Absolute bioavailability and dose proportionality of BMS-181885, an antimigraine agent, following the administration of single intranasal doses to cynomolgus monkeys.

BMS-181885, chemically 3-[[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indol-5-yl]-4-methyl-3-cyclobutene-1,2,-dione free base (Figure 1), is a potential antimigraine agent. Similar to sumatriptan, a 5-HT agonist, the pharmacological activity of BMS-181885 is elicited by binding to 5-HT1-like receptors. A strong rationale to develop a 5-HT agonist to treat migraine episodes is because 5-HT causes constriction of cranial vasculature1,2 and alleviates spontaneous and reserpine-induced migraine attacks.3,4 Intranasal route of drug administration has been evaluated not only for local use5,6 but also for systemic administration.7-13 Intranasal administration is both advantageous and attractive especially if the drug has poor oral absorption, undergoes extensive presystemic metabolism (gut wall and/or hepatic), or shows instability in the gastric conditions. In addition, intranasal administration potentially offers a rapid onset of action and a convenient mode of dosing. Considering the logistical constraints with the parenteral administration, intranasal administration, if feasible, provides a better alternative. However, due to the restrictions imposed on the dosing volume in the intranasal cavity, only drugs that have high potency can be considered for the intranasal route of administration. In this regard, BMS-181885 appears to satisfy all of the above requirements, making it a viable candidate for the intranasal route. Therefore, the absolute bioavailability, dose proportionality, and the pharmacokinetics of BMS181885 were evaluated in monkeys following single intranasal doses. This was an open, four-way randomized crossover study in cynomolgus monkeys (Charles River Primates, Houston, TX). In each session, four male monkeys (3∼4 kg) were randomized to receive a single dose of either 2, 5, or 10 mg of BMS-181885 delivered in two sprays (one spray of 0.1 mL per nostril) or a 2 mg intravenous dose administered as an infusion over a 6-min period. Intranasal doses were administered using a Valois metered pump with an appropriate actuator. During the study, monkeys were restrained on a specially designed chair (i.e., primate chair) to permit dosing (intranasal or intravenous) as well as serial blood collection. The animal protocol was reviewed and approved prior to animal experimentation. The intranasal and intravenous formulations were prepared by dissolving an accurately weighed amount of BMS181885 in 5% dextrose solution, and pH of the formulation was adjusted to 4.0-4.1 with 85% phosphoric acid. The concentrations of dosing solutions were 10, 25, and 50 mg/ mL of BMS-181885, for the single 2, 5, and 10 mg intranasal doses, respectively, whereas a 0.17 mg/mL solution of BMS-181885 (volume of 12 mL) was used for the intravenous administration. Blood samples were collected from the arterial access port of the monkeys at the following schedule: predose, and at 6, 9, 15, 20, 30, and 45 min, and at 1, 2, 4, 6, 8, 10, and 12 h post-dose. Within approximately 30 min of collection, the blood samples were centrifuged for 10 min at 4 °C and 1000g. Plasma was then separated and transferred into properly labeled storage tubes and kept frozen at -20 °C until analyses. Plasma samples were analyzed for intact BMS-181885 by a validated high-performance liquid chromatographic assay with an electrochemical detector.14 BMS-181885 concentrations were determined in monkey plasma by employing standard curves ranging from 2 to 50 ng/mL. Prior to the initiation of the study, three sets of quality control (QC) samples were prepared in monkey plasma. The QC samples were stored and analyzed with the study samples. The mean predicted QC concentrations were within 8.1% of the nominal values. The precision estimates for within-run and between-run variability of the assay were within 6.2% relative standard deviation. The QC data demonstrated accuracy, precision, and reproducibility of the plasma assay for BMS-181885 and the stability of the drug in monkey plasma. Intranasal and intravenous data obtained from the monkeys were subjected to noncompartmental pharmacokinetic analyses.15,16 For the intranasal route, the highest observed plasma concentration was defined as Cmax, and the time of occurrence of Cmax was defined as Tmax. The following parameters were determined using standard procedures: area under the concentration versus time curve from 0 to infinity (AUCinf), mean residence time (MRT), terminal elimination half-life (t1/2). The absolute bioavailability after intranasal administration at each dose level was calculated by the relationship: