Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19.
A preclinical evaluation of RSHZ19, a respiratory syncytial virus-specific reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic studies in rats, adult cynomolgus macaques, and infant baboons after intravenous (iv), subcutaneous, or intramuscular (im) administration. After iv administration to rats and monkeys (1 mg/kg dose), a biphasic decline in plasma concentration was observed. The dominant 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 significant nonlinearity in the pharmacokinetics was observed over a 200-fold dose range (1-200 mg/kg). In rat and monkey, absorption after extravascular administration was rapid relative to elimination (apparent half-lives < or = 24 hr), and bioavailability was high (> or = 82%). After iv or im administration to macaques (> or = 40 mg/kg), 1 of 3 animals in each group developed anti-RSHZ19 antibodies, and this resulted in rapid elimination of RSHZ19 from plasma. After the administration of a second im dose to macaques, no additional animals developed anti-RSHZ19 antibodies. Multiple-dose iv kinetics (5-day repeat dose) in infant baboons were modeled accurately by adult macaque data, suggesting that these species handled RSHZ19 similarly. The pharmacokinetic characteristics of RSHZ19 should support a convenient regimen for treatment or prophylaxis of human respiratory syncytial virus infection.
Davis
C B
CB
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Hepburn
T W
TW
Urbanski
J J
JJ
Kwok
D C
DC
Hart
T K
TK
Herzyk
D J
DJ
Demuth
S G
SG
Leland
M
M
Rhodes
G R
GR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D015707:HN Protein; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015707:HN Protein; C101293:RSHZ19 monoclonal antibody; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C116204:attachment protein G