Evaluation of Pharmacokinetics of a BCS Class III Drug with Two Different Study Designs: Tenofovir Alafenamide Monofumarate Film-coated Tablet.

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25 mg Film Tablet", which contains 25 mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.

Fabric phase sorptive extraction combined with high-performance liquid chromatography-photodiode array detection for the determination of tazarotene in gel dosage forms.

Tazarotene, a member of the acetylenic class of retinoids, is a third-generation prescription topical retinoid sold as a cream, gel, or foam. In its gel or cream formulations, tazarotene is at a concentration of either 0.1 % or 0.05 %. Fabric phase sorptive extraction membranes are used to selectively isolate and preconcentrate target analytes from different sample matrices. In this study, the tazarotene gel formulation was directly applied to fabric phase sorptive extraction membranes and extracted through a mixture of acetonitrile and water (80:20, v/v) to obtain a clean product free of colloidal suspension of tazarotene gel formulation. The final solutions were injected into an HPLC system equipped with a Zorbax 5 µm Phenyl-Hexyl LC Column (250 × 4.6 mm). Injection volume was 50 µL and UV detection was performed at 326 nm. The flow rate was 1.0 mL min-1 while using an isocratic elution with a mixture of ammonium acetate (50 mM) and methanol (15:85, v/v) as the mobile phase. The method was validated according to ICH guideline Q2 (R1) and successfully applied to gel formulations including 0.01 % tazarotene. This is the first reported application of fabric phase sorptive extraction in the analyses of gel formulations. The capability of fabric phase sorptive extraction membranes to clean up the sample matrix and prepare active pharmaceutical ingredients to be analyzed with acceptable recovery (>98.0 %) and reproducibility may encourage quality control laboratories to use fabric phase sorptive extraction in routine applications.