Comparative pharmacokinetics in mice of the novel camptothecin analog DB-67 administered in diluted cremophor/ethanol or a supersaturated solution stabilized by a chemically-modified cyclodextrin.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5538 DB-67 (7- t -butyldimethylsilyl-10-hydroxycamptothecin) is a third generation camptothecin analog engineered to be blood stable and highly potent. After evaluation through the Rapid Access to Intervention Development (RAID) program at the National Cancer Institute (NCI), it will be tested in patients with solid tumors. Presently, the drug is formulated in 50% cremophor EL/ethanol for dilution prior to injection, but this vehicle is known to cause hypersensitivity in patients. Here we compared the DB-67 pharmacokinetics (PK) in mice after oral (PO) or intravenous (IV) administration of a cremophor/ethanol solution and a supersaturated solution containing a chemically-modified cyclodextrin (SBE-CD (Captisol®)) as a potential alternative. DB-67 (1mg/kg) was administered PO or IV as a bolus tail vein injection to mice. Blood was collected via cardiac puncture at 5 and 30 min and at 1, 3, and 6 hours after PO administration. Similarly, samples were collected at 5 and 15 min and at 1, 3, 6, and 8 hours after IV administration. Samples were centrifuged and plasma was extracted with 4 volumes of cold methanol. Extracts were vortexed, centrifuged, and supernatants were analyzed by HPLC. The assay employed a reversed-phase column and a mobile phase consisting of 0.15 M ammonium acetate/10 mM tetrabutylammonium dihydrogen phosphate (pH 6.5): acetonitrile (65:35, v/v) with fluorescence detection to monitor the carboxylate and lactone forms of DB-67. The HPLC method allowed the simultaneous determination of both DB-67 carboxylate and lactone. Validation demonstrated selectivity and specificity for the carboxylate and lactone, with linearity between 5–300 ng/mL for both analytes (accuracy ± 9 % of theory and coefficient of variation ≤5.7 %). Carboxylate to lactone conversion was <4% using this method. Pharmacokinetic parameters were estimated using compartmental modeling. As expected for this blood stable camptothecin, the lactone was the predominant species in blood during the 6 or 8 hour periods of sampling. Drug disposition was identical with either formulation after either PO or IV administration. The oral bioavailability estimated from the ratios of AUCs for the PO and IV doses was ∼33%. We have established an accurate and precise HPLC assay for the quantitation of DB-67 and have demonstrated its utility in pharmacokinetic studies. DB-67 disposition is similar in cremophor/ethanol and SBE-CD formulations. Thus, a supersaturated solution stabilized by a chemically-modified cyclodextrin may be a useful alternative formulation to avoid the adverse reactions to cremophor/ethanol observed in the clinic. Interestingly, the oral bioavailability of DB-67 in mice is similar to reported oral bioavailabilities for other commercially available analogs.