Background:  Amdoxovir (DAPD) is a NRTI that is synergistic in human lymphocytes with zidovudine (ZDV), and in combination prevents selection of thymidine analogue mutations (TAM) and K65R mutations. ZDV, the first NRTI developed for HIV, is active, but has well-characterized hematologic toxicities. In silico, ZDV (200 mg twice daily) produces reduced ZDV-monophosphate levels, associated with toxicity, while maintaining ZDV-triphosphate levels necessary for antiviral effect. The objective was to evaluate the pharmacokinetics and anti-HIV activity of DAPD with and without ZDV at 2 doses, as a prelude to advanced phase II studies.

Methods:  We randomized 24 subjects, not receiving ART and with plasma HIV-1 RNA (viral load) ≥5000 copies/ml, to DAPD 500 mg twice daily, DAPD 500 mg + ZDV 200 or + ZDV 300 mg twice daily for 10 days. In each arm, subjects were randomized 3:1 to DAPD or placebo. Viral load was determined daily, and pharmacokinetic sampling was performed on days 1 and 10. Analyses were performed using an intent-to-treat approach. The mean change in viral load log₁₀ from baseline at day 10 and cumulative change in viral load log₁₀ from baseline to day 10 (AUC_VL) were determined. Plasma DAPD, dioxolane guanosine (DXG) metabolite, and ZDV levels were measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Safety was evaluated by proportion of ≥grade 3 adverse events per treatment, using ACTG toxicity grading scale. ANOVA was performed to relate AUC_DXG and AUC_ZDV with AUC_VL.

Results:  On day 10, mean VL log₁₀ change was +0.10 with placebo, –0.65 with ZDV 200, –0.45 with ZDV 300, –1.07±0.80 with DAPD, –1.97±0.16 with DAPD/ZDV 200, and –1.67±0.21 with DAPD/ZDV 300. DAPD/ZDV 200 was significantly more potent than DAPD (p <0.04), suggesting synergy, and there was markedly decreased viral load variability with DAPD/AZT compared with DAPD alone. Viral load decline was significantly improved with DAPD/ZDV 200 and 300 mg compared with ZDV monotherapy (p ≤0.0001). Adverse events were mild to moderate and transient. As anticipated, no statistically significant drug-drug interactions were noted. Preliminary ANOVA of the pooled data identified AUC_DXG, but not AUC_ZDV, as a significant covariate of AUC_VL (p <0.0008).

Conclusions:  DAPD and DAPD/ZDV were well tolerated, and the combination produced about a 2 log viral load reduction after 10 days. The lack of correlation between variations in plasma AUC_ZDV with viral load decline supports in silico findings. Thus, co-formulated DAPD/ZDV warrants further development for second-line therapy of HIV infections.