A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid.
We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxyamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plasma, and a body compartment. The model incorporates such processes as reversible conversion of topotecan lactone to an inactive hydroxy acid form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of drug from the plasma compartment. Several parameters in the model were obtained from published literature on the physiology of the monkey. The model was then fit to the plasma and CSF data to deduce the other parameters. Calculated clearances of topotecan lactone and total drug from the CSF after intraventricular injection were 3.9 and 2.2 ml/h, respectively. Clearances of topotecan lactone and total drug from the plasma following a 10-min infusion were 26.3 liters/h/m2 and 17.8 liters/h/m2, respectively. The calculated ratios of the area under the concentration curve in the CSF following i.v. infusion to the area under the concentration curve in plasma were 0.11 and 0.19 for topotecan and total drug, respectively, indicating significant CSF penetration. The volume of distribution was 0.77 liters/kg, which represents distribution in a volume approximating total body water. The forward and reverse rate constants for the lactone-to-hydroxy acid conversion were 1.0 and 0.29 h-1, respectively. Comparison of the clearances (normalized to body surface area) with values reported for mice and humans shows reasonable similarity across species. This pharmacokinetic model may help guide future development and refinement of clinical protocols, especially in the treatment of diseases of the central nervous system.
Sung
C
C
Biomedical Engineering & Instrumentation Program, National Center for Research Resources, NIH, Bethesda, Maryland 20892.
Blaney
S M
SM
Cole
D E
DE
Balis
F M
FM
Dedrick
R L
RL
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D000882:Haplorhini; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D019772:Topotecan
D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin