Premium
Population pharmacokinetics, efficacy, and safety of moxetumomab pasudotox in patients with relapsed or refractory hairy cell leukaemia
Author(s) -
Kuruvilla Denison,
Chia Yen Lin,
Balic Kemal,
Yao Nai Shun,
Kreitman Robert J.,
Pastan Ira,
Li Xia,
Standifer Nathan,
Liang Meina,
Tseng ChihMing,
Faggioni Raffaella,
Roskos Lorin
Publication year - 2020
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14250
Subject(s) - medicine , pharmacokinetics , population , renal function , adverse effect , refractory (planetary science) , gastroenterology , incidence (geometry) , pharmacodynamics , immunology , physics , environmental health , astrobiology , optics
Aims To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti‐CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). Methods Data from both studies were pooled ( n = 123) to develop a population PK model. Covariates included demographics, disease state, liver and kidney function, prior treatment, and antidrug antibodies (ADAs). Exposure–response and exposure–safety were analysed separately by study. A 1‐compartment model with linear elimination from the central compartment and 2 clearance (CL) rates was developed. Results Moxetumomab pasudotox was cleared more rapidly after cycle 1, day 1 (CL 1 = 24.7 L/h) than subsequently (CL 2 = 3.76 L/h), with high interindividual variability (116 and 109%, respectively). In Study 1053, patients with ADA titres >10 240 showed ~4‐fold increase in CL. Higher exposures (≥median) were related to higher response rates, capillary leak syndrome and increased creatinine (Study 1053 only), or grade ≥3 adverse events (Study 1001 only). Clinical benefits were still observed in patients with lower exposure or high ADA titres. Conclusion Despite a high incidence of immunogenicity with increased clearance, moxetumomab pasudotox demonstrated efficacy in hairy cell leukaemia.