Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment

Abstract

Purpose: Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients.

Patients and methods: Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts <or= 1), and body weight (36-122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors 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 trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALT(o)) and t (1/2) in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin 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 trabectedin-induced ALT release from hepatocyte by 63% (P < 0.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade >or=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively.

Conclusions: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.