Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma

Abstract

Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma.

Experimental design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition.

Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure.

Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.

Figures

Figure 1

Visual predictive check for the final pharmacokinetic model. Open symbols are observed plasma concentrations of romidepsin from all patients following 4-hour infusion of romidepsin 14 mg/m2 on day 1. The solid line and broken lines indicate the median and 90% prediction intervals from model-derived simulations. The dotted lines with symbols represent the 5, 50, and 95th percentiles of observations.

Figure 2

Box-whisker plots of the association between ABCB1 polymorphisms and romidepsin pharmacokinetic parameters. The whiskers above and below indicate the 5th and 95th percentiles and the lines in the middle represent median values. Diplotypes 1 to 10 are defined in Table 3.

Figure 3

Goodness-of-fit plots for the final model: scatter plots of the observed vs. the population predictions (A) and the observed vs. the individual model predictions of romidepsin concentrations (B); scatter plots of the individual weighted residuals with respect to the population model predictions (C) and time (D).