Compared with the protease inhibitor (PI) and nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) classes of medications, there are relatively few non-nucleoside reverse transcriptase inhibitor (NNRTI) options. Most use of NNRTIs is with either efavirenz (EFV, Sustiva, Stocrin) or nevirapine (NVP,Viramune); while effective options for therapy, use of these drugs is sometimes characterized by central nervous system (CNS) toxicity and hepatitis, respectively, and rash is a relatively common adverse effect of both drugs. In addition, NNRTIs offer no options for sequencing, as genotypic resistance to one member of this drug class generally eliminates options for the whole drug class. As a result, development of new NNRTI options, especially those with activity against NNRTI-resistant viruses, is an important research agenda.

In this study of the investigational NNRTI GW695634, 39 healthy male volunteers received, every 12 hours for 10 days, increasing doses of GW695634 starting with 100 mg and ending with 400 mg. Extensive screening for adverse events, clinical laboratory evaluations, vital signs, ECGs and telemetry were performed, along with pharmacokinetic measurements. Thirty-four of the 39 subjects completed the study.

GW695634 was generally well tolerated. No serious adverse effects occurred during the study. Five study discontinuations due to side effects occurred, with reported symptoms of rash (3), abdominal pain (1), ECG abnormality (1) and mouth ulcerations. There were small and transient declines in systolic and diastolic blood pressure. As GW695634 is a pro-drug of the active compound GW678248, measurements of the latter showed dose-proportional increases in both C_max and AUC.

The study concludes that GW695634 was generally well tolerated, and that doses of 200 mg and 300 mg once every 12 hours would be sufficient for many NNRTI-resistant viruses, while 400 mg once every 12 hours would be needed for highly resistant viruses. The impressive in vitro activity of this drug against NNRTI-resistant viruses has led to clinical efficacy studies of GW695634 in NNRTI-experienced, HIV-infected adults; these studies are currently ongoing.