A PHARMACOKINETIC MODEL OF TOPOTECAN CLEARANCE FROM PLASMA AND CEREBROSPINAL-FLUID

We present a physiological pharmacokinetic model that describes the pl asma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9- dimethylaminomethyl-10-hydroxycamptothecin hydrochloride, SKandF 10486 3-A, NSC 609699] following i.v. and intraventricular administrations i n monkeys. The model consists of three physical spaces: the CSF, the p lasma, and a body compartment. The model incorporates such processes a s reversible conversion of topotecan lactone to an inactive hydroxy ac id form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of dru g from the plasma compartment. Several parameters in the model mere ob tained from published literature on the physiology of the monkey. The model mas then fit to the plasma and CSF data to deduce the other para meters. Calculated clearances of topotecan lactone and total drug from the CSF after intraventricular injection mere 3.9 and 2.2 ml/h, respe ctively. Clearances of topotecan lactone and total drug from the plasm a following a 10-min infusion were 26.3 liters/h/m(2) and 17.8 liters/ h/m(2), respectively. The calculated ratios of the area under the conc entration curve in the CSP following i.v. infusion to the area under t he concentration curve in plasma mere 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 distributi on in a volume approximating total body mater. The forward and reverse rate constants for the lactone-to-hydroxy acid conversion mere 1.0 an d 0.29 h(-1), respectively. Comparison of the clearances (normalized t o body surface area) with values reported for mice and humans shows re asonable similarity across species. This pharmacokinetic model may hel p guide future development and refinement of clinical protocols, espec ially in the treatment of diseases of the central nervous system.