Magali Chartier, Simone Filosto, Thomas Peyret, Manoj Chiney, Francesca Milletti, Justin Budka, Andre Ndi, Jinghui Dong, Saran Vardhanabhuti, Daqin Mao, Stephen Duffull, Michael Dodds, Rhine Shen
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引用次数: 0
Abstract
Background and objective: Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure.
Methods: A population cellular kinetic model (NONMEM® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 106 anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types.
Results: Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids.
Conclusions: No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship.
Clinical trial registration: NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).
期刊介绍：
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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