PRECLINICAL PHARMACOKINETIC EVALUATION OF THE RESPIRATORY SYNCYTIAL VIRUS-SPECIFIC RESHAPED HUMAN MONOCLONAL-ANTIBODY RSHZ19

A preclinical evaluation of RSHZ19, a respiratory syncytial virus-spec ific reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic studies in rats, adult cynomolgus macaques, and infan t baboons after intravenous (iv), subcutaneous, or intramuscular (im) administration, After iv administration to rats and monkeys (1 mg/kg d ose), a biphasic decline in plasma concentration was observed, The dom inant terminal phase was characterized by an 11-day half-life in rats and a 21- to 24-day half-life in monkeys. Plasma clearances of 0.3 ml/ hr/kg in the rat and 0.1-0.2 ml/hr/kg in the monkey were estimated. In the macaque, based on area under the curve, no evidence of significan t nonlinearity in the pharmacokinetics was observed over a 200-fold do se range (1-200 mg/kg), In rat and monkey, absorption after extravascu lar administration was rapid relative to elimination (apparent half-li ves less than or equal to 24 hr), and bioavailability was high (greate r than or equal to 82%). After iv or im administration to macaques (gr eater than or equal to 40 mg/kg), 1 of 3 animals in each group develop ed anti-RSHZ19 antibodies, and this resulted in rapid elimination of R SHZ19 from plasma. After the administration of a second im dose to mac aques, no additional animals developed anti-RSHZ19 antibodies, Multipl e-dose iv kinetics (5-day repeat dose) in infant baboons were modeled accurately by adult macaque data, suggesting that these species handle d RSHZ19 similarly. The pharmacokinetic characteristics of RSHZ19 shou ld support a convenient regimen for treatment or prophylaxis of human respiratory syncytial virus infection.