Pharmacokinetic studies on cladribine
Author: Lindemalm, Synnöve
Date: 2001-12-14
Location: Hudklinikens föreläsningssal, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
Abstract
The aims of the present study were to delineate the pharmacokinetics, in plasma and leukaemia cells, of cladribine (M), and to describe factors influencing the outcome of administration of CdA in order to individualize and optimize treatment.
CdA is a nucleoside analogue with a cytotoxic activity in low-grade lymphoproliferative disorders and childhood acute myelogenous leukaemia. In addition, it has an immunomodulating effect used in multiple sclerosis.
CdA is unstable at low pH and is deglycosylated by bacterial nucleoside phosphorylases. CdA can also be cleaved, in an enzymatic reaction in the presence of the hepatic enzyme methylthioadenosine phosphorylase, to the main metabolite 2chloroadenine (CAde). A more stable fluorinated analogue of CdA has been developed, 2-chloro-2'-arabio-fluoro-2'- deoxyadenosine (CAFdA).
A reversed-phase high-performance liquid chromatographic method was developed for analyses of CdA, CAde and CAFdA. To minimize degradation before analysis, samples should be kept cold and not stored for more than 10 weeks.
In a study Of 17 patients with leukaemia, we found large interpatient variability in both pharmacokinetic variables and a four-fold difference in activating enzyme activity. No clear correlations were seen between the plasma levels of CdA and the intracellular concentration of the active triphosphate, or to the response of treatment. The half-life was to some degree shorter for intracellular CdA-phosphates compared to CdA in plasma.
In another study including 53 patients, we found no correlation between the the activity of the activating enzymes and the antiproliferative activity of CdA or the intracellular nucleotide levels of CdA in vitro. However, there was a large interindividual variability in enzyme activity and cytotoxicity.
In a retrospective study consisting of 163 patients with different diagnoses, receiving different doses of CdA, administered by four different routes, using different treatment schedules, leaving different numbers of blood samples at different times, we used non-linear mixed effect modelling for the pharmaco-kinetic evaluation. For patients in the population with a mean weight of 73 kg, the clearance was 35 L/h with interindividual variability of 49% and half-life was estimated to be 17 hours. The oral bioavailability was 33% but the vari-ability after oral treatment was not increased compared with the variability after intravenous infusion. Individualized dosing on bases of BSA or weight is in this study not superior to administer all patients a fixed dose.
The metabolite CAde has a lower cytotoxic effect than CdA, but may contribute to the cytotoxicity after oral administration, since 5 times more CAde was formed after oral treatment than after iv infusion (n=31 patients) and protein-binding of CAde is twice that of CdA. In conclusion, CdA can, by preference, be orally administered if the dose is adjusted for bioavailability and cytotoxicity of the metabolite, CAde.
CdA is a nucleoside analogue with a cytotoxic activity in low-grade lymphoproliferative disorders and childhood acute myelogenous leukaemia. In addition, it has an immunomodulating effect used in multiple sclerosis.
CdA is unstable at low pH and is deglycosylated by bacterial nucleoside phosphorylases. CdA can also be cleaved, in an enzymatic reaction in the presence of the hepatic enzyme methylthioadenosine phosphorylase, to the main metabolite 2chloroadenine (CAde). A more stable fluorinated analogue of CdA has been developed, 2-chloro-2'-arabio-fluoro-2'- deoxyadenosine (CAFdA).
A reversed-phase high-performance liquid chromatographic method was developed for analyses of CdA, CAde and CAFdA. To minimize degradation before analysis, samples should be kept cold and not stored for more than 10 weeks.
In a study Of 17 patients with leukaemia, we found large interpatient variability in both pharmacokinetic variables and a four-fold difference in activating enzyme activity. No clear correlations were seen between the plasma levels of CdA and the intracellular concentration of the active triphosphate, or to the response of treatment. The half-life was to some degree shorter for intracellular CdA-phosphates compared to CdA in plasma.
In another study including 53 patients, we found no correlation between the the activity of the activating enzymes and the antiproliferative activity of CdA or the intracellular nucleotide levels of CdA in vitro. However, there was a large interindividual variability in enzyme activity and cytotoxicity.
In a retrospective study consisting of 163 patients with different diagnoses, receiving different doses of CdA, administered by four different routes, using different treatment schedules, leaving different numbers of blood samples at different times, we used non-linear mixed effect modelling for the pharmaco-kinetic evaluation. For patients in the population with a mean weight of 73 kg, the clearance was 35 L/h with interindividual variability of 49% and half-life was estimated to be 17 hours. The oral bioavailability was 33% but the vari-ability after oral treatment was not increased compared with the variability after intravenous infusion. Individualized dosing on bases of BSA or weight is in this study not superior to administer all patients a fixed dose.
The metabolite CAde has a lower cytotoxic effect than CdA, but may contribute to the cytotoxicity after oral administration, since 5 times more CAde was formed after oral treatment than after iv infusion (n=31 patients) and protein-binding of CAde is twice that of CdA. In conclusion, CdA can, by preference, be orally administered if the dose is adjusted for bioavailability and cytotoxicity of the metabolite, CAde.
List of papers:
I. Lindemalm S, Albertioni F, Liliemark J (1997). "Stability and analysis of 2-chloro-2-deoxyadenosine, 2-chloro-2-arabino-fluoro-2-deoxyadenosine and 2-chloroadenine in human blood plasma. " Anticancer Drugs 8(5): 445-53
Pubmed
II. Albertioni F, Lindemalm S, Reichelova V, Pettersson B, Eriksson S, Juliusson G, Liliemark J (1970). "Pharmacokinetics of cladribine in plasma and its 5-monophosphate and 5-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia. " Clin Cancer Res 4(3): 653-8
Pubmed
III. Lindemalm S, Liliemark J, Larsson BS, Albertioni F (1999). "Distribution of 2-chloro-2-deoxyadenosine, 2-chloro-2-arabino-fluoro-2-deoxyadenosine, fludarabine and cytarabine in mice: a whole-body autoradiography study. " Med Oncol 16(4): 239-44
Pubmed
IV. Lindemalm S, Karlsson M, Gruber A, Eriksson S, Wang Y, Liliemark J, Albertioni F (2001). "Antiproliferative activity in relation to levels of phosphorylated 2-chloro-2-deoxyadenosine and 2chloro-2-arabino-fluoro-2-deoxyadenosine and levels of activating enzymes in leukaemia cells." (Manuscript)
V. Lindemalm S, Karlsson M, Albertioni F, Juliusson G, Liliemark J (2001). "Application of population pharmacokinetics to cladribine." (Submitted)
VI. Lindemalm S, Liliemark J, Juliusson G, Larsson R, Albertioni F (2001). "Pharmacokinetic and cytotoxicity of cladribine metabolite, 2-chloroadenine." (Manuscript)
I. Lindemalm S, Albertioni F, Liliemark J (1997). "Stability and analysis of 2-chloro-2-deoxyadenosine, 2-chloro-2-arabino-fluoro-2-deoxyadenosine and 2-chloroadenine in human blood plasma. " Anticancer Drugs 8(5): 445-53
Pubmed
II. Albertioni F, Lindemalm S, Reichelova V, Pettersson B, Eriksson S, Juliusson G, Liliemark J (1970). "Pharmacokinetics of cladribine in plasma and its 5-monophosphate and 5-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia. " Clin Cancer Res 4(3): 653-8
Pubmed
III. Lindemalm S, Liliemark J, Larsson BS, Albertioni F (1999). "Distribution of 2-chloro-2-deoxyadenosine, 2-chloro-2-arabino-fluoro-2-deoxyadenosine, fludarabine and cytarabine in mice: a whole-body autoradiography study. " Med Oncol 16(4): 239-44
Pubmed
IV. Lindemalm S, Karlsson M, Gruber A, Eriksson S, Wang Y, Liliemark J, Albertioni F (2001). "Antiproliferative activity in relation to levels of phosphorylated 2-chloro-2-deoxyadenosine and 2chloro-2-arabino-fluoro-2-deoxyadenosine and levels of activating enzymes in leukaemia cells." (Manuscript)
V. Lindemalm S, Karlsson M, Albertioni F, Juliusson G, Liliemark J (2001). "Application of population pharmacokinetics to cladribine." (Submitted)
VI. Lindemalm S, Liliemark J, Juliusson G, Larsson R, Albertioni F (2001). "Pharmacokinetic and cytotoxicity of cladribine metabolite, 2-chloroadenine." (Manuscript)
Issue date: 2001-11-23
Publication year: 2001
ISBN: 91-7349-043-1
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