Cyclophosphamide and 4-Hydroxycyclophosphamide/Aldophosphamide Kinetics in Patients Receiving High-Dose Cyclophosphamide Chemotherapy

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m²) followed by a 96-h i.v. infusion (6 g/m²) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m²) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUC_CP)] and 4-HO-CP/AP (AUC_4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m²). A nonproportional increase was observed for the AUC_CP between the first course [1112 μM · h/g/m² ± 14% coefficient of variation (CV)] and the second course (1579 μM · h/g/m² ± 28% CV) (P < 0.001). In contrast, the AUC_4HOCP (27 μM · h/g/m² ± 25% CV) determined for the first course was 29% higher than the AUC_4HOCP (21 μM · h/g/m² ± 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m²) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC₅₀ values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 μM. However, the clinical relevance of this observation has not been established.