Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys.

Abstract

The pharmacokinetics of recombinant alpha A interferon (rIFN-alpha A) were studied following an intravenous (iv) bolus, 60 min infusion, intramuscular (im), and oral administrations to four African Green monkeys. Each monkey received 3 X 10(6) units/kg of rIFN-alpha A parenterally and 6 X 10(6) units/kg orally. Blood samples were collected and the serum was separated and analyzed for rIFN-alpha A concentrations by an enzyme immunoassay, ELISA. No significant changes in clinical chemistry values resulted from rIFN-alpha A administration. There were no measurable rIFN-alpha A concentrations (less than 20 pg/ml) following oral administration. Serum rIFN-alpha A concentrations declined rapidly in a biphasic manner following iv bolus and infusion doses and were described by a single pharmacokinetic model. The volume of distribution at steady state (Vdss) ranged from 0.034 to 0.31 l/kg after iv infusion. Total clearance ranged from 4.5 to 19 ml/min, which is about 75% the estimated inulin clearance in monkeys, suggesting glomerular filtration without reabsorption. The elimination half-life ranged from 1.8 to 4.8 h. A prolonged absorption profile was seen following im administration and the systemic bioavailability was 93% when compared with intravenous infusion. The overall disposition of rIFN-alpha A is comparable to the disposition of other interferons in both animals and humans. The monkey appears to be a suitable pharmacokinetic model for the testing of rIFN-alpha A and could be useful in conjunction with a viral efficacy model.