Abstract
The aim of the study was to determine whether the concentration of CGP 53437 measured in the sera of normal volunteers following oral administration of a single dose, had retained its anti-HIV activity; and whether such results could be of predictive value for future clinical antiviral 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 53437-treated individuals was compared with that of sera spiked with known concentrations of CGP 53437 (in the presence or absence of α-1 acid glycoprotein). It was found that the concentration of the compound measured in the sera from treated individuals provided the expected in vitro anti-HIV activity. These results not only validate our analytical method for detection of CGP 53437, but also support the notion that interaction of CGP 53437 with plasma proteins does not significantly affect its antiviral activity (shift of the ED90 by a factor of three). In conclusion, ex vivo anti-HIV activity determinations of sera containing an HIV protease inhibitor, in conjunction with the pharmacokinetic evaluation during Phase I clinical studies, can provide valuable information regarding the suitability of such inhibitors for further clinical studies.