title: Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Novakovic
authors.affiliation: Persson Ekblom Sarl, St-Prex, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ekblom
authors.affiliation: Merck Institute for Pharmacometrics, Lausanne, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Munafo
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden. mats.karlsson@farmbio.uu.se.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D017338:Cladribine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy*
chemical_list: D007166:Immunosuppressive Agents; C069484:2-chloroadenine; D017338:Cladribine; D000225:Adenine
keywords: Absorption Delay; Cladribine; Multiple Sclerosis; Oral Tablet; Visual Predictive Check