Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study.

BACKGROUND: In both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0-∞, AUC0-t, and Cmax. METHODS: In this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child-Pugh A) and eight with moderate liver impairment (Child-Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography-mass spectrometry method was used to determine PFD plasma concentrations. RESULTS: The exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child-Pugh A and Child-Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child-Pugh B and Child-Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. CONCLUSION: The pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

Bioequivalence Assessment of an Oral Fixed-Dose Formulation of Dutasteride-Tamsulosin 0.5 mg/0.4 mg: A Randomized, Single-Blind, Single-Dose, 2-Period Crossover Study in Mexican Population Under Fasted Conditions.

The aim of the present study was to compare the bioavailability and to demonstrate the bioequivalence between a dutasteride-tamsulosin 0.5 mg/0.4 mg capsule formulation and the regulatory reference drug (Combodart®, GlaxoSmithKline). A randomized, single-blind, single-dose, 2-way crossover study under fasting conditions, with at least a 28-day washout period was carried out in healthy volunteers. Plasma concentrations of drugs were determined by high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic analysis included maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC) from time 0 to 72 hours, and AUC from baseline to infinity. The test formulation was considered bioequivalent if the geometric mean ratios (test/reference) were within the predetermined range of 80% to 125%. Safety and tolerability were evaluated by clinical assessment. The confidence intervals for the log-transformed test/reference ratios for dutasteride, Cmax (95.4-109.2) and AUC from baseline to 72 hours (93.2-109.1), and for tamsulosin, Cmax (101.9-119.8), AUC from baseline to the last quantifiable concentration (91.4-106.3) and AUC from baseline to infinity (90.9-103.3), were within the allowed limit specified by the regulatory authorities (80%-125%). In addition, both test and reference drugs were safe and tolerated. These results demonstrated the bioequivalence of test product (Dakart®) compared with Combodart®.

Bioavailability assessment of fexofenadine and montelukast in a fixed-dose combination tablet versus the components administered simultaneously

Introduction and Objectives: Allergic rhinitis is a condition with high global prevalence most effectively treated with antihistamines and antileukotrienes. This study aimed to evaluate the bioequivalence of fexofenadine and montelukast in a fixed-dose combination tablet versus the components administered simultaneously. Materials and Methods: An open, randomized, 2×2 crossover study was performed in 78 healthy volunteers. Fexofenadine–montelukast tablets containing 120 mg and 10 mg, respectively, were used as the test treatment, and 120 mg fexofenadine tablets and 10 mg montelukast tablets were used as the reference treatment. Concentrations of fexofenadine and montelukast in plasma were determined by protein precipitation and analysis by liquid chromatography/mass spectrometry or liquid chromatography tandem mass spectrometry. Results: The 90% confidence intervals (CIs) obtained for fexofenadine were 87.612–102.144 for area under the curve of the plasma concentration after administration to the last concentration (AUC0-t), 88.471–102.282 for the AUC of the plasma concentration extrapolated to infinity (AUC0–∞), and 91.413–108.544 for the maximum plasma concentration (Cmax). For montelukast, they were 96.418–108.416 for AUC0-t, 93.273–106.642 for AUC0-∞ and 94.749–110.178 for Cmax. The ratio and CIs of the values subjected to logarithmic transformation for each parameter were within the range of acceptability of 80%–125%, demonstrating the bioequivalence of the combined fixed-dose tablet to the components administered separately at the same doses. No adverse events were recorded during the study. Conclusions: This study has shown the bioequivalence of the combined fixed-dose tablet, which may be considered a new alternative for the treatment of allergic rhinitis (AU)

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.

A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers.

BACKGROUND: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. METHODS: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. RESULTS: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. CONCLUSION: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.

Application of Genomic Technologies in Clinical Pharmacology Research.

Technology is the basis of scientific progress and is an essential component for continued competitiveness in industry. The development of a new drug candidate is a long and expensive process, in which a molecule undergoes several stages of research (both pre-clinical and clinical) before being approved for commercialization. Scientific progress has revolutionized the pharmaceutical industry and reshaped the processes by which new drugs are discovered, investigated, and developed. Currently, the influence of genomic variations in drug metabolism must be better understood to predict an individual´s response to a given treatment. Employing genomics tools, an individual's genetic profile may be obtained and used as the basis for prescription of the best treatment option, thus personalizing medicine. In this review, we discuss how current mainstream genomic technologies used in clinical pharmacology research can accelerate the identification of populations that can benefit the most while reducing adverse events.

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.

Bioequivalence of single 100-mg doses of two oral formulations of topiramate: an open-label, randomized-sequence, two-period crossover study in healthy adult male Mexican volunteers.

BACKGROUND: The proprietary form of topiramate is indicated in Mexico as an antiepileptic agent and in the prophylaxis of migraine headaches. However, before generic topiramate is placed on the market, pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed. OBJECTIVE: The aim of this study was to compare the bioequivalence and tolerability of a generic (test) and a branded (reference) formulation of topiramate 100 mg in healthy Mexican volunteers. METHODS: This open-label, randomized-sequence, 2-period crossover study was conducted at Ipharma SA de CV, Monterrey, Mexico. Eligible subjects were healthy male Mexican volunteers aged 18 to 45 years. Participants were randomly assigned to receive 100 mg of the test or reference formulation, followed by a 3-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(max), AUC(0-t), and AUC(0-infinity), blood samples were obtained over a 144-hour period after dosing. The formulations were to be considered bioequivalent if calculations of a 90% CI for the ratio of the means of the measures for the test and reference formulations fell within bioequivalence limits, 80% to 125%, for logarithmic (log) transformation of C(max) and AUC, and if two 1-sided t tests showed P < 0.05. Tolerability was assessed using vital sign measurement (blood pressure, body temperature, heart rate, and respiratory rate), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview. RESULTS: Twenty-eight men (mean age, 22.21 years [range, 18-28 years]; mean weight, 75.04 kg [range, 62-96 kg]; mean height, 177 cm [range, 163-192 cm]) were enrolled in this study, and 28 (14 each randomized to receive the test or reference formulation first) completed it. No period or sequence effects were observed. The 90% CIs for the log-transformed C(max), AUC(0-t) and AUC(0-infinity) were 94.70 to 112.05, 98.88 to 105.16, and 98.80 to 105.28, respectively (all, P < 0.05). No adverse events were reported by the volunteers or found on clinical laboratory testing during the study. CONCLUSIONS: This study did not find any statistically significant differences in C(max) or AUC values between the test and reference formulations of oral topiramate 100 mg in this population of healthy adult male Mexican volunteers. On that basis, and according to both the rate and extent of absorption, the test and reference formulations met the regulatory criteria for bioequivalence. Both formulations were well tolerated.

Evaluation of the bioequivalence of single 100-mg doses of two oral formulations of cyclosporin A microemulsion: a randomized, open-label, two-period crossover study in healthy adult male Mexican volunteers.

BACKGROUND: Cyclosporin A is widely used in Mexico as immunosuppressive therapy in organ transplantation and in the treatment of autoimmune disorders. Although several generic oral formulations of cyclosporin A are available in Mexico, information concerning the bioequivalence of these formulations in the Mexican population is not available in the published literature. OBJECTIVE: The aim of this study was to compare the bioequivalence and tolerability of a generic (test) and a branded (reference) soft-gelatin capsule formulation of cyclosporin A microemulsion 100 mg available in Mexico. METHODS: This randomized, open-label, 2-period cross-over study was performed at the Universidad Autónomade Nuevo León, Monterrey, México. Eligible subjects were healthy male volunteers who were randomly assigned to receive a single 100-mg dose of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(max), AUC(0-t), and AUC(0-infinity) , blood samples were obtained at intervals over the 48-hour period after dosing. The formulations were considered bioequivalent if the log-transformed ratios of Cma x and AUC were within the predetermined equivalence range (80%-125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events. RESULTS: Thirty-six male subjects (mean age, 22.08 years [range, 18-29 years]; mean weight, 78.23 kg [range, 72-89 kg]; mean height, 177 cm [range, 169-185 cm]) were enrolled in the study, and 34 (17 each randomized to receive the test or reference formulation first) completed it. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity) were 85.12 to 92.85, 92.14 to 99.75, and 92.19 to 99.72, respectively (all, P <0.05). Similar results were found for the data without log-transformation. No adverse events occurred or were reported by patients during the study. CONCLUSIONS: In this small study in healthy adult male Mexican volunteers, a single 100-mg dose of the test formulation was bioequivalent to a single 100-mg dose of the reference formulation based on the regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Bioavailability of two oral formulations of loratadine 20 mg with concomitant ketoconazole: an open-label, randomized, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Loratadine is a long-acting antihistamine with selective peripheral histamine H(1)-receptor antagonistic activity and fewer sedative effects compared with conventional antihistamines, and is widely used in Mexico. Although several generic formulations of loratadine are available in Mexico, based on a literature search, information concerning the bioavailability of each formulation in the Mexican population is not available. OBJECTIVE: The aim of this study was to compare the bioavailability and tolerability of 2 oral formulations of loratadine 20 mg (two 10-mg tablets) used in Mexico: Sensibit (test formulation; Laboratorios Liomont S.A. de C.V., Mexico City, Mexico) and Clarityne (reference formulation; Schering-Plough S.A. de C.V., Mexico City, Mexico) in healthy volunteers. METHODS: This open-label, randomized, 2-period crossover study was conducted at Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico. Eligible subjects were healthy male Mexican volunteers aged > or=18 years. Subjects were randomly assigned to receive a single 20-mg dose (two 10-mg tablets) of the test or reference formulation, followed by a 2-week washout period, followed by the same dose of the alternate formulation. A 400-mg dose of ketoconazole (2 doses in 24 hours) was administered to each subject before the administration of each formulation, and a 200-mg dose of ketoconazole was given together with each formulation (ie, a total of 600 mg of ketoconazole was administered). Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C(maX), AUC(0-t), and AUC(0-infinity), blood samples were drawn at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 5, 8, 12, 16, and 22 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of C(maX) and AUC were within the predetermined equivalence range of 80% to 125%. Tolerability was assessed by monitoring vital signs and subject interview regarding the potential presence of adverse events (AEs). RESULTS: Thirty-two subjects were enrolled in the study (mean age, 22 years [range, 18-28 years]; mean weight, 68.9 kg [range, 58-79 kg]; mean height, 170.8 cm [range, 158-183 cm]). Sixteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of CmaX, AUC(0-t), and AUC(0-infinity) were 81.43% to 106.01%, 83.12% to 100.23%, and 84.06% to 101.10% (all, P < 0.05), meeting the predetermined criteria for bioequivalence. Similar results were found for data without a logarithmic transformation. No AEs were reported throughout the study. CONCLUSIONS: In this small study in healthy Mexican volunteers, a single, 20-mg dose of the test formulation of loratadine was found to be bioequivalent to that of the reference formulation based on the rate and extent of absorption when concomitantly administered with ketoconazole. Both formulations were well tolerated.

Bioavailability of two oral formulations of azithromycin 500 mg: a randomized, open-label, two-period crossover comparison in healthy Mexican adult subjects.

BACKGROUND: Azithromycin is related to erythromycin but is more active against gram-negative bacteria and less active against streptococci and staphylococci compared with erythromycin. For these reasons, and because of convenience of dosing (QD for 3 days), azithromycin is widely used in Mexico. Although several generic formulations of azithromycin are available in Mexico, information concerning the bioavailability of each formulation in the Mexican population is not available. OBJECTIVE: The aim of this study was to compare the bioavailability and tolerability of 2 oral formulations of azithromycin 500 mg used in Mexico: Macrozit (trademark of Laboratorios Liomont, S.A. de C.V., Mexico City, Mexico; test formulation) and Azitrocin (trademark of Pfizer, S.A. de C.V., Mexico City, Mexico; reference formulation). METHODS: This 2 x 2, crossover, randomized, open-label study was conducted at the Department of Pharmacology and Toxicology, Universidad Autóma de Nuevo Leon, Monterrey, Mexico. Eligible subjects were healthy volunteers of either sex and with the following characteristics: age > or =19 to 25 years, weight 54 to 77 kg, and height 159 to 177 cm. Subjects were randomly assigned to receive Macrozit followed by Azitrocin, or vice versa, with a 3-week washout period between doses. After a 12-hour (overnight) fast, subjects received a single, 500-mg dose of each formulation. For analysis of pharmacokinetic properties, including C(max), AUC(0-t), and AUC(0-infinity), blood samples were drawn at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 12, 24, 48, 72, 96, and 120 hours after dosing. The formulations were considered bioequivalent if the logarithm (ln)-transformed ratios of C(max) and AUC were within the predetermined equivalence range of 80% to 125% and if P < or = 0.05 for the 90% CIs. Tolerability was assessed by monitoring and subject interview regarding the potential presence of adverse events (AEs). RESULTS: Twenty-eight subjects were enrolled in the study; 27 completed it (14 men, 13 women; mean age, 21.7 years). Fourteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of C(max), AUC(0-t), and AUC(0-infinity) were 80.67 to 107.21, 91.39 to 107.59, and 90.61 to 106.19 (all, P < 0.05). Similar results were found for data without a logarithmic transformation. No AEs were found throughout the study. CONCLUSIONS: In this small study in healthy Mexican volunteers, a single, 500-mg dose of Macrozit was found to be bioequivalent to that of Azitrocin based on the rate and extent of absorption. Both formulations were well tolerated.