Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis

Abstract

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.

Conflict of interest statement

Funding

This study was supported by Merck Serono S.A., Geneva, Switzerland, an affiliation of Merck KGaA, Darmstadt, Germany.

Conflict of interest

Dr. Savic and Dr. Karlsson were/are, respectively, employees of the Uppsala University, which received financial support for performing this analysis. Mrs Novakovic has received financial support from Merck Serono for attending a symposia. Dr. Ekblom was an employee of Merck Serono S.A., Geneva, Switzerland, an affiliation of Merck KGaA, Darmstadt, Germany, at the time of the analysis. Dr. Munafo is an employee of Merck Institute for Pharmacometrics, Lausanne, Switzerland.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the studies.

Figures

Fig. 1

Schematic representation of the final model. CdA cladribine, Ka absorption rate constant, Ktr transfer rate constant, F bioavailability, TC2 second transit compartment, TCn: nth transit compartment, per 1 first peripheral compartment, per 2 second peripheral compartment, CL clearance, CRCL creatinine clearance, CAde 2-chloroadenine

Fig. 2

Visual predictive checks for CdA and CAde in plasma of intravenously and orally administered CdA. Light blue shaded area indicates simulated median with uncertainty; pink shaded area indicates simulated 5th and 95th percentiles with uncertainty; solid blue line indicates observed median; dashed blue line indicates observed 5th and 95th percentiles. a Based on 193 samples from 16 subjects; b based on 211 samples from 16 subjects; c based on 470 samples from 125 subjects; d based on 81 samples from 16 subjects; e based on 108 samples from 16 subjects; and f based on 466 samples from 125 subjects. CdA cladribine, md multiple dosing, CAde 2-chloroadenine, IV intravenous

Fig. 3

Visual predictive checks for CdA and CAde in urine of intravenously and orally administered CdA. Light blue shaded area indicates simulated median with uncertainty; pink shaded area indicates simulated 5th and 95th percentiles with uncertainty; solid blue line indicates observed median; dashed blue line indicates observed 5th and 95th percentiles. a Based on 83 samples from 16 subjects; b based on 83 samples from 16 subjects; c based on 40 samples from 16 subjects; d based on 49 samples from 16 subjects. CdA cladribine, CAde 2-chloroadenine, IV intravenous

Fig. 4

Visual predictive checks for CdA in plasma after oral administration of CdA in a fasted and fed conditions, and b with and without IFNβ-1a coadministration. Light blue shaded area indicates simulated median with uncertainty; pink shaded area indicates simulated 5th and 95th percentiles with uncertainty; solid blue line indicates observed median; dashed blue line indicates observed 5th and 95th percentiles. (1) Based on 417 samples from 16 subjects; (2) based on 210 samples from 16 subjects; (3) based on 210 samples from 16 subjects; (4) based on 209 samples from 16 subjects. CdA cladribine, IFN interferon