An integrated pharmacokinetic-pharmacodynamic modeling analysis of T-DM1–induced thrombocytopenia and hepatotoxicity in patients with HER2-positive metastatic breast cancer
Bender B (1), Quartino A (2), Li C (2), Chen, S-C (2), Smitt M (2), Strasak A (2), Chernyukhin N (2), Wang B (2), Jin J (2), Girish S (2), Friberg LE (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden ; (2) Genentech Inc, San Francisco, CA
Objectives: T-DM1 is an antibody-drug conjugate for HER2-positive metastatic breast cancer and is associated with Grade 3/4 adverse events (AE) of thrombocytopenia (TCP) and hepatotoxicity [1]. A PKPD model was developed to describe platelet and ALT/AST transaminase response to T-DM1, and to compare weekly (q1w) regimens to the approved dose of 3.6 mg/kg every three weeks (q3w).
Methods: The PKPD model was fit to platelet, ALT, and AST data from five T-DM1 clinical trials (658 patients) using NONMEM software and the FOCE with INTERACTION algorithm. Doses ranged from 0.3–4.8 mg/kg q3w and 1.2–2.9 mg/kg q1w. The platelet model consisted of a proliferative “pool” compartment containing feedback, three transit delay compartments, and a circulation compartment modified from a previous analysis [2]. For ALT and AST, a similar model structure was used but with a zero order production rate for the pool compartment and no feedback. T-DM1 serum concentrations acted directly on the production rates of model pool compartments, describing the within-cycle oscillations of platelets and ALT/AST transaminases. An additional, slowly developing effect was described using a T-DM1 effect compartment. Patient baseline characteristics were tested as covariates on final model parameters. T-DM1 dose modification rules were incorporated into the model based on prescribing information. Model simulations compared dose exposure outcomes between q1w regimens which matched T-DM1 steady state exposure (1.2 mg/kg q1w) and steady state maximum concentrations (2.4 mg/kg q1w) to the approved dose. Posterior predictive checks (PPCs) with the model evaluated predictability for Grade ≥ 3 platelet, ALT, and AST using a Phase III internal evaluation dataset [3].
Results: PPCs showed that the model well-predicted the observed instances of Grade ≥ 3 TCP (18%), ALT (4.1%) and AST (6.5%). T-DM1 driven ALT and AST responses were highly correlated, but not with platelet response. Asian ethnicity was a covariate for Grade 3 TCP. The 2.4 mg/kg q1w regimen resulted in the highest dose intensity (2.07 mg/kg/wk) compared to the 1.2 mg/kg q1w regimen (1.15 mg/kg/wk) and the approved dose (1.18 mg/kg/wk).
Conclusions: Via simulations, q1w dose regimens are found to be associated with more dose modifications due to more frequent Grade 3 events predose. The simulated 2.4 mg/kg q1w dose provided the highest T-DM1 dose intensity. Asian patients are predicted to have higher instances of Grade 3/4 TCP.
References:
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