Population pharmacokinetics and exposure–response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma

British Journal of Clinical Pharmacology - Tập 89 Số 5 - Trang 1640-1655 - 2023
Anne‐Gaëlle Dosne1, Xia Li1, Man Luo2, Ivo P. Nnane2, Meletios Α. Dimopoulos3, Evangelos Terpos3, Pieter Sonneveld4, Tobias Kampfenkel5, Robin Carson6, Himal Amin7, Juan Perez Ruixo8, Honghui Zhou9,10, Yu‐Nien Sun2,11, Yan Xu12,13
1Clinical Pharmacology and Pharmacometrics Janssen Research & Development, LLC Beerse Belgium
2Clinical Pharmacology and Pharmacometrics Janssen Research & Development, LLC, Spring House Pennsylvania USA
3National and Kapodistrian University of Athens, Athens, Greece
4Erasmus University Medical Center Cancer Institute Rotterdam The Netherlands
5Janssen Research & Development, LLC Leiden The Netherlands
6Janssen Research & Development, LLC Spring House Pennsylvania USA
7Janssen Research & Development, LLC Raritan New Jersey USA
8Janssen‐Cilag Spain, Part of Janssen Pharmaceutical Companies Madrid Spain
9Clinical Pharmacology and Pharmacometrics Janssen Research & Development, LLC Spring House Pennsylvania USA; Kira Pharmaceuticals Cambridge Massachusetts USA
10Kira Pharmaceuticals Cambridge Massachusetts USA
11Cognigen Division Simulations‐Plus Company Buffalo New York USA
12Clinical Pharmacology and Pharmacometrics Janssen Research & Development, LLC Spring House Pennsylvania USA; Simcere Pharmaceuticals Cambridge Massachusetts USA
13Simcere Pharmaceuticals Cambridge Massachusetts USA

Tóm tắt

AimA population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D‐Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure–response (E‐R) relationships for efficacy and select treatment‐emergent adverse events (TEAEs).MethodsThe PPK analysis included pooled data from the D‐Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model‐predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO.ResultsThe PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration–time data of daratumumab were well described by a two‐compartment PPK model with first‐order absorption and parallel linear and nonlinear elimination pathways. Treatment with D‐Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E‐R dataset contained data from 290 APOLLO patients (D‐Pd, n = 140; Pd, n = 150). The PK–efficacy relationship of daratumumab supported improved progression‐free survival for patients in the D‐Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D‐Pd group.ConclusionsThe PPK and E‐R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.

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British Journal of Clinical Pharmacology

Tập 89 Số 5

1640-1655

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