Emtricitabine (FTC) is a potent deoxycytidine nucleoside analogue that was recently approved for the treatment of HIV infection. Emtricitabine is activated by intracellular phosphorylation to its 5'-triphosphate (FTC5'-TP), a competitive inhibitor of the HIV reverse transcriptase (RT). Early clinical studies incorporating pharmacokinetic-pharmacodynamic (PK-PD) analyses provided a sound rationale for developing FTC as a once daily drug. A short-term open-label monotherapy trial in therapy naive HIV-infected subjects evaluated various dosage regimens of FTC, i.e., 25, 100, and 200 mg qd and/or bid, with serial measurements of plasma HIV RNA, plasma FTC, and intracellular (PBMC) FTC-5'-TP levels over the 14 days of treatment. PK data were augmented by other steady-state studies, one in healthy volunteers and the other in HIV-infected patients receiving 200 mg FTC qd, with measurements of plasma FTC and/or intracellular FTC-5'-TP levels. Correlation between anti-HIV activity and FTC-5'-TP levels was examined with dose- and concentration-response relationships determined. The once daily dosing schedule is supported by the relatively long half-lives of plasma FTC (8-10 hr) and PBMC FTC-TP (39 hr) and the high plasma FTC and PBMC FTC-5'-TP concentrations. HIV RNA suppression (PD) correlates well with PBMC FTC-5'-TP levels (PK), both reaching a plateau at doses > or = 200 mg/day. The PK and PD characteristics of FTC demonstrate that it is a once daily nucleoside RT inhibitor.