Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.
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ICR Authors
Authors
Luo, MM
Usmani, SZ
Mateos, M-V
Nahi, H
Chari, A
San-Miguel, J
Touzeau, C
Suzuki, K
Kaiser, M
Carson, R
Heuck, C
Qi, M
Zhou, H
Sun, Y-N
Parasrampuria, DA
Usmani, SZ
Mateos, M-V
Nahi, H
Chari, A
San-Miguel, J
Touzeau, C
Suzuki, K
Kaiser, M
Carson, R
Heuck, C
Qi, M
Zhou, H
Sun, Y-N
Parasrampuria, DA
Document Type
Journal Article
Date
2020-11-03
Date Accepted
2020-10-05
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 (Ctrough ) 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.
Citation
Journal of clinical pharmacology, 2020
Source Title
Publisher
WILEY
ISSN
0091-2700
eISSN
1552-4604
Collections
Research Team
Myeloma Group
Myeloma Group
Myeloma Group