Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis

Clin Pharmacokinet. 2017 Oct;56(10):1245-1253. doi: 10.1007/s40262-017-0516-6.


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.

Keywords: Absorption Delay; Cladribine; Multiple Sclerosis; Oral Tablet; Visual Predictive Check.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • Administration, Intravenous
  • Administration, Oral
  • Adult
  • Aged
  • Cladribine / administration & dosage
  • Cladribine / pharmacokinetics*
  • Double-Blind Method
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics*
  • Male
  • Middle Aged
  • Models, Biological*
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / drug therapy*


  • Immunosuppressive Agents
  • 2-chloroadenine
  • Cladribine
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT00213135