Milly E de Jonge(1), Alwin DR Huitema(1), Sjoerd Rodenhuis(2) and Jos H Beijnen(1).
(1) Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. (2) Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Aim: Cyclophosphamide (CP) and thiotepa (TT) are frequently administered simultaneously in high-dose chemotherapy regimens. The prodrug CP shows strong autoinduction resulting in increased formation of its activated metabolite 4-hydroxycyclophosphamide (4OHCP). TT was shown to inhibit this activation of CP [1]. Recently we suggested that CP may also induce metabolism of TT to its metabolite tepa. The aim of the current study was to investigate whether the latter newly recognized interaction could be described with a mechanistic population pharmacokinetic model of sequentially administered CP and TT including their active metabolites 4OHCP and tepa, respectively.
Methods: Plasma samples were collected from 50 patients receiving 87 courses of a combination of high-dose CP (6000 or 4000 mg/m2), TT (480 or 320 mg/m2) and carboplatin (1600 or 1067 mg/m2) given in short infusions during 4 consecutive days. For each patient, approximately 20 plasma samples were available per course. Concentrations of CP, 4OHCP, TT and tepa were determined using GC and HPLC. Kinetic data were processed using the nonlinear mixed effect modeling program NONMEM with log transformed data and the first order (FO) method. For several parameters both interindividual variability (IIV) and interoccasion variability (IOV) were estimated.
Results: The pharmacokinetics of TT, tepa and CP were described with a two-compartment model and those of 4OHCP with a one-compartment model. Both CP and TT were eliminated with a non-inducible and an inducible pathway, the latter resulting in formation of 4OHCP and tepa, respectively (ClindTT= 16.0 L/h, Clnon-indTT=16.8 L/h, ClindCP= 2.9 L/h, Clnon-indCP=2.3 L/h, VTT=45.6 L, Vtepa=13.5 L, VCP=37.6 L, V4OHCP=1 FIX). Induction of CP and TT metabolism was mediated by two hypothetical amounts of enzyme whose quantities were increased with time in the presence of CP. The amount of enzyme involved in CP metabolism increased with a zero-order rate constant of 0.024 h-1, and the one involved in TT metabolism followed a zero order formation with a decrease of the first order elimination rate constant (Kenz=0.034 h-1). Interindividual variabilities on the enzyme formation rate constants were rather large, 43% and 240% for those involved in CP and TT metabolism, respectively. Inhibition of CP autoinduction by TT was modeled as a reversible, non-competitive, concentration-TT-dependent deactivation reaction. The elimination rate constants of tepa and 4OHCP were 0.6 h-1 and 136 h-1, respectively.
Conclusion: The developed mechanism-based enzyme model successfully described the complex pharmacokinetics of CP and TT given in combination. The model confirmed induction of TT metabolism and it is obvious to assume that CP is responsible for this phenomenon by increasing the amount of enzyme involved. The existence of a mutual pharmacokinetic interaction between CP and TT may be relevant in clinical practice.
[1] Huitema ADR, Mathot RAA, Tibben MM et al. A mechanism-based pharmacokinetic model for the cytochrome P450 drug-drug interaction between cyclophosphamide and thioTEPA and the autoinduction of cyclophosphamide. J Pharmacokinet Pharmacodyn 2001; 28: 211-30.
Reference: PAGE 12 () Abstr 398 [www.page-meeting.org/?abstract=398]
Poster: poster