In vivo Pharmacokinetics and Toxicity of a Novel Hydrophilic Oral Formulation of the Potent Non-Nucleoside Reverse Transcriptase Inhibitor Compound N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443)

 

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Abstract

The thiophene ethyl thiourea (TET) compound N'-[2-(2-thiophene) ethyl]-N'- [2-(5-bromopyridyl)]-thiourea (HI-443) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). The pharmacokinetics of 17 different novel oral formulations of HI-443 were compared in an attempt to identify the most suitable dosage form for clinical use in HIV-infected persons. Plasma concentrations of HI-443 were monitored in mice after administration of the drug using these 17 different formulations at three time points. Two-way ANOVA showed highly significant formulation (p<0.0001), time (p<0.0001) and formulation*time interaction effects (p=0.0003). Planned linear contrasts were performed to identify which formulations showed the highest bioavailability at 10, 30, 60 min and at all time points relative to DMSO alone. A significant positive regression was observed comparing bioavailibility of HI-443 at 10 min and hy-drophilic-lipophilic balance (HLB) values of the formulations (R² = 26%, p<0.0001). The results showed that formulations that were hydrophilic, containing PEG400 and propylene glycol, gave the highest overall drug concentrations over the 60-min time period. The lead oral formulation of HI-443 exhibited a very favorable toxicity profile in BALB/c mice.