7th Conference - Abstract 84

Evaluation of Potential Pharmacokinetic Interactions between Emivirine + Combivir or Indinavir following Steady-State Administration in Healthy Male and Female Volunteers

M. R. BLUM*, G. E. CHITTICK, D. J. KARGL, J. WALSH, B. LAMPERT, and L. H. WANG. Triangle Pharmaceuticals, Inc., Durham, NC

Emivirine (EMV, Coactinon, formerly MKC-442) is a potent NNRTI currently under Phase III clinical development for the treatment on HIV infection. EMV is both a substrate as well as an inducer of the cytochrome P450 enzyme, CPY3A/4 and, therefore has the potential for interactions with other drugs that are metabolized by this enzyme system. The results of two separate steady-state PK interaction studies of EMV with three other widely used anti-HIV drugs are reported here. The first, a 25-day study (N=15), evaluated the PK of EMV 750 mg BID alone and in combination with ZDV and 3TC (given as Combivir BID). The second, a 21-day study (2 cohorts, N=15 each), evaluated the PK of EMV 500 mg BID alone and in combination with IDV 800 mg TID. The PK results (mean, %CV) are summarized below:

The PK results indicate that at steady-state, Combivir does not affect EMV PK and EMV does not affect 3TC PK. At steady-state EMV increased ZDV AUC_0-Q by ~40% but had no effect on ZDV C_max,ss. Thus, EMV can be administered with ZDV and 3TC without dosage adjustment. IDV inhibited the metabolism of EMV resulting in an 88.5% increase in EMV AUC, while EMV induced the metabolism of IDV resulting in a 74.5% reduction in IDV AUC. Because of the significant PK interaction, EMV should not be combined with IDV in a single PI containing regimen.

Key Words: drug interaction, emivirine, pharmacokinetics