EX-VIVO ANTI-HIV ACTIVITY OF HUMAN SERUM OBTAINED FROM NORMAL VOLUNTEERS FOLLOWING ORAL-ADMINISTRATION OF THE HIV-1 PROTEASE INHIBITOR CGP-53437 - VALUE AS PREDICTOR OF ANTIVIRAL EFFICACY

The aim of the study was to determine whether the concentration of CGP 53437 measured in the sera of nor mal volunteers following oral admin istration of a single dose, had retained its anti-HIV activity; and wh ether such results could be of predictive value For future clinical an tiviral efficacy studies. CGP 53437 is an inhibitor of HIV-1 protease that suppresses HIV-1 replication in human lymphocytes in vitro at 100 nM. The in vitro anti-HIV activity of human sera obtained from CGP 53 437-treated individuals was compared with that of sera spiked with kno wn concentrations of CGP 53437 (in the presence or absence of alpha-1 acid glycoprotein). It was found that the concentration of the compoun d measured in the sera from treated individuals provided the expected in vitro anti-HIV activity. These results not only validate our analyt ical method for detection of CGP 53437, but also support the notion th at interaction of CGP 53437 with plasma proteins does not significantl y affect its antiviral activity (shift of the ED(90) by a factor of th ree). in conclusion, ex vivo anti-HIV activity determinations of sera containing an HIV protease inhibitor, in conjunction with the pharmaco kinetic evaluation during Phase I clinical studies, can provide valuab le information regarding the suitability of such inhibitors for furthe r clinical studies.