Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.

A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m2 plus docetaxel 75 mg/m2 to the registered capecitabine dose of 1,250 mg/m2 plus docetaxel 75 mg/m2. We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and determine a minimum capecitabine dose noninferior to 1,250 mg/m2. Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000 mg/m2 starting dose and an increased number of PFS events. A starting dose of 1,000 mg/m2 could be established as noninferior in terms of efficacy to the registered dose in the second-line MBC setting, with a potentially improved safety, in line with medical practice.

This work proposes and evaluates two methods (CM1 and CM2) for detecting non-compliance using concentration-time data and for obtaining estimates of population pharmacokinetic model parameters in a population with prevalent non-compliance. CM1 estimates individual residual variability (RV) and identifies subjects with higher than average RV as non-compliant. Exclusion of subjects with high RV from the analysis dataset reduces the bias in the estimates of the model parameters. Various methods of identification and exclusion of non-compliant subjects were tested, compared, and shown to reduce or eliminate bias in parameter estimates associated with non-compliance. The tested methods were (i) a pre-defined cutoff value of the random effect on RV, (ii) sequential exclusion of subjects with the highest RV percentiles, and (iii) use of a mixture model for RV. CM2 is applicable for the data with a specific sampling pattern that includes a potentially non-compliant outpatient part with several trough samples followed by a dense profile after the inpatient (compliant) dose. It relies only on the doses known to be administered (e.g., inpatient doses). In this method, all concentration measurements during the outpatient part of the study (except the trough value immediately preceding the inpatient dose) are removed from the dataset and an additional parameter (individual relative bioavailability of the outpatient doses) is introduced. For a number of simulated datasets with various sampling schemes and non-compliance patterns the proposed methods allowed to identify subjects with compliance problems and to reduce or eliminate bias in the estimates of the model parameters.

Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m(2), administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030).

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