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 (CL(R)) was correlated with creatinine clearance (CL(CR)), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CL(CR) = 65 ml/min), moderate (CL(CR) = 40 ml/min) and severe (CL(CR) = 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-CL(R) (CL(NR)) 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 CL(CR). Trial registration number for study 25643: NCT00213135. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-017-0516-6) contains supplementary material, which is available to authorized users.