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

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor wit h potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate mod el and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administrat ion of an intravenous dose of 50 mg of KNI-272 per kg of body weight ( approximately 1,000 mg/m(2)) to three nonhuman primates, The pharmacok inetics of KNI-272 were also studied in 18 children (9 males and 9 fem ales; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m(2) per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal v ariability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h), The level of drug exposure achieved in CSF, as me asured by the area under the KNI-272 concentration-time curve, was onl y 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in ch ildren were characterized by rapid elimination (clearance, 276 ml/min/ m(2); terminal half-life, 0.43 h), limited (12%) and apparently satura ble bioavailability, and limited distribution (volume of distribution at steady state, 0,11 liter/kg), The concentrations in plasma were mai ntained above a concentration that is active in vitro for less than ha lf of the S-h dosing interval. There was no significant increase in CD 4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharma cokinetic 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.