Population pharmacokinetics of cyclophosphamide and its 4-OH metabolite in patients with glomerulonephritis
Georgia Charkoftaki, Aris Dokoumetzidis, Melanie Joy
University of Colorado, Skaggs School of Pharmacy, University of Athens, School of Pharmacy, University of Colorado, Skaggs School of Pharmacyand School of Medicine, Division of Renal Diseases and Hypertension
Objectives: The purpose of this study was to develop a population pharmacokinetic (PK) model for cyclophosphamide (CY) and its 4-hydroxy cyclophosphamide (4-OH CY) metabolite in patients with glomerulonephritis secondary to lupus and small vessel vasculitis and to identify patient characteristics that may influence the drug's absorption and disposition.
Methods: The study consisted of patients with glomerulonephritis (n=23) who participated in pharmacokinetic evaluations of CY and 4-OH CY. All patients had received monthly i.v. cyclophosphamide prior to study participation. The i.v. cyclophosphamide dosages were dependent on body surface area; mean dose was (i) 1.5±0.5 g/m2 or (ii) 0.8±0.2 g/m2. Blood samples for CY and 4-OH CY determination were collected at the beginning of the infusion and at 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24 h after commencement and were assayed by LC/MS/MS method. Kidney function, serum albumin and polymorphisms in drug metabolism and transport genes were evaluated. Plasma concentration-time data of CY and 4-OH CY (metabolite) were analyzed in two stages with a population approach using NONMEM®. 4-OH CY was analyzed conditional to the results of CY.
Results: The parent drug (CY) model was found to be one compartment with linear elimination with apparent volume of distribution V=154*(WT/95)0.373 L, IIV= 21.2% and with apparent clearance CL =14.4*(WT/95)0.471 L/h, IIV= 20.4%. The metabolite (4-OH CY) was modeled as one compartment with linear elimination and the production rate was proportional to the elimination of the parent drug. The typical Vm/Fm was 17.3 L with IIV= 33% and the fraction converted from parent to metabolite was Fm=0.441. Elimination rate constant of the 4-OH CY was Kmet=8 h-1. The production rate constant of 4-OH CY was Fm*CLP/VP=0.041 h-1 and was found to be lower than the Kmet, therefore half-life of 4-OH CY is determined by its production rate rather than its elimination (flip-flop pharmacokinetics). The final PK model was validated using nonparametric bootstrapping and a visual predictive check.
Conclusions: The population PK data described here suggest that only 44% of CY gets metabolized to the 4-OH CY metabolite in patients with glomerulonephritis, while this percentage is around 75% for patients receiving CY as an anti-cancer therapeutics.
