Pharmacogenetics of amfepramone in healthy Mexican subjects reveals potential markers for tailoring pharmacotherapy of obesity: results of a randomised trial.

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1-rs1045642 and CYP3A4-rs2242480, had a significant effect on AFP pharmacokinetics (P < 0.05) and were the predictor factors in a log-linear regression model. The ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1-rs1045642 and CYP3A4-rs2242480 may partially explain the AFP pharmacokinetic variability.

Isotretinoin conundrum: a randomized, openlabel, crossover study in Mexico to evaluate the bioavailability and bioequivalence of three pharmaceutical preparations of isotretinoin in healthy participants.

OBJECTIVE: The oral retinoid agent isotretinoin (13-cis-retinoic acid) is approved for the treatment of severe recalcitrant cystic acne. For registrational renewal of Oratane® in Mexico (isotretinoin; Laboratorios Dermatologicos Darier S.A. de C.V., Mexico), it was necessary to establish bioequivalence to the reference product Roaccutan® (Isotretinoin; Roche, Mannheim, Germany). Three prior studies failed to establish the bioequivalence of Oratane to Mexican-sourced Roaccutan. However, 13 studies demonstrated the bioequivalence of Oratane to Roaccutane® from multiple sources. This study compared the bioavailability of Oratane with that of Mexicansourced Roaccutan and Australian-sourced Roaccutane. METHODS: Study participants received each of the three agents in a randomized, open-label, 6-sequence, 3-way crossover study with a 2-week washout period between treatments. RESULTS: Pharmacokinetic analysis revealed that peak plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 (dosing) to infinite time (AUC0-∞) were lower for Roaccutan than for Roaccutane and Oratane (Cmax: 1,023.35, 1,223.08, and 1,224.25 ng/mL, respectively; AUC0-∞: 13,653.65, 15,681.35 and 15,733.55 ng/mL x h, respectively). The 90% CIs (test/reference) for the ratios of the geometric means indicated that Oratane was bioequivalent to Roaccutane but not to Roaccutan. In addition, Roaccutane (R2) was not bioequivalent to Roaccutan (R1; R1/R2 90% CIs: Cmax, 76.12 - 91.04; AUC0-t, 82.19 - 91.13; AUC0-∞, 82.94 - 91.57). CONCLUSION: Oratane and Australian-sourced Roaccutane could be considered bioequivalent, but neither formulation was found to be bioequivalent to Mexican-sourced Roaccutan.