rare (discussed in safety section below). Age >30 years was also identified as a factor affecting PK variability.

Safety and Immunogenicity

Emicizumab demonstrated a favorable safety profile across all studies, with most adverse events being mild and not leading to treatment discontinuation.

Injection Site Reactions and General Tolerability

Injection site reactions were the most frequent treatment-related adverse event. In the Phase I/II extension, mild injection site reactions occurred in 38.9% of patients (7/18). In the infant studies, 16.4-16.7% of participants experienced emicizumab-related injection site reactions, all Grade 1. The HAVEN 4 study reported injection site reactions in 22% of patients.

Most participants in infant studies experienced at least one adverse event (92.6-100%), but importantly, no adverse events led to treatment withdrawal, modification, or interruption. The long-term Phase I/II extension reported no discontinuations due to safety concerns, and the treatment was generally well tolerated with limited toxicity.

Thrombotic Events

Notably, no thromboembolic events or thrombotic microangiopathies occurred in the infant studies or the long-term Phase I/II extension. The HAVEN 4 study also observed no thrombotic events. In the HAVEN 1 study, two participants experienced thrombotic microangiopathy and thromboembolism, but these were associated with the use of bypassing agents (activated prothrombin complex concentrate) rather than emicizumab itself. The systematic review noted an increased thrombotic risk when emicizumab was used with high doses of activated prothrombin complex concentrate.

Immunogenicity

Emicizumab demonstrated minimal immunogenicity across studies. None of the participants in the HAVEN 7 studies tested positive for anti-drug antibodies (ADAs) at any timepoint (baseline, Week 5, or 12-weekly thereafter). The early Phase I study reported no development of antibodies to emicizumab.

In the Phase I/II extension, 4 patients tested positive for ADAs, but these were nonneutralizing and did not affect PK/PD parameters. Similarly, the systematic review noted that neutralizing antidrug antibodies affected PK variability but their actual development was rare. The HAVEN 4 study observed no development of de-novo antidrug antibodies with neutralizing potential.

Regarding development of FVIII inhibitors in previously untreated patients, one PUP in HAVEN 7 was confirmed positive for FVIII inhibitors on Day 603 after three FVIII exposure days (for traumatic bleed treatment), and another PUP tested positive on Day 428 after 10 FVIII exposure days (for post-tonsillectomy bleed management), with confirmatory titer pending at the analysis cut-off.

Laboratory Safety Parameters

Emicizumab did not significantly affect key laboratory safety parameters. Platelet count, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were not significantly affected. FIX and FX plasma antigen levels, prothrombin time, and concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen) were not notably affected. In the infant study, aPTT was normalized by Week 3 and mean FIX and FX concentrations were unaffected by emicizumab.

Serious Adverse Events

Serious adverse events were infrequent and not attributed to emicizumab. In HAVEN 7, 29.1% of participants (16/55) reported 30 serious adverse events, all considered serious due to hospitalization, but none were considered emicizumab-related. The Phase I/II extension reported that 4 patients experienced serious adverse events, but none were related to emicizumab treatment. One participant in HAVEN 7 experienced an anaphylactic reaction following food allergy, not considered emicizumab-related. The systematic review noted joint pain episodes at high concentrations (90 µg/mL).

Five participants were withdrawn from emicizumab treatment in HAVEN 1 due to adverse events or physician/patient decision, though specific details were not provided.

Study Methodologies

The studies employed diverse methodological approaches to assess emicizumab pharmacokinetics and pharmacodynamics, ranging from Phase I dose-escalation studies to large Phase III randomized trials and sophisticated modeling analyses.

Study Designs

The evidence base included open-label, non-randomized, dose-escalation Phase I studies, Phase III multicenter, open-label, randomized studies, Phase IIIb multi-center, open-label studies, and a two-stage Phase III study with run-in and expansion cohorts. The systematic review pooled data from 15 studies including 469 patients with hemophilia A and 140 volunteers. The exposure-response modeling study analyzed pooled Phase III trial data. One real-world study employed a retrospective single-center design.

Pharmacokinetic Assessment Methods

PK sampling strategies varied by study. The HAVEN 1 study collected blood samples before the first dose, weekly for the first month, every 2 weeks for the second month, every 4 weeks from the third to sixth month, every 8 weeks from the seventh to twelfth month, and every 12 weeks thereafter. HAVEN 7 measured plasma trough emicizumab concentrations at Week 5 and thereafter. The Chinese pediatric study collected peripheral blood samples during both loading and maintenance phases.

Bioanalytical methods for emicizumab concentration measurement included validated enzyme-linked immunosorbent assay (ELISA) in Phase I-III studies and a modified one-stage clotting assay (OSA) in Phase IV studies. The HAVEN 1 study used a validated ELISA, while the Chinese pediatric study employed a modified one-stage assay.

PK analysis approaches included graphical exploratory analyses and linear regressions, population pharmacokinetic modeling using NONMEM software, and application of published population PK models. The systematic review employed non-linear least squares regression using a maximum effect (Emax) model. Statistical approaches included descriptive analysis, negative binomial regression for calculating ABRs, generalized Poisson distribution and inhibitory Emax relationship for exposure-response modeling, and linear regression and Spearman correlation for PK/PD relationships.

Pharmacodynamic Assessment Methods

FVIII-equivalent activity was measured using chromogenic assays, including the Hyphen Biophen FVIII:C assay containing human factors and the HYPHEN chromogenic FVIII assay. Thrombin generation was assessed using the Calibrated Automated Thrombogram method. Efficacy endpoints in the infant studies were estimated using a negative binomial regression model for annualized bleeding rates.

Assay precision and accuracy for emicizumab concentration measurement were validated in key studies, though detailed validation information for pharmacodynamic assays was not consistently reported across all studies.

Study Limitations

Several methodological limitations were noted. The Phase I/II extension was not randomized or controlled and had small patient numbers in each dose cohort. Sample sizes in some studies were based on clinical considerations rather than statistical power calculations. The systematic review cited limitations including a limited number of available studies, heterogeneous study populations, and lack of blinded, placebo-controlled studies. The exposure-response modeling study noted a limited range of exposure concentrations at the lower end of the dose-response curve.

Synthesis

The pharmacokinetic and pharmacodynamic characteristics of emicizumab demonstrate remarkable consistency across diverse populations and study designs, supporting its use as a prophylactic treatment for hemophilia A. Several key findings emerge from synthesis of the evidence.

Dose-Concentration-Response Relationships

The evidence establishes a clear hierarchy of dose-proportional pharmacokinetics leading to sustained therapeutic concentrations, which in turn correlate with pharmacodynamic biomarkers and translate to clinically meaningful bleeding control. The convergence of findings from mechanistic studies, clinical trials, and sophisticated modeling analyses provides robust evidence for a threshold effect, with bleeding control plateauing above concentrations of 30 µg/mL. This plateau has important implications: it explains why all three approved maintenance regimens (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, 6 mg/kg every 4 weeks) achieve similar efficacy despite different trough concentrations, and it suggests that therapeutic drug monitoring could enable dose reduction in patients maintaining concentrations substantially above this threshold.

Age-Related Pharmacokinetic Differences

The consistently higher emicizumab concentrations observed in infants compared to older populations receiving identical dosing regimens represents a genuine population-specific difference rather than measurement artifact, as it was replicated across studies and correlates with known developmental changes in antibody pharmacokinetics. Infants have lower total body weight but proportionally higher body surface area and different tissue composition compared to adults, which may reduce volume of distribution relative to body weight. Additionally, the neonatal Fc receptor (FcRn), which protects IgG antibodies from catabolism, may function differently in infants, potentially reducing clearance and increasing bioavailability. These age-related differences in exposure did not translate to safety concerns, as thrombotic events remained absent in the infant population despite higher concentrations. This suggests the concentration-safety relationship may also plateau, or that young children have different thrombotic risk profiles. The decrease in bioavailability with age, particularly after 65 years, suggests older patients may require adjusted dosing to maintain therapeutic concentrations.

Clinical Implications of PK/PD Variability

The moderate 32% interindividual variability in trough concentrations remains consistent across FVIII inhibitor status, age groups, and dosing intervals, supporting body weight-based dosing without routine therapeutic drug monitoring. However, specific subpopulations may benefit from concentration monitoring: patients with low albumin or those who develop neutralizing antibodies, patients over 65 years with reduced bioavailability, and potentially African patients given ethnic effects on distribution volume. The finding that prior FVIII prophylaxis reduces bleeding hazard by 44.7%—the single largest covariate effect identified—suggests that the benefits of emicizumab may be partially additive to those of prior prophylaxis, possibly through prevention of joint damage that would otherwise increase bleeding risk.

Reconciling Safety Findings

The favorable safety profile, particularly the absence of thromboembolic events in most studies, requires reconciliation with the two thrombotic events in HAVEN 1. These events occurred specifically with concomitant use of high-dose activated prothrombin complex concentrate (aPCC), representing a drug-drug interaction rather than an inherent property of emicizumab. The mechanism likely involves emicizumab providing baseline hemostatic activity that, when combined with high doses of bypassing agents, creates excessive thrombin generation exceeding physiologic regulatory capacity. This context-specific risk led to modifications in clinical practice guidelines recommending caution with bypassing agents in emicizumab-treated patients. The very low immunogenicity likely reflects the humanized antibody design and subcutaneous route of administration, which promotes tolerance compared to intravenous dosing.

References

C. Schmitt, J. Adamkewicz, Jin Xu, Claire Petry, O. Catalani, and 4 more\ (2020).Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thrombosis and Haemostasis

A. Kiialainen, J. Adamkewicz, Claire Petry, J. Oldenburg, S. Pipe, and 9 more\ (2023).Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks. Research and Practice in Thrombosis and Haemostasis

A. Donners, C. Rademaker, Lisanne A H Bevers, A. Huitema, R. Schutgens, and 2 more\ (2021).Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review. Clinical Pharmacokinetics

S. Pipe, M. Shima, M. Lehle, A. Shapiro, S. Chebon, and 12 more\ (2019).Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. The Lancet Haematology

F. Jonsson, C. Schmitt, Claire Petry, F. Mercier, N. Frey, and 1 more\ (2021).Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII. Clinical Pharmacokinetics

M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\ (2016).Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. New England Journal of Medicine

M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\ (2017).Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Advances

S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 10 more\ (2022).Emicizumab Prophylaxis for the Treatment of Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Interim Analysis of the HAVEN 7 Study. Blood

Qianqian Mao, Zhengping Li, Zhenping Chen, Runhui Wu\ (2025).Pharmacokinetic and pharmacodynamic characteristics of emicizumab in Chinese pediatric patients with hemophilia A: A retrospective single-center study. Blood

S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 12 more\ (2023).Emicizumab Prophylaxis in Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Primary Analysis of the HAVEN 7 Study. Blood

Download BIBDownload RISDownload TXT

Report

Status

Gather sources

200 sources found

Details

Screen sources

10 sources included

Details

Extract data

80 data points extracted

Details

Generate report

Save PDF

BIBLaTeX, ZoteroRISZotero, MendeleyTXTAPA BibliographyPDFPDFDOCXMicrosoft Word

Chat

Got some follow-up questions?

Sign up or sign in to chat with this report.

Back

Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

A. Donners, C. Rademaker, Lisanne A H Bevers, A. Huitema, R. Schutgens, T. Egberts, K. Fischer

Clinical Pharmacokinetics·

2021·

34 citations

SourceDOI

Plain textPDF

Searching for PDF

Unable to find PDF from source

Back

Study Population

- Age range: 0 to <12 years (children), ≥12 years (adolescents and adults) - Hemophilia A severity: Severe - FVIII inhibitor status: Presence and absence represented - Geographic/ethnic population: Predominantly Asian and Caucasian, with mention of African race affecting PK variability - Sample size for PK/PD analyses: 469 PwHA - Other patient factors: Body weight, neutralizing antidrug antibodies, age > 30 years, abnormal albumin levels

Dosing Regimen

- Dose level(s) tested: 1.5 mg/kg per week, 3 mg/kg per 2 weeks, 6 mg/kg per 4 weeks - Dosing frequency: Weekly (75%), every 2 weeks (11%), every 4 weeks (14%) - Loading dose regimen: Not mentioned - Maintenance dose regimen: Body weight-based dosing - Route of administration: Subcutaneous - Duration of treatment/observation: At least 16 weeks - Dose adjustments or individualization strategies: Potential for individualized monitoring to adjust dosing - Sampling timepoints for PK/PD measurements: Trough concentrations in steady-state conditions

PK Parameters

- Plasma/serum emicizumab concentrations: Dose-linear PK; trough concentrations show moderate interindividual variability (32%). - Clearance (CL/F): Comparable to other therapeutic IgG4-based mAbs (within 0.2-0.5 L/day). - Volume of distribution (V/F or Vss/F): Increased distribution volumes (10 vs. 6 L). - Half-life (t½): Longer due to increased distribution volumes. - Time to steady-state: Not explicitly mentioned. - Bioavailability or relative bioavailability: Not explicitly mentioned. - Dose-proportionality findings: Dose-linear PK. - PK variability (inter-patient, intra-patient): Moderate interindividual variability (32%); total PK interindividual variability approximately 60%. - Population PK modeling results: Influenced by body weight, neutralizing antidrug antibodies, age, and albumin levels. - Comparison across different dosing regimens: Variability similar across dosing intervals; children have slightly less variability than adults and adolescents.

PD Outcomes

- Annualized bleeding rates (ABR) for treated bleeds: Baseline ABR = 28.0; ABR at 30 µg/mL = 2.4; ABR at 50 µg/mL = 1.9 - Annualized bleeding rates (ABR) for treated joint bleeds: Baseline ABR = 21.6; ABR at 30 µg/mL = 1.1; ABR at 50 µg/mL = 1.0 - Proportion of patients with zero bleeds: Increased from 70.8% to 80.2% after 1 year of treatment - Methods used: Negative binomial regression for ABRs

PK/PD Relationships

- Exposure-efficacy relationships: Concentration vs. bleeding rates - The control of bleeds does not improve above 30 µg/mL. - Threshold concentrations for efficacy: Effectiveness plateau at concentrations above 30 µg/mL. - Model parameters: EC50 for treated bleeds = 1.47 µg/mL, Emax = 0.96; EC50 for treated joint bleeds = 1.09 µg/mL, Emax = 0.98. - Predictions or simulations: ABRs at different concentrations (e.g., 30 and 50 µg/mL) with corresponding RRRs.

Safety Profile

- Limited toxicity - Increased thrombotic risk with high doses of activated prothrombin complex concentrate - Neutralizing antidrug antibodies (ADAs) affect PK variability - Joint pain episodes at high concentrations (90 µg/mL) - No detailed information on injection site reactions, other adverse events, or laboratory safety parameters - No mention of discontinuations due to safety concerns

Covariates

- Age effects on PK/PD parameters: Bioavailability decreases with age, particularly after 65 years. - Body weight/size effects: Including body weight in the model reduces interindividual variability in CL/F and V/F. - Inhibitor status effects on efficacy: No significant effect on PK variability. - Prior treatment history effects: Not mentioned. - Genetic factors or ethnic differences: African race affects PK variability. - Concomitant medications effects: Not mentioned. - Disease-related factors affecting drug disposition: FVIII inhibitor status does not significantly affect PK variability. - Other identified sources of PK/PD variability: Neutralizing antidrug antibodies (ADAs), abnormal albumin (ALB) levels. - Magnitude and clinical significance of covariate effects: PK variability is approximately 60%, with body weight and ADAs being primary sources.

Study Methods

- Study design: Systematic review of existing studies on emicizumab's PK and PD in humans. - PK sampling strategy: Analysis of trough concentrations (C trough,ss) in steady-state conditions. - Bioanalytical methods: ELISA for phase I-III studies; modified OSA for phase IV studies. - PK analysis methods: Non-linear least squares regression using a maximum effect (Emax) model. - Statistical approaches: Weighted non-linear least squares regression; negative binomial regression for efficacy parameters. - Validation of bioanalytical and PD assays: Not explicitly mentioned. - Limitations: Limited number of studies; heterogeneous population; lack of blinded, placebo-controlled studies.

Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose–concentration–response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted. The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (Emax) model. The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

1Introduction

Hemophilia A is an inherited bleeding disorder caused by an absence or dysfunction of coagulation factor VIII (FVIII) [1]. Without adequate treatment, people with hemophilia A (PwHA) who are severely affected suffer from recurrent bleeds, predominantly in joints, which results in crippling arthropathy, functional limitations and a significantly reduced life expectancy [2,3]. The primary goal in the management of these PwHA is to prevent bleeds, preferably through regular coagulation factor replacement therapy (prophylaxis) [1,4]. Prophylaxis with plasma-derived and, supplementary data SD1 for an example of the EMBASE search algorithm. In the EMBASE database, the search was conducted using the corresponding Emtree terms, and for the PubMed and CENTRAL databases, the National Library of Medicine Medical Subject Heading (MeSH) search terms were used. Finally, the included studies were manually searched for relevant references, and the European Public Assessment Report (EPAR) for emicizumab was used as a cross-reference for possible missed studies [12].

2.2Study Selection

The search results from the three databases were merged in Endnote X9 version 19.3.3 .13966 (Clarivate Analytics, Philadelphia, PA, USA), and duplicate records (title, abstract, or both) were removed automatically. Hereafter, the records were imported into the web-based tool Rayyan (https:// rayyan. qcri. org/ [17]) and were screened and categorized. First, the records and then the full-text articles were screened and categorized in duplicate by two reviewers (AD, LB). The following inclusion criteria were applied: emicizumab studies providing (1) data on humans, (2) original PK data or modeled PK data or PK/PD relationships, and (3) access to the abstract and the full text in English. In the event of doubt regarding eligibility, the records or articles were included. Disagreements were discussed until consensus was reached, and, when necessary, a third reviewer (TE) was consulted.

2.3Data Extraction

The following data were extracted from the included studies:

(1) study characteristics (authors, year of publication, number of subjects, phase, design, dosing regimen, follow-up, funding); (2) population characteristics (population [volunteer/PwHA], anti-FVIII antibodies, age group, hemophilia A severity, ethnicity); and (3) evaluated PK and efficacy data. Relevant primary PK parameters included the absorption rate constant (k a ), apparent clearance (CL/F), and apparent volume of distribution (V d /F), while secondary (exposure) PK parameters included terminal half-life (t ½ ), area under the plasma concentration-time curve extrapolated to infinity (AUC ∞ ), maximum plasma concentration (C max ), trough plasma concentration in steady-state conditions (C trough,ss ) and time to reach C max (t max ). The relevant efficacy parameter was expressed as the annualized bleeding rate (ABR) of different bleeding types (i.e. treated bleeds or treated joint bleeds). When relevant data were missing from the text, a data request was sent to the corresponding authors or sponsors.

Trough concentrations with corresponding errors [standard deviation (SD) and 95% confidence interval (CI)] from steady-state conditions per study subgroup were primarily extracted from the text; however, when data were presented later, recombinant FVIII products has effectively reduced episodes of bleeding from an annual average of 20-30 to 1-4 [5][6][7][8]. However, replacement therapy with FVIII products has some disadvantages. This treatment is invasive, requiring intravenous administration every 24-48 h, usually starting before the age of 2 years [9]. Additionally, neutralizing antibodies against FVIII (known as inhibitors) develop in 30% of severely affected PwHA, rendering treatment with FVIII products ineffective [4,10].

Emicizumab (Hemlibra ® ) is the first non-factor replacement product and was approved in 2018 by the US FDA and the European Medicines Agency as prophylaxis for PwHA, both with and without FVIII inhibitors. This humanized, immunoglobulin (Ig) G4, bispecific monoclonal antibody (mAb) effectively restores the hemostatic function of missing FVIII by bridging activated factor IX and factor X. Moreover, subcutaneous administration and the less frequent dosing interval of once every 1-4 weeks offer dosing convenience, especially for (pediatric) PwHA with difficult venous access. Emicizumab has limited toxicity, although concomitant use of high doses of activated prothrombin complex concentrate increases the thrombotic risk and should be avoided [11,12].

A body weight-based standard dosing regimen for emicizumab (1.5 mg/kg per week, 3 mg/kg per 2 weeks, 6 mg/ kg per 4 weeks) without the requirement of dose adjustments based on laboratory monitoring has been approved by the regulatory authorities [13]. This dosing recommendation assumes clear dose-concentration [pharmacokinetics (PK)] and concentration-response [pharmacodynamics (PD)] relationships with acceptable variability due to factors other than body weight. Unexpected variability (e.g. resulting from antidrug antibodies or population characteristics) should be absent, as differences in concentration, and even response, require monitoring and individualized dose tailoring [14,15]. Therefore, the objective of this study was to investigate these basic principles by conducting a systematic review on the PK and associated efficacy of emicizumab in humans.

2.1Sources

The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. The EMBASE, PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception through 28 April 2020, and updated on 13 November 2020. The search terms included 'emicizumab' and 'pharmacokinetics' and their associated synonyms (see electronic in graphs only and the data requests remained unanswered, the data were extracted from the graphs [18][19][20]. To minimize bias, two independent and blinded reviewers (AD, LB) visually scored the data with magnification and a set square. The data were then scored using WebPlotDigitizer, a reliable and validated web-based tool for extracting underlying numerical data from plots (https:// autom eris. io/ WebPl otDig itizer [21]) [22]. Both the visually and digitally extracted values were compared and, if necessary, reassessed. The data were entered (LB/AD) into a database for systematic data extraction and were double-checked by a second reviewer (AD/LB).

2.4Data Synthesis

Extracted data relating to study and population characteristics were categorized and summarized. The PK data (C trough,ss ) were plotted according to doses of the multipleinjection regimens in PwHA and for the single-injection regimens in volunteers (primary and secondary parameters). The percentage coefficient of variation (%CV, or the variability) of trough concentrations was calculated as (SD/mean) × 100%. If unavailable, the SD was derived from the 95% CI using the formula √n × ((upper limit -lower limit)/3.92), or from the interquartile range (IQR) using (IQR max -IQR min )/1.35 [23].

Exposure effects modeling was conducted with weighted (study size) non-linear least squares regression using a standard inhibitory maximum effect (E max ) model. The ABRs of treated bleeds and treated joint bleeds were used as efficacy parameters if calculated by means of negative binominal regression (model-based). As data for the extremes of the curve were lacking, values for baseline ABR and E max , derived from other sources, were assumed and the Hill coefficient was fixed to 1. The baseline ABRs for treated bleeds and treated joint bleeds were assumed at values of 28.0 and 21.6, respectively, as reported for severe PwHA treated with on-demand therapy in a real-world setting [6]. These values were in line with the reported baseline ABRs for treated bleeds of 21.9, 23.3 and 38.2, and for treated joint bleeds of 6.7 and 26.5 in severe PwHA without prophylactic treatment [18,19,24]. The E max for treated bleeds was set at a value of 0.96 (i.e. 96% drug effect at infinite exposure, corresponding to an ABR of 1), and for treated joint bleeds, the E max was set at 0.98 (corresponding to an ABR of 0.5). This was done to account for the occurrence of traumatic bleeding (based on clinical experience) and the lack of complete of coagulation by emicizumab (based on mouse and primate models). In addition, the FVIII-equivalent (hemostatic) activity of emicizumab was hypothesized at only 10-20% in humans [24][25][26]. An ABR of 1 was therefore perceived as more realistic than an ABR of 0, and is also in line with the reported ABR range of 0.2-5.1 (electronic supplementary Table ST2 ). The ABR baseline values were also used to calculate the relative risk reduction (RRR). Sensitivity analysis was performed to assess the validity of the ABR baseline and E max assumptions.

Summary statistics and graphics were performed using GraphPad Prism version 8.3.0 (GraphPad Software LLC, San Diego, CA, USA), and modeling was performed using R version 4.0.2 (R Core Team, Vienna, Austria).

3Results

A total of 368 records were identified with the computerized search. After the removal of duplicates (n = 83), 285 titles and abstracts and 77 full-text articles were assessed for eligibility. The updated search in November 2020 yielded 15 studies meeting the inclusion criteria (electronic supplementary Fig. SF1 ).

3.1Study Characteristics

The 15 included studies were published between 2016 and 2020 (Table 1 ). During the drugs' development, phase I (n = 4), simultaneous phase I/II (n = 1) and phase III (n = 6) clinical studies were conducted in combination with two pharmacometric analyses reporting on the dose-response relationship, with data from the previously published studies. Two studies were conducted after market approval. The majority of the included studies were global multicenter (n = 8), open-label (n = 12), non-randomized (n = 8), noncontrolled (n = 9), industry-funded (n = 13) clinical studies with a follow-up period of at least 16 weeks (n = 11). Eight studies had a parallel comparative design, including six reporting on an intra-individual comparison of emicizumab with previous treatment. The multiple-dose injection studies most often included the weekly dosing interval (QW; 75%), followed by the once every 4 weeks regimen (Q4W; 14%) and once every 2 weeks regimen (Q2W; 11%).

3.2Population Characteristics

Eleven studies [18][19][20][27][28][29][30][31][32][33][34] provided original PK data of emicizumab in humans and yielded 607 subjects (Table 2 ) after excluding four studies [24,[35][36][37] with doublereported subjects. These 607 unique subjects were either volunteers (n = 140) or PwHA (n = 467). The PwHA included adults and adolescents (n = 328) and children younger than 12 years (n = 139). The PwHA with and without FVIII inhibitors were similarly represented across studies. Severe hemophilia A and the Asian and Caucasian races were predominant across the studies.

3.3Dose-Concentration Relationship

The original PK data were used to investigate the dose-concentration relationship, therefore excluding two pharmacometric analysis studies (reused data), two preliminary studies (shorter follow-up period than their consecutive studies) and a case report (no steady-state conditions). The PK data from the PwHA (n = 469) demonstrated a linear dose-concentration relationship when the C trough,ss was plotted according to increasing doses of emicizumab per week (Fig. 1 ). The longer dose intervals (Q2W and Q4W) were associated with a lower C trough,ss .

The PK data from the volunteers (n = 112) in the singledose injection studies with increasing doses (0.1, 0.3 and 1 mg/kg) demonstrated constant primary PK parameters and a dose-linear increase in the exposure metrics C max and AUC ∞ , with an exponential decay over time. These PK parameters obtained per study subgroup are presented in electronic supplemental Fig. SF2 and electronic supplementary Table ST1 and were similar across ethnicities.

The study size weighted variability (%CV) of the C trough,ss was similar across FVIII inhibitor status (present or absent) and the various dosing intervals (QW, Q2W or Q4W), whereas children had slightly less variability than adults and adolescents (Fig. 2 ). The overall weighted %CV of the C trough,ss in PwHA was 32% and ranged from 17 to 44% (electronic supplementary Table ST2 ). [24,36]. The total PK interindividual variability (approximately 60% [36]) could be explained primarily by the covariates body weight, neutralizing antidrug antibodies (ADAs) against emicizumab, age > 30 years, and, to a lesser extent, abnormal albumin (ALB) levels, as well as African race.

3.4Concentration-Response Relationship

Eleven PwHA study subgroups within five studies [18-20, 31, 32] provided the model-based mean ABRs of treated bleeds. The C trough,ss was the only exposure metric that could be extracted in combination with these ABRs. The ABRs were fitted with corresponding C trough,ss values in an E max model (Fig. 3 ). The half maximal effective concentration (EC 50 ) was estimated at 1.47 µg/mL [standard error (SE) 0.90], assuming an ABR baseline of 28.0 and E max of 0.96. The effectiveness plateau of the concentration-response relationship was clearly established, and all ABR observations resided herein. Based on this model, a C trough,ss of 30 and 50 µg/mL would result in an ABR of treated bleeds of 2.4 and 1.9, respectively, and with an RRR of 91% and 93%, respectively. A second E max model was fitted with the ABRs of treated joint bleeds, instead of treated bleeds, with corresponding C trough,ss values (electronic supplementary Fig. SF3 ). The EC 50 was estimated at 1.09 µg/ mL (SE 0.36), assuming baseline ABR of 21.6 and E max of 0.98, and C trough,ss values of 30 and 50 µg/mL would result in ABRs of treated joint bleeds of 1.1 and 1.0, respectively, and with an RRR of 94.9% and 95.4%, respectively.

For C trough,ss of 30 and 50 µg/mL, sensitivity analyses showed ABRs of treated bleeds of 2.9 and 1.9, respectively, with a conservative setting (baseline ABR 21.9 and E max 1 [24]), and ABRs of 1.9 and 1.9, respectively, with a more liberal setting (baseline ABR 38.2 and E max 0.90 [18]) [see electronic supplementary Table ST3 ]. In addition, the C trough,ss of 30 and 50 µg/mL showed in sensitivity analyses ABRs of treated joint bleeds of 1.4 and 0.9, respectively, with a conservative setting (baseline ABR 6.7 and E max 1 [18]), and ABRs of 1.0 and 0.9, respectively, with a more liberal setting (baseline ABR 26.5 and E max 0.97 [19]).

4Discussion

For emicizumab in humans, this systematic review demonstrated a linear dose-concentration relationship with moderate interindividual variability, with all ABR observations residing in the effectiveness plateau of this concentration-response relationship.

4.1Dose-Concentration Relationship

With increasing doses of emicizumab, the primary PK parameters remained constant, while the exposure metrics exhibited a linear dose increase. These findings are in line with the results of the model by Retout et al., who showed a dose-proportional AUC increase due to constant clearance [36]. Compared with the primary PK parameters of other therapeutic IgG4-based mAbs, the clearance of emicizumab was comparable (within 0.2-0.5 L/day), but distribution volumes were increased (10 vs. 6 L), and, consequently, the reported half-life of emicizumab is longer [38]. This higher volume of distribution is notable, indicating distribution to other compartments or binding of emicizumab, possibly to its targets in the blood circulation. In general, therapeutic mAbs demonstrate linear PK at high doses when the targetsaturated concentration is achieved [39,40], and this was already observed at doses of ≥ 0.1 mg/kg for emicizumab (electronic supplementary Fig. SF2 ).

The sources for variability of the PK parameters were explored in the two published population PK modeling studies, in which body weight and neutralizing ADAs against emicizumab were identified as influential covariates [24,36]. A body weight-based dosing regimen was justified because including body weight in the model reduced the interindividual variability in CL/F from 56.4 to 30.0%, and in V/F from 60.7 to 28.1% [36]. ST2 ). PwHA people with hemophilia A, C trough,ss trough plasma concentration in steady-state conditions, Q2W 2-weekly dose interval, Q4W 4-weekly dose interval Additionally, Retout et al. reported that age and ALB concentration were significantly correlated to primary PK parameters in their model. For age > 30 years, bioavailability gradually decreased, and for age > 65 years, bioavailability strongly decreased (e.g. a 31% lower exposure for a PwHA aged 77 years than for a PwHA aged 30 years), which is uncommon for therapeutic mAbs [41]. Although the authors did not report a relationship with clinical response, PwHA older than 65 years may be more susceptible to lower emicizumab concentrations, potentially even reducing bleeding control in a small proportion of PwHA. A low ALB concentration of 33 g/L was associated with a 16% decrease in exposure [36].

The PK variability across several studies has been previously described in modeling studies, but this review is the first to investigate variability across seven studies. We have reported slightly higher %CV for adults and adolescents compared with children. This finding is in line with the considerable influence of the covariate 'age' on exposure identified by Retout et al. [36]. Therefore, we recommend to investigate the bioavailability and exposure in this patient subgroup (i.e. aged > 30 years, especially > 65 years) in future studies.

4.2Concentration-Response Relationship

Our search did not yield individual patient data, making it unfeasible to use a complex model, such as repeated timeto-event. However, the estimated EC 50 of 1.47 µg/mL for treated bleeds was close to the previously reported values of 1.19 μg/mL [24] and 3.58 µg/mL [42] obtained by more sophisticated models, endorsing our model. The C trough,ss Fig. 2 Trough concentrations of emicizumab with variability across various subgroups in PwHA. The weighted variability (%CV) of the C trough,ss of emicizumab was similar across FVIII inhibitor status and across various dosing intervals, whereas children had slightly less variability than adults/adolescents. The overall weighted %CV was 32%. Data from PwHA (n = 469) receiving multiple dose regimens were included (see footnote 'a' for 15 study subgroups, in electronic supplementary Table ST2 ). PwHA people with hemophilia A, %CV percentage coefficient of variation, C trough,ss trough plasma concentration in steady-state conditions, Q2W 2-weekly dose interval, Q4W 4-weekly dose interval of 51.1 µg/mL obtained by the approved standard dosing regimens is 35-fold this EC 50 , which is abundant [13]. Our E max model visualized the concentration-response relationship and revealed a clear effectiveness plateau from 30 µg/ mL, beyond which no further increase in beneficial drug effect was achieved. All the bleeding rate observations of the included studies were well within this plateau, potentially enabling lower dosing for a substantial proportion of the PwHA. Unquestionably, setting other values for E max and baseline ABRs would result in other predictions. A sensitivity analyses was performed (see electronic supplementary Table ST3 ) to show the impact of the ABR baseline and E max assumptions on the estimates of EC 50 and the ABRs for C trough,ss of 30 μg/mL and 50 μg/mL. In this regard the estimates remained approximately the same, indicating robustness. Furthermore, the EC 50 decreased fivefold when the ABRs (outliers) from HAVEN 1 were excluded from the model. We hypothesized that many subjects from this study had long-term inhibitors, and, by definition, had severe arthropathy, which is something to keep in mind for physicians. The ABR of treated joint bleeds was also explored because treated joint bleeds are generally better defined, reducing misclassification [43][44][45][46]. In the E max model of treated joint bleeds, the effectiveness plateau was reached at even lower concentrations of 20 µg/mL.

4.3Dosing and Monitoring Considerations

The question that remains is to what extent are we overdosing our PwHA? Based on our E max models, a C trough,ss of 30 and 50 µg/mL would result in ABRs of treated bleeds of 2.4 and 1.9, respectively (RRRs of 91% and 93%, respectively) and ABRs of treated joint bleeds of 1.1 and 1.0, respectively +EC 50 ) . Included ABRs were model-based, estimated using negative binominal regression. The EC 50 was estimated at 1.47 µg/mL (SE 0.90) and the effec-tiveness plateau was established. The dashed line is the 95% confidence interval, and symbol size equals study size. Data from PwHA receiving maintenance were included (see footnote 'b' for 11 study subgroups, in electronic supplementary Table ST2 ). E max maximum effect, PwHA people with hemophilia A, ABRs annualized bleeding rates, C trough,ss trough plasma concentration in steady-state conditions, EC 50 half maximal effective concentration, SE standard error (RRRs of 94.9% and 95.4%, respectively). Are the theoretic ABR differences of 0.5 and 0.1 clinically relevant while the RRRs remain essentially equal? Understandably, manufacturers design dosing regimens without laboratory monitoring because this is user friendly and robust. Moderate interindividual variability in PK without monitoring necessitates higher dosing to guarantee efficacy for all users. In combination with an absence of toxicity at high drug concentrations, which is the case for most therapeutic mAbs, this makes overdosing clinically not problematic. Nonetheless, concerns were expressed by Hooimeijer et al., who reported joint pain episodes in a PwHA at high emicizumab concentrations of 90 µg/mL, which resolved after dose reduction to concentrations of approximately 30 µg/mL [33]. Furthermore, when drugs are costly (the wholesale acquisition cost of emicizumab is approximately US$482,000 for the first year of treatment and US$448,000 for the following years), monitoring and subsequent dose reduction may lead to substantial savings in health care [47]. The weighted overall variability of the C trough,ss was 32%, which is common for therapeutic mAbs. Notably, individual C trough,ss ranged widely from 2.8 to 148 μg/mL [18]. No specific loss of efficacy or adverse effects for these extreme individual cases were described. As more studies presented subjects with plasma concentrations < 20 μg/mL (electronic supplementary Table ST2 ), we propose a beneficial role for Therapeutic Drug Monioting (TDM) to increase the dose to an efficacious concentration. In addition, we recommend conducting a prospective, individual PK-guided dosing study to target an efficacious trough concentration of 30 μg/mL, and to collect data on both interindividual and interoccasion variability in the realworld setting to optimize efficacy, safety, and cost effectiveness of emicizumab treatment.

Laboratory monitoring with PD biomarkers has been unsuccessful, and functional assays should be interpreted with caution and as relative indications of the procoagulant potential [34,48]. Until proper functional tests become available, the emicizumab concentration appears to be the best predictor for bleeding risk [24]. The concentration is not routinely monitored in clinical practice, although monitoring may be useful for research purposes, to check adherence, or in case of suspected neutralizing ADA against emicizumab [49]. The emicizumab concentration was measured in PK samples during phase I-III clinical studies using an enzymelinked immunosorbent assay (ELISA), and during phase IV studies using a modified, calibrated one-stage clotting assay (OSA). Unfortunately, Roche has not provided access to the ELISA, while the OSA is only available at specialized laboratories, as it needs to be calibrated by a standardized kit of two reference values [50]. An assay capable of measuring emicizumab concentrations in human plasma on routinely available platforms, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), would be valuable. An LC-MS/MS method for the quantification of emicizumab has been developed and validated at the University Medical Center Utrecht [51].

4.4Limitations and Strengths

This systematic review was limited by the number of available studies, the inclusion of funded studies, a heterogeneous population, limited study sizes, and lack of studies with a blinded, placebo-controlled, head-to-head design owing to the rarity and severity of hemophilia A. There is some uncertainty in our findings, particularly in the estimated ABRs at C trough,ss of 30 μg/mL and 50 μg/mL, as a consequence of limited availability of data at lower and higher emicizumab concentrations. A search in the ClinicalTrials.gov database in January 2021 identified at least three relevant ongoing studies on the PK of emicizumab (i.e. HAVEN 5-7), of which two are still recruiting PwHA. Therefore, it is certain that the present review will require an update in the near future. Another difficulty was the risk-of-bias assessment in the included studies due to a lack of standardized tools for such PK studies, in contrast to the quality assessment tools used for (randomized) clinical studies. However, the data used were considered methodologically sound as PK parameters are objective measurements, studies were included using a systematic PRISMA search approach, and we only used, for the E max model, negative binomial mean ABRs (excluding the median ABRs [28,34,35]) and excluded the studies with baseline imbalances [28,35].

The ABR is not an entirely objective outcome parameter. Misinterpretation of bleeds might have occurred, as verification by the physician and complementary imaging were often missing. Subjective assessments, combined with follow-up periods of < 12 months and small study sizes, may have affected the calculated ABRs. Moreover, clinically unstable disease leads to numerous (spontaneous) bleeds, especially in the first weeks of emicizumab treatment, leading to overestimation of ABRs in shorter studies [43][44][45][46]. Recently, the analysis of pooled bleeding data from HAVEN 1-4 reported ABRs maintaining < 1 in 24-week intervals and an increase in the proportion of PwHA without treated bleeds from 70.8% in the first 6 months to 80.2% after 1 year of emicizumab treatment [52]. Consequently, predicted ABRs may be overestimated in our model.

The strength of this review was the large amount of information that has been summarized in tables and graphs. The novelty of this review was the critical appraisal by an independent research group, the dosing and monitoring considerations, and the proposed role for TDM in relation to low concentrations and cost effectiveness. This information may offer guidance in clinical decision making and in future study designs assessing (cost) effectiveness, safety, and PK/PD modeling studies [53].

5Conclusion

This systematic review provided a comprehensive overview of PK and associated efficacy data for emicizumab in humans. Emicizumab demonstrated a clear linear dose-concentration profile with moderate interindividual variability. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. In conclusion, this review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

Data availability

Original data are available upon request.

Code availability Not applicable.

Author contributions TE conceived the topic of the manuscript; AD and LB performed the literature search and data analysis; AH and AD performed exposure-effects modeling; AD drafted the manuscript, and KF, AH, LB, RS, CR, and TE critically revised the work.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by-nc/4. 0/.

Supplementary Information

The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s40262-021-01042-w.

Declarations

Funding The authors received no funding for this review.

Conflict of interest/Competing interest AD, CR, LB, AH, RS, TE, KF declare no conflicts of interest.

Ethics approval Not applicable.

Consent to participate Not applicable.

Consent to publish Not applicable.

Acknowledgements

AcknowledgementsThe authors would like to acknowledge Rolf Urbanus for his thoughtful involvement, and Erik van Maarseveen for his important contribution to this review in an early phase.

Loading PDF...

Paper sources

Abstract screening pilot

Abstract screening results

Extraction pilot

Extraction results

Research report
\