title: Pharmacokinetics of the protease inhibitor KNI-272 in plasma and cerebrospinal fluid in nonhuman primates after intravenous dosing and in human immunodeficiency virus-infected children after intravenous and oral dosing.
abstract: KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug's efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.
authors.affiliation: Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. mueller_b@a1.tch.harvard.edu
authors.forename: B U
authors.initials: BU
authors.lastname: Mueller
authors.forename: B D
authors.initials: BD
authors.lastname: Anderson
authors.forename: M Q
authors.initials: MQ
authors.lastname: Farley
authors.forename: R
authors.initials: R
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Zuckerman
authors.forename: P
authors.initials: P
authors.lastname: Jarosinski
authors.forename: K
authors.initials: K
authors.lastname: Godwin
authors.forename: C L
authors.initials: CL
authors.lastname: McCully
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: P A
authors.initials: PA
authors.lastname: Pizzo
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C077822:kynostatin 272