Changing Body Weight-Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma.

Autor: Novakovic AM; Merck KGaA, Darmstadt, Germany., Wilkins JJ; Occams, Amstelveen, The Netherlands., Dai H; EMD Serono, Billerica, Massachusetts, USA., Wade JR; Occams, Amstelveen, The Netherlands., Neuteboom B; EMD Serono, Billerica, Massachusetts, USA., Brar S; Pfizer, Inc., San Diego, California, USA., Bello CL; Pfizer, Inc., San Diego, California, USA., Girard P; Merck Institute of Pharmacometrics, Merck Serono SA, Lausanne, Switzerland., Khandelwal A; Merck KGaA, Darmstadt, Germany.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2020 Mar; Vol. 107 (3), pp. 588-596. Date of Electronic Publication: 2019 Nov 18.
DOI: 10.1002/cpt.1645
Abstrakt: Avelumab, an anti-programmed death-ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum-treated urothelial carcinoma, was initially approved with a 10 mg/kg weight-based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight-based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight-based and flat-dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure-safety (various tumors) and exposure-efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight-based dosing, with slightly lower variability. Exposure-safety and exposure-efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.
(© 2019 MERCK KGAA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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