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This study aimed to investigate the bioequivalence of 2 formulations of gliclazide modified‐release tablets 60 mg in 48 healthy Caucasian volunteers under fasting conditions. A test product, Gliclazide MR (Ranbaxy Laboratories Limited, now Sun Pharmaceutical Industries, India), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single‐dose, 2‐treatment, 2‐period, 2‐sequence crossover design in a fasted condition with a washout period of 21 days. Blood samples were collected for 96 hours after drug administration. Drug plasma concentrations were determined by a liquid chromatography–tandem mass spectrometry method. Analysis of pharmacokinetic characteristics was based on a noncompartmental model. The logarithmically transformed data of Cmax and AUC were analyzed for 90% confidence intervals using analysis of variance. There was no significant difference in pharmacokinetic characteristics between the products, and the 90% confidence intervals were within the acceptance range of 80.00%–125.00%. The investigated products were bioequivalent under fasted conditions. [ABSTRACT FROM AUTHOR]

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Orlistat is a non-systemic treatment for obesity. The drug inhibits lipase in the gastrointestinal track mainly in the lumen of the stomach and small intestine by binding reversibly with the active site of gastric and pancreatic lipases, preventing the absorption of ∼30-35% of dietary fat. The undigested triglycerides are not absorbed, resulting in a caloric deficit and positive effect in weight control. The objective of this study was to assess the bioequivalence of orlistat administered as a generic and reference capsule formulations using a pharmacodynamic end-point. A total of 60 healthy volunteers followed a 5-day run-in diet period to be accustomed to a low fat diet; subjects were then randomized to receive under fed conditions oral doses of orlistat (60 mg) 3-times daily for 10 days as the generic (Ranbaxy Laboratories) or reference (Alli™, GlaxoSmithKline) capsule formulations. Subjects followed a standardized diet (2500 kcal/day, ∼30% as fat) for the entire study. Feces were collected over the last 2 days of the run-in period (baseline) and over the last 5 days of the two treatment periods. The amount of fat in meals and feces were assayed using the validated FTIR method with a limit of detection of 1.00 g%, respectively. Fecal fat excretion over 24 h (FFE24SS, calculated as the amount of fat excreted in feces adjusted by the amount of fat ingested) was used as a pharmacodynamic end-point to assess the bioequivalence between the two orlistat formulations. An analyses of variance (ANOVA) was performed on the log-transformed FFE24SS parameter to establish bioequivalence of the generic product with respect to the innovator formulation. Mean FFE24SS values at baseline and after repeated oral administrations of the generic and innovator formulations of orlistat were 0.88%, 40.55% and 40.54%, respectively. The ratio of least-squares means (LSM) of FFE24SS of the generic to the innovator formulation was 101.90%, with 90% confidence intervals of 97.94-106.01%. Orlistat was well tolerated by subjects in both periods of study and no serious adverse events were observed during the study. In conclusion, mean FFE24SS values were used as pharmacodynamic end-points to assess bioequivalence between two formulations of orlistat. Results from this study suggest that the test formulation of Orlistat capsule is bioequivalent to the reference marketed Alli™ when administered to healthy volunteers as a multiple dose under fed conditions. [ABSTRACT FROM AUTHOR]

Abstract: A reliable, selective and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of lamotrigine in human plasma using lamotrigine-13C3, d3 as an internal standard. Analyte and internal standard were extracted from human plasma by solid-phase extraction and detected in positive ion mode by tandem mass spectrometry with electrospray ionization (ESI) interface. Chromatographic separation was performed on a Chromolith® SpeedROD; RP-18e column (50−4.6mm i.d.) using acetonitrile: 5±0.1mM ammonium formate solution (90:10, v/v) as the mobile phase at a flow rate of 0.500mL/min. The calibration curves were linear over the range of 5.02–1226.47ng/mL with the lower limit of quantitation validated at 5.02ng/mL. The analytes were found stable in human plasma through three freeze (−20°C)-thaw (ice-cold water bath) cycles and under storage on bench-top in ice-cold water bath for at least 6.8h, and also in the mobile phase at 10°C for at least 57h. The method has shown good reproducibility, as the intra- and inter-day precisions were within 3.0%, while the accuracies were within ±6.0% of nominal values. The validated LC–MS/MS method was applied for the evaluation of pharmacokinetic and bioequivalence parameters of lamotrigine after an oral administration of 50mg lamotrigine tablet to thirty-two healthy adult male volunteers. [Copyright &y& Elsevier]

A rapid, simple, and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the determination of clopidogrel in human plasma was developed and validated using clopidogrel-d4 as the internal standard (IS). The analyte and the IS were extracted from 500 µl aliquots of human plasma via solid phase extraction. The precursor to product ion transitions monitored for clopidogrel and IS were m/z 322.2 → 212.0 and 326.2 → 216.0, respectively. The method was fully validated for sensitivity, accuracy and precision, linearity, recovery, matrix effect, dilution integrity, and stability. The Linearity range was 20.4-10,772.6 pg/mL with mean correlation coefficient ( r) ≥ 0.9977. The back conversion was also evaluated during method validation as per EMA recommendation. Results proved that clopidogrel was accurately and reliably estimated by the method without any evidence of back conversion of clopidogrel acid. The method was successfully applied to a bioequivalence study of 75 mg clopidogrel bisulfate tablet formulation in 32 healthy male volunteers under fasting conditions. The ratios of least-squares means (with 90% confidence intervals) for the pharmacokinetic parameters Cmax, AUC0- t and AUC0-α were 107.98% (94.52-123.35%), 100.25% (91.28-110.09%), and 100.49% (91.37-110.51%), respectively. [ABSTRACT FROM AUTHOR]

Tretinoin belongs to the class of retinoids indicated in induction of remission in acute promyelocytic leukemia (APL-FAB classification AML-M3). It is an endogenous metabolite of Vitamin A and is normally present in human plasma. The objective of the present study was to evaluate the bioequivalence between the Tretinoin 10 mg capsules of Ranbaxy Laboratories Limited and VESANOID® 10 mg capsules of Roche Pharmaceuticals Inc. It was a 2-way cross-over single dose study in 60 adult Indian male volunteers under fasting conditions. Since tretinoin is endogenously present in the human body, for baseline adjustment four pre-dose samples were collected. Plasma samples were analyzed for tretinoin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. This method has separated both isomeric metabolites (i.e. isotretinoin and 9-oxo retinoic acid) from tretinoin to accurately measure the tretinoin concentrations in plasma for this study. The Mean ± SD of pharmacokinetic parameters Tmax, Cmax, and AUC0− t for tretinoin were 2.55 ± 0.84 and 2.40 ± 0.86 h, 34.29 ± 10.45 and 32.77 ± 9.16 ng/ml, 87.28 ± 30.99 and 80.81 ± 24.68 ng.h/ml, respectively, for test and reference. The ratios of least square means and its 90% confidence interval for Cmax, AUC0− t and AUC0-∞ on both baseline corrected and uncorrected data were found to be within 80-125%. [ABSTRACT FROM AUTHOR]

Background: Valsartan is a selective angiotensin II type 1 receptor blocker indicated for the treatment of hypertension. Although the bioavailability and pharmacokinetic properties of valsartan have been well characterized, a literature search did not identify any reports concerning the bioavailability of valsartan in the Indian population. Objective: This study was undertaken to compare the pharmacokinetic properties of 2 branded generic valsartan formulations (tests A and B) with a branded innovator product (reference) in healthy Indian male subjects. Methods: This single-dose, randomized, open-label, 3-period crossover study compared the pharmacokinetic properties of 3 marketed brands of valsartan 160-mg tablets in healthy Indian male volunteers aged 18 to 45 years under fasting conditions. Subjects were assigned to receive, in randomized order, a single oral dose of 1 of 2 test formulations (A or B) or a reference formulation of valsartan 160 mg. Each study period was separated by a 5-day washout period. Blood samples were collected at prespecified times over a period of 24 hours after administration. An HPLC method was used for the estimation of plasma valsartan concentrations. A noncompartmental method was employed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0∓t, AUC0∓∞, and t1/2) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80% to 125%. Tolerability was assessed using physical examination, including vital sign measurement, and direct questioning. Results: The study was conducted in 18 subjects (mean age, 24.8 years; weight, 54.5 kg; and height, 164.67 cm). For test formulation A versus the reference formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0∓t, and AUC0∓∞ were 81.18% to 115.74%, 77.27% to 108.75%, and 79.32% to 108.70%, respectively. For test B versus reference, the corresponding values were 84.69% to 120.73%, 83.72% to 117.84%, and 84.40% to 115.67%. No adverse events were found or reported by subjects throughout the study. Conclusions: In this single-dose study in a small sample of healthy Indian male subjects, test formulation B of valsartan 160 mg was considered bioequivalent to the reference formulation as per predetermined regulatory criteria, whereas test formulation A was not. All 3 formulations were well tolerated. [Copyright &y& Elsevier]

Losartan and in-vivo active metabolite losartan carboxylic acid (LCA) formation into systemic circulation have been poorly characterized in different races. A bioequivalence study was therefore conducted on healthy male Indian volunteers with 50 mg losartan formulation and unique comparative analysis with other population is presented. Non-compartmental pharmacokinetic analysis elucidated metabolite formation ratio (MR) for losartan: LCA [Cmax = 1.30 and AUC = 0.32] of 50 mg losartan was more varying compared to innovator [Cmax = 0.82 and AUC = 0.22] though bioequivalence requirements were met successfully. This variation was less for losartan 100 mg losartan- hydrochlorothiazide formulation in our previous published bioequivalence study. [ABSTRACT FROM AUTHOR]

The aim of this study is to compare the single-dose oral bioavailability of memantine hydrochloride 10 mg tablets of Ranbaxy Laboratories Limited, with NAMENDA™ tablets (containing memantine hydrochloride 10 mg) of Forest Pharmaceuticals Inc. in healthy, adult, human subjects under fasting condition. The study was carried out as 2-way crossover design on 8 subjects in fasting and fed conditions. The plasma samples were obtained over a 72 h post dose in each period. Plasma memantine samples were analyzed by liquid chromatography coupled to tandem mass spectrometry (LCMS/ MS) with positive ion electro spray ionization using multiple reactions monitoring (MRM). A sensitive, reproducible, accurate and validated LCMS/ MS method with limit of quantification (LOQ) 0.200 ng/mL was used to analyze memantine. Ln transformed AUC0-72 and Cmax were assessed for bioequivalence using 90% confidence interval (CI). 90% confidence intervals for the ratio of test and reference (Ratio of least-squares mean) for ln-transformed AUC0-72 and Cmax were within the regulatory acceptance criteria of 80-125%. [ABSTRACT FROM AUTHOR]

A reliable, simple, and robust liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated that employs solid-phase extraction for the simultaneous estimation of amlodipine and valsartan in human K3EDTA plasma using amlodipine-d4 and valsartan-d9 as internal standards. Chromatographic separation of amlodipine and valsartan was achieved on the Luna C18 (2)100A (150 × 4.6 mm, 5 μm) column using acetonitrile: 5 mM ammonium formate solution (80:20, v/v) as the mobile phase at a flow rate of 0.8 mL/min in isocratic mode. Quantification was achieved using an electrospray ion interface operating in positive mode, under multiple reaction monitoring (MRM) conditions. The assay was found to be linear over the range of 0.302-20.725 ng/mL for amlodipine and 6.062-18060.792 ng/mL for valsartan. The method has shown good reproducibility, as intra- and interday precisions were within 10% and accuracies were within 8% of nominal values for both analytes. The method was successfully applied for the bioequivalence study of amlodipine and valsartan after oral administration of a fixed dose of the combination. Additionally, as required by the current regulatory bodies, incurred sample reanalysis was performed and found to be acceptable. [ABSTRACT FROM AUTHOR]

Abstract: Background: Because of the lack of suitable pediatric antiretroviral (ARV) agents, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. Objective: The objective of the present study was to evaluate the bioequivalence of a new pediatric fixed-dose combination (FDC) ARV tablet for oral suspension as compared with individual liquid formulations. Methods: The FDC ARV tablet for oral suspension contained lamivudine 40 mg, nevirapine 70 mg, and stavudine 10 mg. This formulation was compared with 4 mL of lamivudine 10 mg/mL, 7 mL of nevirapine 50 mg/5 mL, and 10 mL of stavudine 1 mg/mL. This was an open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose crossover study in 36 Indian male volunteers under fasting conditions. Blood samples were collected before dosing and at 0.167, 0.25, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours after dosing in each period. Results: The mean (SD) age, weight, and height of the Indian volunteers were 24.78 (5.31) years (range, 18–38 years), 57.06 (8.59) kg (range, 45–77 kg), and 165.14 (5.34) cm (range, 156–176 cm), respectively. The mean (SD) values for Tmax, Cmax, and AUC0-t for the FDC and the individual liquid formulations, respectively, were as follows: lamivudine, 0.71 (0.22) and 0.89 (0.50) hour, 594 (167) and 514 (139) ng/mL, 2382 (617) and 2227 (666) ng /mL per hour; nevirapine, 1.7 (1.1) and 2.5 (1.2) hours, 1248 (275) and 1185 (238) ng/mL, 70,372 (14,869) and 71,278 (17,435) ng/ mL per hour; and stavudine, 0.44 (0.11) and 0.43 (0.11) hour, 348 (82) and 395 (107) ng/mL, and 576 (113) and 631 (142) ng/mL per hour. The ratios and 90% CIs for the least-squares mean Cmax and AUC values were found to be within the prespecified range of 80% to 125% for each component. Conclusion: The FDC pediatric formulation of lamivudine, nevirapine, and stavudine was bioequivalent to the individual liquid formulations in these fasting, healthy Indian men. [Copyright &y& Elsevier]