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Clinical Trial
. 2021 Jun;87(6):2511-2520.
doi: 10.1111/bcp.14658. Epub 2020 Dec 7.

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

Ekaterina Gibiansky  1 , Claire Petry  2 , Francois Mercier  2 , Andreas Günther  2 , Ann Herman  3 , Ludwig Kappos  4 , Stephen Hauser  5 , Yumi Yamamoto  2 , Qing Wang  2 , Fabian Model  2 , Heidemarie Kletzl  2
Affiliations
Clinical Trial

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

Ekaterina Gibiansky et al. Br J Clin Pharmacol. 2021 Jun.

Abstract

Aims: Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.

Methods: A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.

Results: The ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing <60 kg and 21% lower for patients weighing >90 kg when compared with the 60-90 kg group. The terminal half-life of ocrelizumab was estimated as 26 days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.

Conclusion: The pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

Keywords: multiple sclerosis; neurology; pharmacodynamics; pharmacokinetic-pharmacodynamic; population analysis.

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Conflict of interest statement

Ekaterina Gibiansky is a paid consultant for F. Hoffmann‐La Roche Ltd.

Claire Petry is an employee of F. Hoffmann‐La Roche Ltd.

Francois Mercier is an employee of F. Hoffmann‐La Roche Ltd.

Andreas Günther is an employee of F. Hoffmann‐La Roche Ltd.

Yumi Yamamoto is an employee of F. Hoffmann‐La Roche Ltd.

Ann Herman is an employee of Genentech, Inc., and a shareholder of F. Hoffmann‐La Roche Ltd.

Ludwig Kappos's institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board, consultancy fees and support of educational activities from: Actelion, Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/Receptos, CSL‐Behring, Desitin, Excemed, Eisai, Genzyme, Japan Tobacco, Merck, Minoryx, Novartis, Pfizer, F. Hoffmann‐La Roche Ltd, Sanofi Aventis, Santhera, Teva and license fees for Neurostatus‐UHB products; the Research of the MS Center in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, Innosuisse, the European Union and Roche Research Foundations.

Stephen Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Alector, Annexon, Bionure and Molecular Stethoscope, and has received travel reimbursement and writing assistance from F. Hoffmann‐La Roche Ltd and Novartis for CD20‐related meetings and presentations.

Qing Wang is an employee of F. Hoffmann‐La Roche Ltd.

Fabian Model is an employee and shareholder of F. Hoffmann‐La Roche Ltd.

Heidemarie Kletzl is an employee and shareholder of F. Hoffmann‐La Roche Ltd.

Figures

FIGURE 1
FIGURE 1
Proportion of: (A) patients with RMS (WA21092 and WA21093); and (B) patients with PPMS (WA25046) with a B‐cell count of ≤5 cells/μL in blood by ocrelizumab Cmean exposure quartiles over time. In patients with RMS, Cmean quartile ranges (μg/mL) were: Q1: Min–15.38; Q2: 15.38–18.72; Q3: 18.72–22.17; Q4: 22.17–max, and median (range) body weights (kg) were: Q1: 89 (49–170); Q2: 79 (49–123); Q3: 67 (46–108); Q4: 60 (38–97). In patients with PPMS, Cmean quartile ranges (μg/mL) were: Q1: Min–15.83; Q2: 15.83–18.92; Q3: 18.92–23.15; Q4: 23.15–max, and median (range) body weights (kg) were: Q1: 84 (46–136); Q2: 74 (46–125); Q3: 68 (46–115); Q4: 56 (40–93). Cmean, mean concentration over time; OCR, ocrelizumab; PPMS, primary progressive multiple sclerosis; Q, quartile; RMS, relapsing multiple sclerosis
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