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Clinical Trial
. 2020 Nov;59(11):1451-1466.
doi: 10.1007/s40262-020-00899-7.

Population Pharmacokinetic-Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28-Joint C-Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis

Lei Ma  1 , Christine Xu  2 , Anne Paccaly  3 , Vanaja Kanamaluru  1
Affiliations
Clinical Trial

Population Pharmacokinetic-Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28-Joint C-Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis

Lei Ma et al. Clin Pharmacokinet. 2020 Nov.

Abstract

Background: Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs.

Objective: The aim of the current analysis was to describe sarilumab exposure-response relationships.

Methods: Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I-III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50-150 mg every week or 100-200 mg every 2 weeks.

Results: The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model.

Conclusion: The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.

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Conflict of interest statement

Christine Xu and Vanaja Kanamaluru are employees of Sanofi Genzyme and may hold stock and/or stock options in the company. Lei Ma was an employee of Sanofi Genzyme at the time of this work and may hold stock and/or stock options in the company. Anne Paccaly is an employee of Regeneron Pharmaceuticals, Inc and may hold stock and/or stock options in the company. None of the authors have any non-financial conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
DAS28-CRP and ANC PopPK/PD model structure. ANC absolute neutrophil count, C concentration, CL clearance, DAS28-CRP 28-joint disease activity score by C-reactive protein, γ Hill coefficient for sigmoidicity, EC50 concentration at 50% of Emax, Emax maximum drug effect, Imax maximum drug effect, IC50 concentration at 50% of Imax, Ka first-order absorption rate constant, Kin zero-order production rate, Km Michaelis–Menten constant, Kout first-order degradation rate, PopPK/PD population pharmacokinetic/pharmacodynamic, Q intercompartmental clearance, SC subcutaneous, Vm maximum rate. DAS28-CRP model: Eff(C) = Emax × (C + placebo)γ/(IC50γ + (C + placebo)γ). ANC model: Eff(C) = Emax × Cγ/(EC50γ + Cγ)
Fig. 2
Fig. 2
DAS28-CRP PopPK/PD model. a Goodness-of-fit analysis; b normalized prediction distribution error; c conditional weighted residuals; d visual predictive check. CWRES conditional weighted residuals, DAS28-CRP 28-joint disease activity score by C-reactive protein, NPDE normalized prediction distribution error, PopPK/PD population pharmacokinetic/pharmacodynamic, qw every week, q2w every 2 weeks. In a, dashed blue line indicates y = x, solid blue line indicates y = 0, solid red line indicates tendency. In d, solid red line represents the median of observations; solid dashed lines represent the 2.5th and 97.5th percentiles of observations; and pink and gray areas represent the confidence intervals of the median and 5th and 95th percentiles of predictions. Placebo + 200 mg q2w defines the cohort of patients initially randomized to placebo who subsequently received sarilumab 200 mg q2w
Fig. 2
Fig. 2
DAS28-CRP PopPK/PD model. a Goodness-of-fit analysis; b normalized prediction distribution error; c conditional weighted residuals; d visual predictive check. CWRES conditional weighted residuals, DAS28-CRP 28-joint disease activity score by C-reactive protein, NPDE normalized prediction distribution error, PopPK/PD population pharmacokinetic/pharmacodynamic, qw every week, q2w every 2 weeks. In a, dashed blue line indicates y = x, solid blue line indicates y = 0, solid red line indicates tendency. In d, solid red line represents the median of observations; solid dashed lines represent the 2.5th and 97.5th percentiles of observations; and pink and gray areas represent the confidence intervals of the median and 5th and 95th percentiles of predictions. Placebo + 200 mg q2w defines the cohort of patients initially randomized to placebo who subsequently received sarilumab 200 mg q2w
Fig. 3
Fig. 3
DAS28-CRP time profiles (observed vs. model-predicted). DAS28-CRP 28-joint disease activity score by C-reactive protein, P5 5th percentile, P95 95th percentile, q2w every 2 weeks
Fig. 4
Fig. 4
ANC PopPK/PD model. a Goodness-of-fit; b normalized prediction distribution error; c conditional weighted residuals; and d visual predictive check. ANC absolute neutrophil count, CWRES conditional weighted residuals, NPDE normalized prediction distribution error, PopPK/PD population pharmacokinetic/pharmacodynamic, qw every week, q2w every 2 weeks. In a, dashed blue lines indicate y = x, solid blue line indicates y = 0, solid red line indicates tendency. In d, solid red line represents the median of observations; solid dashed lines represent the 2.5th and 97.5th percentiles of observations; and pink and gray areas represent the confidence intervals of the median and 5th and 95th percentiles of predictions
Fig. 4
Fig. 4
ANC PopPK/PD model. a Goodness-of-fit; b normalized prediction distribution error; c conditional weighted residuals; and d visual predictive check. ANC absolute neutrophil count, CWRES conditional weighted residuals, NPDE normalized prediction distribution error, PopPK/PD population pharmacokinetic/pharmacodynamic, qw every week, q2w every 2 weeks. In a, dashed blue lines indicate y = x, solid blue line indicates y = 0, solid red line indicates tendency. In d, solid red line represents the median of observations; solid dashed lines represent the 2.5th and 97.5th percentiles of observations; and pink and gray areas represent the confidence intervals of the median and 5th and 95th percentiles of predictions
Fig. 5
Fig. 5
ANC time profiles (observed vs. model predicted). ANC absolute neutrophil count, P5 5th percentile, P95 95th percentile, q2w every 2 weeks
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