Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.

PURPOSE: The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.

METHODS: This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.

RESULTS: The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR ) was correlated with creatinine clearance (CLCR ), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR  = 65 ml/min), moderate (CLCR  = 40 ml/min) and severe (CLCR  = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR ) by 21%, resulting in an increase of 11% in total clearance.

CONCLUSIONS: Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR . Trial registration number for study 25643: NCT00213135.