A multicompartmental population PK model elucidating the complex disposition of trastuzumab emtansine (T-DM1): an antibody-drug conjugate for the treatment of HER2-positive cancer
Bender B (1,2), Leipold D (1), Liu L (1), Xu K (1), Shen B.-Q. (1), Friberg LE (2), Tibbitts J (1)
(1) Genentech Inc, San Francisco, CA; (2) Dept of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: T-DM1 is an antibody-drug conjugate (ADC) in clinical development for treatment of HER2-positive cancers. T-DM1 drug product is a mix of drug:antibody ratio (DAR) moieties in which trastuzumab is conjugated with 1–8 molecules of the microtubule inhibitor DM1. T-DM1 targets the HER2 receptor to deliver DM1 intracellularly to kill tumor cells. A population pharmacokinetic (PK) model was developed from preclinical data to conceptualize this system, and to quantify PK and rates of DM1 deconjugation.
Methods: Model development was done using NONMEM 7 software. Preclinical data included T-DM1 PK studies in rats (N=34) and cynomolgus monkeys (N=18) at doses from 0.3–30 mg/kg, and in vitro plasma stability. Two different lots of nonclinical T-DM1 dose solution were used, one with an average DAR=3.1 (3.1 DM1/trastuzumab) and one with an average DAR=1.5. Concentrations of the DAR moieties (free trastuzumab (DAR0) and DAR1‒DAR8) were obtained using affinity capture liquid chromatography-mass spectrophotometry [1] and ELISA. The model was fit simultaneously to total trastuzumab and DAR concentrations from in vivo and in vitro data. Total trastuzumab clearance (CLtrastuzumab) was modeled as composed of plasma degradation and in vivo antibody clearance processes. T-DM1 CL was modeled as composed of CLtrastuzumab and first order deconjugation of DM1 from DAR moieties. The data allowed for a robust analysis and is an extension upon previous modeling work based on monkey data(n=4)[2].
Results: A three compartment PK model, with a catenary chain of 8 subcompartments within the central compartment, described all DAR concentration–time data well. In rats and monkeys, values for CLtrastuzumab were 2.32 and 16.0 mL/day, respectively. Terminal half-lives for total trastuzumab and T-DM1 were 10.5 and 8.33 days in rats, and 15.3 and 11.6 days in monkeys, respectively. Higher conjugated DAR moieties (DAR3‒DAR8) deconjugated faster than lower conjugated DAR moieties (DAR1, DAR2). There was no difference between species with regard to plasma stability.
Conclusions: The disposition of all individual DAR moieties for T-DM1 was well described by a multicompartmental PK model. This model can be used to predict concentrations of DAR moieties, free trastuzumab, total trastuzumab, T-DM1, as well as the average DAR versus time. This modeling and simulation analysis provides a framework for study designs towards PK and PKPD modeling of T-DM1 and other similar ADCs.
References:
[1] Xu K et al. Characterization of intact antibody-drug conjugates from plasma/serum in vivo by affinity capture capillary liquid chromatography-mass spectrometry. Anal Biochem 412, 56-66 (2011)
[2]Leipold D, Bender B, Xu K, Theil F-P, and Tibbitts J. Understanding the de-conjugation of Trastuzumab-MCC-DM1 through application of a multi-compartmental model of individual drug:antibody species in cynomolgus monkey. Presented at the 2009 American Association for Cancer Research (AACR) Meeting, Denver, Colorado. April 18th, 2009
