ABSTRACT: BACKGROUND: S-1153 is a novel NNRTI which has a 10-fold greater in-vitro activity against HIV-1 than nevirapine and delavirdine. Resistance of HIV-1 to S-1153 is seen only after double or triple mutations, as opposed to the one mutation for the current FDA approved NNRTI's.
METHODS: A Phase I dose escalation PK/safety study was conducted with S-1153 administered over 7 dose levels-1.7, 3.3, 5.0, 6.7, and 8.3 mg/kg t.i.d, and 10.0 and 12.5 mg/kg b.i.d. Patients received study drug for 14 days (first 4 dose levels) or for 28 days (last three dose levels). S-1153 drug levels were evaluated with and without food at some of the levels. Entry CD4+ cell counts were 50-500 cells/ml. Concomitant antiRetroviral therapy, other than protease inhibitor or other NNRTI's, was permitted but not required, provided it was stable for > 4 weeks prior to study entry.
RESULTS: 54 patients received S-1153. Bioavailability was high, and drug levels were not significantly affected by food. All patients completed dosing without any evidence of S-1153 related Grade 3 or 4 toxicity. The study drug related adverse events were mild nausea and metallic taste. These side effects were ameliorated by taking S-1153 with food. No rashes have been observed. Target S-1153 blood levels were maintained at 8 and 12 hours dosing intervals. In patients who received S-1153 for 28 days (N = 25), all but two had received > 6 month of NRTIs, four had failed PIs and ten were taking NRTIs while on study. Only one patient had an undetectable viral load < 200 copies/ml (Amplicor HIV-1 PCR) on entry, 11 patients had > 10,000 copies/ml. In these 11 patients, the average decrease in viral load was > 1.74 log10, (range 0.74-2.6) Viral load levels became undetectable in 12 of 25 patients while receiving S-1153. The average rise in CD4+ cells was 122 cells/ml in these 25 patients.
CONCLUSIONS: S-1153 administered either twice or thrice daily is well-tolerated, achieves therapeutic plasma levels, and demonstrates potent antiviral activity even in antiretroviral experienced patients.
