Plasma and brain pharmacokinetics of letrozole and drug interaction studies with temozolomide in NOD-scid gamma mice and sprague dawley rats.

Abstract

The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs). To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently employed for assessing efficacy against patient-derived tumor cells. Furthermore, we evaluated the potential PK interactions between letrozole and temozolomide (TMZ) in Sprague-Dawley rats. NSG mice were administered letrozole (8mg/kg; i.p) as a single or multiple dose (b.i.d, 10 days). Brain tissue and blood samples were collected over 24h. Letrozole and TMZ interaction study employed jugular vein-cannulated rats (three groups; TMZ alone, letrozole alone and TMZ + letrozole). Intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured employing HPLC and PK analysis was conducted using Phoenix WinNonlin®. In NSG mice, peak plasma and brain tissue letrozole concentrations (Cmax) were 3-4 and 0.8-0.9µg/ml, respectively. The elimination half-life was 2.6h with minimal accumulation following multiple dosing. In the drug interaction study, no PK changes were evident when TMZ and letrozole were given in combination. For instance, peak plasma and brain ECF TMZ levels when given alone were 14.7 ± 1.1 and 4.6 ± 0.6µg/ml, respectively, and 12.6 ± 2.4 and 3.4 ± 0.8µg/ml, respectively, when given with letrozole. These results will guide the optimization of dosing regimen for further development of letrozole for HGG treatment.