Integrated Population Pharmacokinetic Model of both cyclophosphamide and thiotepa suggesting a mutual drug-drug interaction

Journal of Pharmacokinetics and Pharmacodynamics
Milly E de JongeJos H Beijnen

Abstract

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 inhibits this bioactivation of CP. Previously, we successfully modelled CP bioactivation and the effect of TT on the autoinduction. Recently we suggested that CP may also induce the conversion of TT in to its metabolite tepa (T). The aim of the current study was to investigate whether the influence of CP on TT metabolism can be described with a population pharmacokinetic model and whether this interaction can be incorporated in an integrated model describing both CP and TT pharmacokinetics. Plasma samples were collected from 49 patients receiving 86 courses of a combination of high-dose CP (4000 or 6000 mg/m2), TT (320 or 480 mg/m2) and carboplatin (1067 or 1600 mg/m2) given in short infusions during four consecutive days. For each patient, approximately 20 plasma samples were available per course. Concentrations of CP, 4OHCP, TT and T were determined using GC and HPLC. Kinetic data were processed using NONMEM. The pharmacokinetics of TT and T were described with a two-com...Continue Reading

Citations

Apr 20, 2005·Cancer Chemotherapy and Pharmacology·Milly E de JongeSjoerd Rodenhuis
Apr 24, 2008·Cancer Chemotherapy and Pharmacology·Corine EkhartAlwin D R Huitema
Apr 26, 2008·Cancer Chemotherapy and Pharmacology·Corine EkhartAlwin D R Huitema
Feb 10, 2009·Investigational New Drugs·Anthe S ZandvlietAlwin D R Huitema
Jun 3, 2009·Pharmaceutical Research·Amelia Ramon-LopezJuan Jose Perez-Ruixo
Feb 3, 2005·Cancer Chemotherapy and Pharmacology·Milly E de JongeSjoerd Rodenhuis
Apr 15, 2011·Cancer Treatment Reviews·Hendrik van den BergJos H Beijnen
Dec 17, 2008·British Journal of Clinical Pharmacology·Corine EkhartAlwin D R Huitema
Jul 10, 2008·Clinical Pharmacokinetics·Anthe S ZandvlietAlwin D R Huitema
Oct 20, 2005·Clinical Pharmacokinetics·Milly E de JongeJos H Beijnen

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