Altered pharmacokinetics of indinavir by a novel nonnucleoside reverse transcriptase inhibitor (HBY-097): A pharmacokinetic evaluation in HIV-positive patients

HBY-097 (HBY), an investigational nonnucleoside reverse transcriptase inhib itor (NNRTI), and indinavir (IDV) share a common metabolic pathway, cytochr ome P4503A4 (CYP3A4), and may clinically be used together as well as with z idovudine (ZDV). Thus, the potential pharmacokinetic (PK) interaction betwe en these drugs was evaluated HBY (500 mg Q8H), IDV (800 mg Q8H), and ZDV (2 00 mg Q8H) were given to 8 HIV-infected subjects. Serial plasma samples wer e collected at baseline (ZDV and IDV alone) and day 11 (all 3 drugs) to det ermine PK parameters using noncompartmental analysis.. PK parameters for ZD V in the presence and absence of HEY were not appreciably different However both the maximum (C-max) and minimum (C-min) concentrations of IDV were si gnificantly reduced, from a mean of 7514 +/- 1636 and 146 +/- 81 mcg/L to 4 725 +/- 2494 mcg/L and 54 +/- 24 mcg/L (p < .05) after addition of HBY. Fur thermore, apparent clearance (CL/F) of IDV before and after I I days of con comitant HBY administration was significantly higher, from 0.69 +/- 0.14 to 3.94 +/- 0.63 L/h/kg (p < .05) with an associated reduction in area under the curve (AUC(0-8)) from 16,034 +/- 4903 to 6134 +/- 2702 mg/L/h (p < .05) . The increase in IDV CL/F is consistent with the observed metabolic induct ion effects of other NNRTIs. The results of this trial showed that HEY sign ificantly alters the pharmacokinetic parameters of IDV at the dose studied. Journal of Clinical pharmacology 1999;39:1085-1093 (C)1999 the American Co llege of Clinical Pharmacology.