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.

The Bioequivalence Study of Two Dexketoprofen 25 mg Film-Coated Tablet Formulations in Healthy Males Under Fasting Conditions.

Objectives: Dexketoprofen is a non-steroidal analgesic/anti-inflammatory drug and its trometamol salt is extensively preferred in mild or moderate pain due to its rapid onset of relief. A new formulation of 36.9 mg of dexketoprofen trometamol (equivalent to 25 mg dexketoprofen) tablet has been developed and its bioequivalence to the reference product was proven. Materials and Methods: An open-label, single-dose, randomized, two-period, and cross-over bioequivalence study was conducted with healthy males under fasting conditions for two different tablet formulations of 25 mg dexketoprofen. To prove the bioequivalence of the test product with the reference product, a comparison study has been performed in compliance with regulations in force under Good Clinical Practice principles. A single-center clinical study was run and blood samples of the participants were withdrawn at specified time points, before and after dosing, to measure the plasma concentrations of dexketoprofen trometamol. A validated analytical method has been developed using an liquid chromatography with tandem mass spectrometry. Instrument to assess the plasma concentrations of the test and reference products. Results: Forty-seven volunteers completed clinical phase of the study. For the test and reference products, the mean ± standard deviations (SD) of Cmax were found 2543.82 ± 655.42 ng/mL and 2539.11 ± 662.57 ng/mL, and the mean ± SD of area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-tlast) were found 3483.49 ± 574.42 h.ng/mL and 3560.75 ± 661.83 h.ng/mL, respectively. The primary target variables data demonstrate the bioequivalence of test and reference products with regard to 90% confidence interval for Cmax of 92.45-108.53% and for AUC0-tlast of 95.57-100.87%. The geometric mean ratios were found as 100.16% and 98.18% for Cmax and AUC0-tlast, respectively. There were no serious adverse events or adverse reactions reported throughout the study. Conclusion: After statistical evaluation of the analytical results, the test and reference products were considered bioequivalent. Both products were well tolerated and considered as safe.

A Study to Compare Bioequivalence Approach Between FDA and EMA in a Highly Variable Drug: Pinaverium Bromide Film Tablets.

The aim of this study is to investigate pharmacokinetic parameters of test and reference film tablet formulations of a highly variable drug, pinaverium bromide, under fasting conditions and to assess their bioequivalence in accordance with the FDA and EMA criteria. A randomised open-label, single oral dose, three-sequence, three-period, semi-replicated, cross-over trial was conducted with 36 healthy subjects. The intrasubject variability of reference products for Cmax and AUC0-tlast was found to be more than 50%. While bioequivalence was proven according to the FDA reference scaled average bioequivalence approach with only 36 subjects, more than 200 subjects are required to demonstrate bioequivalence in accordance with the EMA bioequivalence guideline. It is believed that the EMA bioequivalence criteria are too stringent for highly variable drugs whose intrasubject variability are more than 30% for both Cmax and AUC0-tlast and that in consequence the EMA ought to revise their bioequivalence guidelines for such drugs in the future.

Bioequivalence study of two favipiravir tablet formulations in healthy male subjects.

OBJECTIVE: The global pandemic called COVID-19 has dragged the world into a healthcare crisis, and favipiravir is one of the most prescribed agents against the virus so far. Favipiravir is a repurposed antiviral agent in treatment of SARS-CoV-2 infection, and to meet the current need, pharmaceutical companies are working for manufacturing licensed generic favipiravir. For getting the marketing authorization, the bioequivalence of the generic product must be proven first. The aim of this study is to demonstrate the bioequivalence of a new favipiravir tablet formulation as compared to the reference tablet formulation in healthy male subjects under fasting conditions. MATERIALS AND METHODS: To prove the bioequivalence, a randomized, single oral dose, cross-over, two-period study was carried out in 30 healthy subjects under fasting conditions. Plasma favipiravir levels were quantified by using an in-house-developed high performance liquid chromatography with mass spectrometry detector (LC-MSD) method. RESULTS: The 90% CIs for the test/reference geometric mean ratios of the Cmax and AUC0-tlast were 88.02 - 103.11% and 98.19 - 102.06%, respectively. CONCLUSION: This single-dose study has shown that the test and reference favipiravir products met the required bioequivalence criteria. Besides, both products were well tolerated and safe.

Determination of albendazole sulfoxide in human plasma by using liquid chromatography-tandem mass spectrometry.

A rapid, simple and sensitive method was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for determination of albendazole sulfoxide (ABZOX) in human plasma. The plasma samples were extracted by protein precipitation using albendazole sulfoxide-d3 as internal standard (IS). The chromatographic separation was performed on Waters Xbridge C18Column (100×4.6mm, 3.5µm) with a mobile phase consisting of ammonia solution, water and methanol at a flow rate of 0.70mL/min. ABZOX was detected and identified by mass spectrometry with electrospray ionization (ESI) in positive ion and multiple-reaction monitoring (MRM) mode. The method was linear in the range of 3-1500ng/mL for ABZOX. This method was successfully applied to the bioequivalence study in human plasma samples.