Leticia McGuffey

Plasma and Cerebrospinal Fluid Pharmacokinetics of Imatinib after Administration to Nonhuman Primates

Purpose: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. Experimental Design: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods. Results: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 μm after i.v. dosing and 0.8 to 2.8 μm after p.o. dosing. The mean ±SD area under the plasma concentration versus time curve was 2480 ±1340 μm·min and 1191 ±146 μm·min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 ±167 min after i.v. dosing and 266 ±88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 ±2.8 liter/kg, and the total body clearance was 12 ±5 ml/min/kg. The mean peak CSF concentration was 0.25 ±0.07 μm after i.v. dosing and 0.07 ±0.04 μm after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% ±2%. Conclusions: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.

Plasma and Cerebrospinal Fluid Pharmacokinetics of Clofarabine in Nonhuman Primates

Introduction: Clofarabine (2-chloro-2′fluoro-2′-deoxy-9-β-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model. Methods: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy. Results: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 μmol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%). Conclusion: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.

Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates

Purpose: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans. Methods: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC. Results: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 μg/ml and the mean plasma AUC was 1075 ± 202 μg/ml · min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t1/2α) of 18 ± 7 min and an elimination half-life (t1/2β) of 109 ± 7 min. Total body clearance (ClTB) was 9.4 ± 1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168 ± 83 μg/ml · min and the mean peak CSF concentration was 0.7 ± 0.3 μg/ml. The ratio of the AUCs in CSF and plasma was 15.5 ± 7.1%. Conclusions: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors.

Incorporation of an enrichment program into a study protocol involving long-term restraint in macaques.

Nonhuman primates might experience stress during periods of restraint associated with research procedures. In an attempt to minimize such stress, the authors describe an enrichment program they designed for use with restrained adult male rhesus macaques.