Effects of ketoconazole and rifampin on TMC278

TMC278 is a new non-nucleoside reverse transcriptase inhibitor in early stage clinical development. It had been previously reported that many of the commonly used HIV treatments and drugs used to treat and prevent opportunistic infections might interact with TMC278.

Two separate studies, involving 16 HIV-negative individuals in each study, evaluated how ketoconazole and rifampin might affect TMC278 drug levels. Rifampin significantly reduced TMC278 levels by an average of 80% over a 24 hour period and perhaps more importantly, TMC278 levels were reduced by 89% at its lowest level (commonly referred to as Cmin), usually found right before taking the next dose. TMC278 had no effects on rifampin drug levels. This marked reduction in TMC278 levels has led to the recommendation that the two drugs should not be used together.

The second study found that ketoconazole increased TMC278 levels by an average of 49% over a 24 hour period and TMC278 reduced ketoconazole levels by 24%. It is likely that there will have to be a change in the dose of TMC278 if the drug is used in combination with ketoconazole.

van Heeswijk R et al. The effects of CYP3A4 modulation on the pharmacokinetics of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 74.