Population pharmacokinetics, efficacy, and safety of moxetumomab pasudotox in patients with relapsed or refractory hairy cell leukaemia. Issue 7 (16th March 2020)

• Record Type: Journal Article
• Authors: Kuruvilla, Denison; Chia, Yen Lin; Balic, Kemal; Yao, Nai Shun; Kreitman, Robert J.; Pastan, Ira; Li, Xia; Standifer, Nathan; Liang, Meina; Tseng, Chih‐Ming; Faggioni, Raffaella; Roskos, Lorin
• Is Part Of: British journal of clinical pharmacology. Volume 86:Issue 7(2020)
• Page Start: 1367
• Page End: 1376
• Publication Date: 2020-03-16
• Subjects: cancer -- modelling and simulation -- pharmacokinetic–pharmacodynamic -- pharmacokinetics; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14250
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : 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 (CL1 = 24.7 L/h) than subsequently (CL2 = 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.