Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2'-deoxyadenosine.
2-Chloro-2'-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD10) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD10 (AUCapprox. one-half the LD10)/AUC(MTD) was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (Km) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (Vmax)/Km indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded the Km in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.
Reichelová
V
V
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Juliusson
G
G
Spasokoukotskaja
T
T
Eriksson
S
S
Liliemark
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D017338:Cladribine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D017321:Clinical Trials, Phase I as Topic; D003842:Deoxycytidine Kinase / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D051379:Mice; D011485:Protein Binding; D012189:Retrospective Studies; D013045:Species Specificity
D000970:Antineoplastic Agents; D017338:Cladribine; D003842:Deoxycytidine Kinase