ABSTRACT:
PNU-140690, is a potent, non-peptidic HIV protease inhibitor being developed as an oral antiviral therapeutic agent for the treatment of HIV infection. In order to assess the effects of food and elevated gastric pH on the oral absorption of PNU-140690, a single-dose study was conducted according to a randomized, crossover design in 12 healthy volunteers aged 20-51 years. Subjects received 900 mg PNU-140690 as six 150-mg capsules under fasted conditions, immediately after a high-fat breakfast, or 10 minutes after 20 mL Maalox TC, fasted. Blood samples were taken over a 48-hour period and plasma PNU-140690 concentrations were determined with a validated HPLC method. Taking the capsules after the high-fat meal greatly increased the extent of drug absorption relative to the fasted treatment; AUC was approximately two-fold higher (p=.0001) and C(max) was 55% higher (p=.0001). Mean T(max) was delayed approximately 1 hour (p=.020) for the fed treatment. When taken with antacid, AUC was about 33% lower and C(max) was 41% lower than for the fasted treatment, but only the difference in C(max) was statistically significant (p=.015). There was no change in T(max). The primary adverse events were gastrointestinal related: mild diarrhea, mild to moderate nausea and abdominal discomfort. These results show that PNU-140690 absorption can be substantially increased when capsules are taken with meals; however, an antacid appears to reduce drug absorption.
