Application of population pharmacokinetics to cladribine

BMC Pharmacology BioMed Central Research article Open Access Application of population pharmacokinetics to cladribine Synnöve Lindemalm1, Radojka M Savic2, Mats O Karlsson2, Gunnar Juliusson3, Jan Liliemark1 and Freidoun Albertioni*1,4 Address: 1Department of Oncology-Pathology, Cancer centre Karolinska, Karolinska Institute, Stockholm, Sweden, 2Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, 3Department of Haematology, Linköping University Hospital, Linköping, Sweden and 4Department of Clinical Pharmacology, University Hospital, Linköping, Sweden Email: Synnöve Lindemalm - ; Radojka M Savic - ; Mats O Karlsson - ; Gunnar Juliusson - ; Jan Liliemark - ; Freidoun Albertioni* - * Corresponding author Published: 09 March 2005 BMC Pharmacology 2005, 5:4 doi:10.1186/1471-2210-5-4 Received: 23 September 2004 Accepted: 09 March 2005 This article is available from: http://www.biomedcentral.com/1471-2210/5/4 © 2005 Lindemalm et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. LeukemiaCladribinePharmacokineticNONMEMClearance Abstract Background: The nucleoside analog cladribine is used for the treatment of a variety of indolent B- and T-cell lymphoid malignancies. The primary aim of the study was to evaluate the population distribution of pharmacokinetic parameters in patients undergoing treatment with cladribine and to detect the influence of different covariates on the pharmacokinetic parameters. Methods: This pharmacokinetic study presents the results of a retrospective population pharmacokinetic analysis based on pooled data from 161 patients, who were given cladribine in different administration routes in various dosing regimens. The plasma concentrations of cladribine were determined by reversed-phase high-performance liquid chromatography using a solid phase extraction with a limit of quantitation of 1 nM using 1 mL of plasma. Results: A three compartment structural model best described the disposition of cladribine. Clearance was found to be 39.3 L/hour, with a large interindividual variability. The half-life for the terminal phase was 16 hours. Bioavailability was 100% and 35% for subcutaneous and oral administration, respectively, with low interindividual variability. None of the investigated covariates were found to be correlated with the pharmacokinetic parameters. Conclusion: As interindividual variability in apparent clearance after oral administration was not significantly higher compared to that following infusion, cladribine could be administered orally instead of intravenously if compensated for its lower bioavailability. Individualized dosing on basis of body surface area or weight does not represent an improvement in this study as compared to administering a fixed dose to all patients. Background Cladribine [Leustatin®] is a purine analogue that entered clinical testing fifteen years ago, with major activity in the treatment of B- and T-cell lymphoid malignancies. Cladribine has an outstanding therapeutic activity against hairy cell leukemia, a disease in which the drug induces longPage 1 of 8 (page number not for citation purposes) BMC Pharmacology 2005, 5:4 http://www.biomedcentral.com/1471-2210/5/4 6 Log (concentration) (nmol/L) Log (concentration) (nmol/L) 6 5 4 3 2 1 0 5 4 3 2 1 0 10 30 50 70 0 90 50 100 150 200 250 300 Time after dose (h) Time after dose (h) Figure 1 after Observed cladribine administration plasma once a 2concentration hour daily iv infusion, versus oraltime andprofile subcutaneous for Observed plasma concentration versus time profile for cladribine after a 2- hour iv infusion, oral and subcutaneous administration once daily. Concentrations are given on a logarithmic scale. Figure 2 plasma Observed administration (steady concentrations -state observations) after repeated intravenous Observed plasma concentrations after repeated intravenous administration (steady -state observations). Concentrations are given on a logarithmic scale. lasting complete remissions in the vast majority of patients treated. The activity of cladribine has also been demonstrated in chronic lymphocytic leukaemia (CLL) non-Hodgkin's lymphoma, cutaneous T-cell lymphoma and myeloid leukemia. Cladribine and the other newer purine analogues are unique, when compared to traditional antimetabolites, in that they are equally cytotoxic to both dividing and resting cells [1]. Cladribine is usually administered at 0.09 mg/kg daily as a continuous intravenous infusion over 7 days. However, pharmacokinetic studies supporting the use of intermittent intravenous (iv) infusions have shown a long terminal half-life of cladribine after a 2-hour infusion with the same anti tumour activity seen with continuous iv infusion [2]. The pharmacokinetic profile of oral administration of cladribine resembles that of a 2-hour iv infusion, with a bioavailability of 37–51% [3,4]. Subcutaneous administration gives a high peak concentration of short duration with an area under the curve (AUC) identical to that of the iv infusion and a bioavailability of 100%. The primary aim of the study was to evaluate the population distribution of pharmacokinetic parameters in patients undergoing treatment with cladribine and to detect the influence of different covariates on the pharmacokinetic parameters. This analysis was performed in order to evaluate the plasma concentration-time profiles in relation to previously presented pharmacokinetic data and to elucidate the possibilities to create a better tailoring of cladribine dosing. Results The population pharmacokinetic analysis of cladribine was based on 1102 plasma concentrations obtained from 161 individuals. The observed plasma concentrations of cladribine versus time are presented in Figure 1 and 2. The initial runs carried out were aimed at finding a base model (pharmacokinetic and statistical submodels). A three compartment structural model best described the time course of plasma concentrations of cladribine for all patients and was therefore chosen for the present analysis. The final disposition model is described as follows: a three compartment model with interindividual variability on clearance (CL), central and peripheral volumes of distribution (V1, V2, V3), intercompartmental clearances (Q2, Q3), and with a proportional residual error model for residual variability. The final population parameter estimates based on the model are given in Table 3. The clearance in the typical patient was calculated to be 39.3 L/h, with relative standard error (RSE) of 4.9 % while the interindividual variability, as expressed by the coefficient of variation, was 54%. Diagnostic plots (...truncated)