Integrated population pharmacokinetic model of both cyclophosphamide and thiotepa suggesting a mutual drug-drug interaction

Purpose/aims: 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. Methods: Plasma samples were collected from 49 patients receiving 86 courses of a combination of high-dose CP (4000 or 6000mg/m ²), TT (320 or 480mg/m ²) and carboplatin (1067 or 1600mg/m ²) 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.Results: The pharmacokinetics of TT and T were described with a two-compartment model. TT was eliminated through a non-inducible and an inducible pathway, the latter resulting in formation of T (Cl _indTT = 12.4 l/hr, Cl _nonindTT = 17.0 l/hr). Induction of TT metabolism was mediated by a hypothetical amount of enzyme, different from that involved in CP induction, whose amount increased with time in the presence of CP. The amount of enzyme followed a zero-order formation and a decrease with a first-order elimination rate constant of 0.0343 hr ^-1 (t _1/2 = 20 hr). This model was significantly better than a model lacking the induction by CP. The model was successfully incorporated into the previously published pharmacokinetic model for CP, and resulted in comparable parameter estimates for this compound and its metabolite 4OHCP.Conclusion: The pharmacokinetics of TT, when administered in combination with CP, were successfully described. The model confirms induction of TT metabolism with time and it appears likely that CP is responsible for this phenomenon. The existence of a mutual pharmacokinetic interaction between CP and TT, as described in our integrated model, may be relevant in clinical practice.