Mechanism-Based Pharmacokinetic / Pharmacodynamic Model for Hepatoprotective Effect of Dexamethasone on Transient Transaminitis After Trabectedin (ET-743, Yondelis®) Treatment

Authors: Fetterly GJ, Owen JS, Stuyckens K, Passarell JA, Zannikos P, Soto-Matos A, Izquierdo MA, Perez Ruixo JJ
Conference: ASCO
Keywords: ALT, antineoplastics, cancer, dose reduction, heptocyte, indirect response model, intravenous, IV, liver, mixture model, Oncology, PK/PD, precursor-dependent model, safety, simulation, time course
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Hepatoprotective Effect of Dexamethasone on Transient Transaminitis After Trabectedin (ET-743, Yondelis®) Treatment

Gerald J. Fetterly, Joel S. Owen, Kim Stuyckens, Julie A. Passarell, Peter Zannikos, Arturo Soto-Matos, Miguel Angel Izquierdo, and Juan Jose Perez Ruixo

Cognigen

ABSTRACT
Background: Reversible transient elevations in transaminases have been observed after trabectedin (T) administration, despite no alteration in plasma PK. A PKPD model was developed to evaluate the time course of ALT elevation, tolerance development, and covariate effects following different dosing schedules in cancer subjects.

Methods: T was administered to 711 subjects as monotherapy (dose range: 0.024-1.8 mg/m2) as 1-, 3-, or 24-hr infusions every 21 days; 1- or 3-hr infusions on days 1, 8, and 15 every 28 days; or 1-hr infusions daily for 5 consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), Eastern Cooperative Oncology Group PS scores (89.7% pts ² 1), and BW (36-122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected covariates on the time course of ALT and the effectiveness of the dose reduction strategy.

Results: A precursor-dependent PKPD model described the temporal relationship between ALT elevation and T concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentration. Overall, 66% of subjects had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and T1/2 in plasma were 31.5 (5.1) U/L and 1.4 days, respectively. The magnitude of the T stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of T-induced ALT release from hepatocyte by 63% (P<0.001). Model validation results showed good concordance with the observed incidence of grade 3/4 toxicity. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade ³3 toxicity by 13% and 39% following 2 and 4 cycles of therapy, respectively.

Conclusions: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis after T treatment has been developed. The model predicts that coadministration of dexamethasone and the suggested dose reduction strategy will enhance the safe use of T in the clinic.

American Society of Clinical Oncology (ASCO), Chicago, Illinois, June 2007

By Gerald J. Fetterly, Joel S. Owen, Kim Stuyckens, Julie A. Passarell, Peter Zannikos, Arturo Soto-Matos, Miguel Angel Izquierdo, and Juan Jose Perez Ruixo