Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates. METHODS: Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used. RESULTS: A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V(c)) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure. CONCLUSIONS: T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users

AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs)