Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults

Tenofovir DF is an antiviral nucleotide with activity against human immunod eficiency virus type I (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomize d, double-blind, placebo-controlled, escalating-dose study of four doses (7 5, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafte r, subjects received their assigned study drug once daily for 28 days. Phar macokinetic parameters were dose proportional and demonstrated no change wi th repeated dosing. Reductions in plasma HIV-1 RNA were dose related at ten ofovir DF doses of 75 to 300 mg, but there was no increase in virus suppres sion between the 300- and 600-mg dose cohorts, despite dose-proportional in creases in drug exposure. Grade III or IV adverse events were limited to la boratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and wi thout sequelae. No patients developed detectable sequence changes in the re verse transcriptase gene.