Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Abstract

IntroductionDaratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.MethodsFour clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.ResultsPharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.ConclusionThese data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.FundingJanssen Research & Development.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0815-9) contains supplementary material, which is available to authorized users.

Delayed neutrophil engraftment in patients receiving Daratumumab as part of their first induction regimen for multiple myeloma

“…In a pharmacokinetic model, the mean half-life of daratumumab was 23.3 days, with a SD of 11.8 days. 6 This suggests that circulating daratumumab is likely present during stem cell mobilization and collection and is able to bind to In this proof of concept study, we investigated dabigatran secretion into breast milk following oral administration to non-breast-feeding women. We then estimated the systemic exposure in the neonate and investigated the potential effect on neonatal (cord blood) coagu-…”

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

“…Previous exposure-response analysis for daratumumab monotherapy and combination therapy studies has demonstrated a strong correlation between efficacy endpoints, including overall response rate and progression-free survival as well as daratumumab serum exposure [18,19]. In contrast, no apparent relationship between serum drug exposure and adverse events was observed [18,19].…”

“…The final covariate model included body weight, albumin, type of myeloma, and sex as significant yet non-clinically relevant covariates. PK parameter estimates for individual patients treated with other regimens were obtained from previously developed population PK models [18,19,25]. Simulations were performed to predict the PK profiles for all patients who had participated in previous daratumumab studies and to compare the difference in PK between the split-and single-first dose of daratumumab among those patients.…”

“…The recommended dose regimen of 16 mg/kg weekly for 8 weeks rapidly saturates targetmediated clearance, and subsequent dosing every 2 weeks for 16 weeks and every 4 weeks thereafter maintains target saturation. Population PK and exposure-response analyses have demonstrated a strong association between daratumumab concentration (maximum trough concentration [C trough ]) and efficacy in patients with relapsed/refractory MM [18,19]. A maximum C trough of 274 lg/ml was associated with 90% maximal effect on overall response rate, and a concentration of 236 lg/ml was required to achieve 99% model-predicted target (CD38) saturation [18].…”

New developments in the treatment of multiple myeloma &ndash; <br />clinical utility of daratumumab

“…Population PK analysis, mainly using data from the CASTOR and POLLUX trials, was performed by Xu et al47 PK was observed to be similar in single-agent and combination studies, and none of the intrinsic or extrinsic factors affected PK significantly.…”