A mechanism-based pharmacokinetic model for the cytochrome P450 drug-drug interaction between cyclophosphamide and thioTEPA and the autoinduction of cyclophosphamide

Cyclophosphamide (CP) is widely used in high-dose chemotherapy regimens in combination with thioTEPA. CP is a prodrug and is activated by cytochrome P 450 to 4-hydroxycyclclophosphamide (HCP) which yields the final cytotoxic m erabolite-phosphoramide mustard IPM). The metabolism of CP into HCP exhibit s autoinduction but is inhibited by thioTEPA. he aim of this study was to d evelop a population pharmacokinetic model for the bioactivation route of CP incorporating the phenomena of both autoinduction and the drug-drug intera ction between CP and rhioTEPA. Plasma samples were collected from 34 patien ts who received high-dose CP. thioTEPA and carboplatin in short infusions d uring 4 consecutive days. Elimination of CP was described by a noninducible route and an inducible route leading to HCP. The latter route was mediated by a hypothetical amount of enzyme. Autoinduction leads to a zero-order in crease in amount of this enzyme during treatment. inhibition by thioTEPA wa s modeled as a reversible, competitive, concentration-dependent inhibition. PM pharmacokinetics were described by first-order formation from HCP and f irst-order elimination. The final models for CP, HCP, and PM provided an ad equate fit of the experimental data. The volume of distribution, noninducib le and initial inducible clearances of CP were 31.0L, 1.58L/hr and 4.76L/hr . respectively. The enzyme amount increased with a zero-order rate constant of 0.041 amount*hr(-1). After each thioTEPA infusion, however, approximate ly 80% of the enzyme was inhibited. This inhibition was reversible with a h alf-life of 6.5 hr. The formation and elimination rare constants of PM were 1.58 and 0.338 hr(-1) respectively. The developed model enabled the assess ment of the complex pharmacokinetics of CP.