7th Conference - Abstract 103

Preliminary Assessments of the Pharmacokinetics of DAPD and Its Active Metabolite DXG in HIV-Infected Subjects

L. H. WANG*, J. W. BIGLEY, R. L. ST CLAIRE, N. SISTA, and F. ROUSSEAU. Triangle Pharm. Inc., Durham, NC

DAPD is a novel dioxolane guanosine reverse transcriptase inhibitor (RTI) being developed for the treatment of HIV infection. DAPD is deaminated in vivo by adenosine deaminase, a ubiquitous enzyme, to yield DXG. Both compounds have demonstrated potent in vitro anti-HIV activity against wild-type viral strains and strains resistant to other RTIs. Biochemical analysis showed that DXG-5'-triphosphate is a more potent inhibitor of HIV-RT than DAPD-5'-triphosphate. A 14-day Phase I/IIa monotherapy trial is being conducted to evaluate the safety, antiviral activity and pharmacokinetics (PK) of escalating doses of DAPD in HIV-infected subjects. PKs of DAPD and DXG were evaluated after the first dose on Day 1 and then at steady state, after the last dose on Day 15. Serial blood samples were collected into EDTA-VACUTAINER tubes containing deoxycoformycin to prevent in vitro deamination of DAPD during sample collection/storage. Plasma concentrations of DAPD and DXG were analyzed by a specific LC/MS/MS method. Preliminary data from 6 treatment naive subjects each receiving 100, 200 and 300 mg bid DAPD doses showed that DAPD is rapidly absorbed and converted to DXG with C_max occurring between 1–2 hrs following oral dosing. Plasma DXG levels were generally higher than DAPD, with a mean AUC ratio (DXG/DAPD) of 3 to 10 irrespective of dose levels. C_max and AUC of both compounds increased in a dose-related fashion along with similar t_1/2 estimates across dose levels, i.e., ~1 hr for DAPD and ~7 hrs for DXG. Plasma DAPD and DXG reached levels above their respective in vitro IC₅₀ and IC₉₀, which are consistent with the antiviral activity observed in the clinic. All doses of DAPD tested to date have been well tolerated. These initial PK results along with good tolerability and antiviral activity warrant further evaluations of DAPD at higher doses and/or under different dosing schedules.

Key Words: anti-HIV therapy-clinical, drug interactions, pharmacokinetics