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Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

ABSTRACT: We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C_trough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.

SUBMITTER: Luo MM

PROVIDER: S-EPMC8048619 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

Luo Man Melody MM Usmani Saad Z SZ Mateos Maria-Victoria MV Nahi Hareth H Chari Ajai A San-Miguel Jesus J Touzeau Cyrille C Suzuki Kenshi K Kaiser Martin M Carson Robin R Heuck Christoph C Qi Ming M Zhou Honghui H Sun Yu-Nien YN Parasrampuria Dolly A DA

Journal of clinical pharmacology 20201103 5

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; ...[more]

PMID: 33145788

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Project description:IntroductionDaratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers.MethodsThe feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications.ResultsIn MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab.ConclusionThese data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM.Trial registrationClinicalTrials.gov number, NCT01998971.

Project description: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.

Project description:Background: The second most common hematologic cancer worldwide is multiple myeloma (MM), with incidence and mortality rates that have more than doubled over the past 30 years. The safety and efficacy of daratumumab regimens in the treatment of newly diagnosed MM (NDMM) is demonstrated in clinical trials. Objective: To assess the financial effects of the adoption of subcutaneous daratumumab (dara-SC) rather than intravenous daratumumab (dara-IV) for the treatment of NDMM in three Gulf countries (Qatar, Oman and the United Arab Emirates; UAE), a cost-minimization model was constructed. Methods: We performed static cost minimization analyses from a societal perspective to evaluate the costs and possible reductions in resource utilization associated with a shift from dara-IV infusion to dara-SC injection for NDMM patients over a 5-year time horizon. The model included 2 scenarios: the current scenario in which 100% of patients with NDMM are treated with dara-IV infusion and a future scenario in which dara-SC injection is gradually adopted over the modeled time horizon. The model differentiated precisely between autologous stem cell transplantation (ASCT)-eligible and ASCT-ineligible NDMM patients in terms of their number in each group and the associated therapeutic regimens. One-way sensitivity analyses were also conducted. Results: The model showed that the use of dara-SC in NDMM patients who were eligible or ineligible for ASCT resulted in lower non-drug costs, including premedication drug costs, adverse-effect costs, administration costs, medical staff costs, and indirect costs. The resulting total savings over the 5-year time horizon of the model for Hamad Medical Corporation, Sultan Qaboos University Hospital/Royal Hospital, Sheikh Shakhbout Medical City (SSMC), and Tawam Hospital were QAR -2 522 686, OMR -143 214, AED -30 010 627, and AED -5 003 471, respectively. Conclusion: The introduction of dara-SC as a front-line treatment for NDMM patients in Qatar (Hamad Medical Corporation), Oman (Sultan Qaboos University Hospital, Royal Hospital-MOH), and the UAE (SSMC and Tawam Hospital) can help save resources and minimize constraints on the healthcare system.

Dataset Information

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

Publications

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

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