752   The Disposition of DAPD and Its Active Metabolite DXG in Therapy-Naive and -Experienced HIV-Infected Subjects.

L. H. Wang*, J. W. Bigley, M. Brosnan-Cook, N. Sista, F. Rousseau, and the DAPD-101 Clinical Trial Group.
Triangle Pharmaceuticals, Inc., Durham, NC.

Background:DAPD is a novel dioxolane guanosine reverse transcriptase inhibitor (RTI) under Phase I/II development for the treatment of HIV infection. DAPD is deaminated in vivo by adenosine deaminase, a ubiquitous enzyme, to yield DXG. Biochemically, DXG-5´-triphosphate is a more potent inhibitor of HIV-RT than DAPD-5´-triphosphate. In a 14-day Phase I/II open-label, dose-escalation trial, DAPD monotherapy demonstrated potent anti-HIV activity in therapy-naïve and -experienced HIV-infected subjects. In this trial, the pharmacokinetics (PK) of escalating oral doses of DAPD/DXG was also characterized.

Methods:Blood and urine samples were collected after the first dose (day 1, up to 12 hrs) and then at steady state, after the last dose (day 15, up to 48 hrs) for analysis of plasma and urine concentrations of DAPD and DXG by specific LC/MS/MS methods.

Results:Preliminary data from 5-6 therapy-naïve and -experienced subjects each receiving DAPD at doses of 100 (naïve only), 200, 300, and 500 mg bid showed that DAPD was rapidly absorbed and converted to DXG with C_maxof both compounds occurring between 1—2 hrs post dose. Plasma DXG levels were higher than DAPD levels, with a mean AUC ratio (DXG/DAPD) of 2 to 10 irrespective of dose level. There were no major differences in DAPD/DXG PKs between therapy-naïve and -experienced subjects. C_maxand AUC of DAPD and DXG increased in a dose-related fashion but exhibited large inter-subject variabilities. Both compounds exhibited multi-exponential decay curves in plasma, as evidenced by longer plasma sampling time (12 vs. 48 hrs). Both compounds also demonstrated linear kinetics with similar t_1/2estimates across all dose levels, i.e., 1-2 hr for DAPD and 7—8 hrs for DXG. Appox. 20—30% of a DAPD oral dose was recovered in urine as DXG and 2- -10% as DAPD, indicating that the majority of the DAPD dose absorbed was converted to DXG, consistent with the observed higher plasma DXG concentrations. The unrecovered DAPD dose is likely due to incomplete absorption or metabolism.

Conclusion:The extensive conversion of DAPD to DXG and high plasma levels of DXG, the active moiety of anti-HIV activity, following oral administration of DAPD support its further development.