Pharmacokinetics of MKC-422, One of the Next Non-nucleoside Reverse Transcriptase Inhibitors, Together with ZDV, 3TC, d4T, and ddI
MKC-442 is a non-nucleoside reverse transcriptase inhibitor with potent activity in early phase I/II studies. Prior to moving forward with larger trials testing the drug's activity, this pharmacokinetic study was conducted to investigate the possible interactions between the drug and ZDV, 3TC, d4T, and ddI. MKC-422 is metabolized by the cytochrome P450 liver enzyme CYP3A4, the enzyme responsible for metabolizing the other non-nucleoside reverse transcriptase inhibitors as well as the protease inhibitors. Other NNRTIs and protease inhibitors have not been shown to have any effects on the pharmacokinetics of the nucleoside reverse transcriptase inhibitors, and none was expected in this study.
30 uninfected men and women volunteered for the study and took either MKC-442 alone, the combination of ZDV + 3TC or d4T + ddI, or MKC-442 together with ZDV + 3TC or d4T + ddI. Concentrations of MKC-442 were not effected by either of the nucleoside combinations. However, peak concentrations of ZDV and the area under the curve (a calculation of the total drug exposure following a single dose) were elevated by 50% when taken together with MKC-422, suggesting that MKC-422 inhibits the metabolism and/or secretion of ZDV. This was an unexpected finding. The mechanism for this interaction is under investigation, and its clinical significance is being studied in clinical studies of the combination.