Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form.

Ibuprofen is a widely used and well-tolerated analgesic and antipyretic. It is desirable to have a formulation with a rapid rate of absorption because it is required for rapid pain relief and temperature reduction. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption. The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. This study was a phase-1 clinical study, open-label, randomized and two-way crossover with one-week washout period comparing the absorption profile of equal dose of ibuprofen administered rectally in two treatment phases: ibuprofen suppository and enema. Blood samples were collected post dose for pharmacokinetic analyses. Tmax was analyzed using a Wilcoxon matched paired test. A standard ANOVA model, appropriate for bioequivalence studies was used and ratios of 90% confidence intervals were calculated. This study showed that Tmax for ibuprofen enema was less than half that of ibuprofen suppository (median 40 min vs. 90 min, respectively; p-value=0.0003). Cmax and AUC0-12 for ibuprofen enema were bioequivalent to ibuprofen suppository, as the ratio of test/reference=104.52%, 90% CI 93.41-116.95% and the ratio of test/reference=98.12%, 90%CI 93.34-103.16%, respectively, which fell within 80-125% bioequivalence limit. The overall extent of absorption was similar to the both, which were all well tolerated. In terms of Tmax, Ibuprofen enema was absorbed twice as quickly as from ibuprofen suppository. Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefit.

A bioequivalence study of two telmisartan 80 mg tablets in healthy Indonesian subjects: an open label, three-way, three-period, partial replicate crossover study.

Telmisartan is highly variable drug indicated for treatment of hypertension. This study aimed to compare the bioavailability of two 80 mg telmisartan tablets in healthy Indonesian subjects. A randomized, open-label, single-dose, three-sequence, three-way, reference-formulation-replicated crossover study was conducted under fasting period with two-week washout period. In this study, 31 Indonesian subjects were enrolled and 28 subjects were completed the study. Serial blood samples were collected up to 72 h following drug administration. Plasma concentrations of telmisartan were determined using high-performance liquid chromatography method with fluorescence detector. The pharmacokinetic parameters of AUC0- t , AUC0-∞, and C max were assessed for bioequivalence. Bioequivalence acceptance was based on predefined criteria of 90% confidence interval (CI) of 80.00-125.00% for AUC parameters and reference-scaled-average bioequivalence of 71.73-139.42% for C max. The 90% CI for AUC0- t , AUC0-∞, and C max was 96.11-107.25%, 93.06-104.36%, and 94.23-127.01%, respectively. These results indicated that the two formulations of telmisartan were bioequivalent.

Efficacy and tolerability of a nutraceutical combination of red yeast rice, guggulipid, and chromium picolinate evaluated in a randomized, placebo-controlled, double-blind study.

Hypercholesterolemia is the major risk factor in the development of coronary heart disease. Coronary heart disease is a leading cause of morbidity and mortality in many countries worldwide. An increasing attention is now paid to nutraceuticals development for prevention and cure of dyslipidemia, especially for patients who do not wish to use chemical statins. The cholesterol lowering effect and the tolerability of NutraforChol®, a nutraceutical product containing red yeast rice extract, guggulipid extract and chromium picolinate, was evaluated on subjects who had total cholesterol level 200-239 mg/dL and LDL cholesterol level 100-159 mg/dL. In this study, a randomized, placebo-controlled, double-blind study which consisted of 4 weeks run-in period and 8 weeks treatment period was performed. Based on the study results, NutraforChol® effectively decreased total cholesterol (-15.9 %) and LDL level (-19.9 %) after two weeks consumption. The total cholesterol and LDL reduction were maintained during 8 weeks study period. At study termination (week 8), there was a significant difference between total cholesterol level of NutraforChol® treated group (173.5 ± 21.7 mg/dL) and placebo-treated group (204.5 ± 22.8 mg/dL) (p < 0.05). In addition, there was a significant difference between LDL level at week 8 in NutraforChol® group (115.5 ± 22.2 mg/dL) and placebo-treated group (145.1 ± 23.7 mg/dL) (p < 0.05). The tolerability of NutraforChol® was also evaluated. There were no significant changes (p > 0.05) on renal and liver function parameters between baseline and study termination. Thus, NutraforChol® may be considered as a complementary or alternative safe nutraceuticals for the treatment of mild dyslipidemic subjects.

Bioequivalence of two memantine tablet formulations in healthy Indonesian subjects.

AIM: To compare the bioequivalence of two 10-mg memantine tablet formulations. MATERIALS AND METHODS: 19 subjects were included in this single-dose, open-label, randomized, two-way crossover study following an overnight fast. A 5-week washout period was applied. Blood samples were collected up to 72 hours following drug administrations. Plasma memantine concentrations were determined by LC-MS/MS. The pharmacokinetic parameters AUC0-72h and Cmax were calculated and used for bioequivalence evaluation after log-transformation. RESULTS: The point estimates and 90% confidence intervals for AUC0-72h and CCmax for memantine were 100.72% (97.43 - 104.13%) and 101.46% (97.15 - 105.96%), respectively. CONCLUSION: These results indicated that the two formulations of memantine were bioequivalent; therefore, they may be prescribed interchangeably.

Study on bioequivalence of beraprost in healthy volunteers by liquid chromatography with tandem mass spectrometry.

Beraprost sodium is an oral prostacyclin analog that was first approved in 1992 (Japan) for the treatment of peripheral vascular disorders. It is administered orally as a tablet available in strength 20 µg. In this paper, we described a liquid chromatography tandem mass spectrometry method that was developed for the quantification of beraprost in human plasma with high sensitivity at picogram per milliliter concentration. The method had been validated in terms of selectivity, sensitivity, accuracy and precision, matrix effect, linearity, recovery and carry-over according to the Guideline on Bioanalytical Validation from the European Medicines Agency. The standard calibration curve for beraprost was 9.5-1419 pg/mL. This method has been applied successfully to a bioequivalence study with 60 µg of beraprost (three tablets) in 29 healthy volunteers. The results showed that the two formulations of beraprost are bioequivalent.

In-vitro Equilibrium Phosphate Binding Study of Sevelamer Carbonate by UV-Vis Spectrophotometry.

Sevelamer carbonate is a cross-linked polymeric amine; it is the active ingredient in Renvela® tablets. US FDA provides recommendation for demonstrating bioequivalence for the development of a generic product of sevelamer carbonte using in-vitro equilibrium binding study. A simple UV-vis spectrophotometry method was developed and validated for quantification of free phosphate to determine the binding parameter constant of sevelamer. The method validation demonstrated the specificity, limit of quantification, accuracy and precision of measurements. The validated method has been successfully used to analyze samples in in-vitro equilibrium binding study for demonstrating bioequivalence.

Impact of Truncated Area on Point Estimate and Intra-Subject Variability in Bioequivalence of Dutasteride with Long Half-Life.

PURPOSE: To investigate the effect of using truncated area under the curve (AUC0-72) on bioequivalence of dutasteride with long half-life in point estimate and intra-subject variability. METHODS: Fifteen subjects were enrolled in this single-dose, open-label, randomized two-way crossover design following an overnight fasting with five-week washout period. Plasma samples were collected to 72 h and 144 h following drug administration and dutasteride were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The pharmacokinetic parameters for bioequivalence assessment were AUC0-72 and AUC0-144. RESULTS: The estimated point and the 90% confidence intervals were 91.07% (84.54-98.11%) for AUC0-72 and 91.43% (84.65-98.75%) for AUC0-144, that is, within the ranges for acceptance of bioequivalence. The intra-subject variability's were 11.45% for AUC0-72 and 11.87% for AUC0-144. CONCLUSIONS: There was no statistically significant difference in point estimated and intra-subject variability between truncated AUC at 72 h and 144=h and the truncated AUC (AUC0-72) approach could be considered for bioequivalence assessment for dutasteride.

A bioequivalence study of quetiapine 25 mg film-coated tablets in healthy Indonesian subjects
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AIM: This study was conducted in order to compare the bioavailability of two film-coated tablets containing 25 mg of quetiapine. METHODS: 24 subjects were enrolled in and completed a single-center, randomized, single-dose, open-label, two-way crossover study with a 1-week washout period. Plasma samples were collected up to 24 hours following drug administration; thus, quetiapine was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with turbo-ion-spray mode. The pharmacokinetic parameters used for bioequivalence assessment were AUC0-t, AUC0-∞, and Cmax. The 90% confidence intervals were obtained by analysis of variance for AUC0-t, AUC0-∞, and Cmax. RESULTS: The results were all within the range of 80.00 - 125.00%. CONCLUSION: Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.
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Bioequivalence study of two rosuvastatin tablet formulations in healthy Indonesian subjects.

AIM: To compare the bioavailability of two 40-mg Rosuvastatin tablet formulations. METHODS: 24 subjects were included in this single-dose, open-label, randomized, two-way crossover study following an overnight fast. A 2-week wash out period was applied. Blood samples were drawn up to 72 hours following drug administrations. Rosuvastatin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry method with TurboIon-Spray mode. Pharmacokinetic parameters AUC(0-t), AUC(0-∞), and Cmax were determined and used for bioequivalence evaluation after log-transformation, whereas tmax ratios were evaluated nonparametrically. RESULTS: The estimated point and 90% confidence intervals (CI) for AUC(0-t), AUC(0-∞), and C(max) for rosuvastatin were 95.21% (87.56 - 103.53%), 95.76% (88.01 - 104.18%), and 99.33% (89.37 - 110.41%), respectively. CONCLUSION: These results indicated that the two formulations of rosuvastatin were bioequivalent; therefore, they may be prescribed interchangeably.

A bioequivalence study of two tamsulosin sustained-release tablets in Indonesian healthy volunteers.

The bioavailability of two 0.4 mg tamsulosin sustained-release film-coated tablet formulations was compared; using generic tablets (Prostam(®)) as test formulation and the originator product as reference formulation. Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover design following an overnight fasting. A one-week wash-out period was applied. Blood samples were drawn up to 72 h following drug administration. Plasma concentration of tamsulosin was determined by liquid chromatography-tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC(0-t,) AUC(0-∞), C (max) and t (½) were determined and used for bioequivalence evaluation after log-transformation, whereas t (max) ratios were evaluated non-parametrically. The estimated point and 90% confidence intervals (CI) for AUC(0-t,) AUC(0-∞), C (max) and t (½) were 109.55% (96.41-124.49%), 109.94% (96.85-124.81%), 105.87% (92.88-120.67%) and 100.00% (90.56-110.43%), respectively. These results indicated that the two formulations of tamsulosin were bioequivalent; therefore they may be prescribed interchangeably.

Comparative bioavailability of two irbesartan/hydrochlorothiazide tablet formulations in Indonesian healthy subjects.

AIM: The bioavailability of two 300 mg irbesartan (CAS 138402-11-6)/12.5 mg hydrochlorothiazide (CAS 58-93-5) tablet formulations was compared, using Co-Ir-vell tablets as test formulation and the originator product as reference formulation. METHODS: Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover study following an overnight fasting. A two-week wash-out period was applied. Blood samples were drawn up to 48 h following drug administrations. Irbesartan and hydrochlorothiazide plasma concentrations were determined by liquid chromatography-tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and t were determined and used for bioequivalence evaluation after log-transformation, whereas t max ratios were evaluated non-parametrically. RESULTS: The estimated point and 90% confidence intervals (CI) for AUC(0-t), AUC(0-infinity), Cmax and t for irbesartan were 97.74% (85.40-111.86%), 96.36% (83.25-111.55%), 103.30% (90.65-117.71%), 92.38% (82.68-103.21%) and for hydrochlorothiazide, 106.30% (97.72-115.63%), 106.28% (98.14-115.10%), 108.01% (95.48-122.18%), 105.52% (96.70-115.14%), respectively. CONCLUSION: These results indicated that the two formulations of irbesartan/hydrochlorothiazide were bioequivalent; therefore they may be prescribed interchangeably.

Comparative bioavailability of two dexamethasone tablet formulations in Indonesian healthy volunteers.

AIM: To compare the bioavailability of two dexamethasone (CAS 50-02-2) tablet formulations -- 4 mg Dexmethsone tablets as test formulation and 4 mg tablets of the originator product as reference formulation. METHODS: The study was conducted according to an open-label, randomized two-way crossover design with a one-week washout period. Twenty-four volunteers received a single dose of two tablets of the two different dexamethasone formulations. Blood samples for pharmacokinetic profiling were taken up to 24 h after drug administration in fasting condition. Plasma concentrations of dexamethasone were determined with a validated HPLC method using an ultraviolet detector. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. RESULT: The mean AUC0-t, AUC0-infinity, and Cmax were 501.61 ng x h/ml, 518.88 ng x h/ ml and 98.02 ng/ml, respectively for the test formulation and 507.10 ng x h/ml, 525.20 ng x h/ml and 97.82 ng/ml, respectively, for the reference formulation. The median Tmax, for both formulations was 0.75 h. Plasma elimination half-lives (t1/2) were 3.44 h (test) and 3.38 h (reference). The point estimates and 90% confidence intervals (CI) for AUC0-t, AUC0-infinity and Cmax were 98.92% (94.62-103.41%), 98.80% (94.51-103.28%) and 100.20% (91.43-109.81%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that the two formulations of dexamethasone are bioequivalent and thus may be prescribed interchangeably.

Simultaneous quantification of losartan and active metabolite in human plasma by liquid chromatography-tandem mass spectrometry using irbesartan as internal standard.

A simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method employing electronspray ionization was developed and validated for quantification of losartan and its carboxylic acid metabolite in human plasma using irbesartan as internal standard (IS). Following a simple pretreatment procedure, the analytes were separated using a gradient mobile phase on reverse phase C18 column. Selected reaction monitoring was specific for losartan, losartan acid and irbesartan. The method validation demonstrated the specificity, lower limit of quantification, accuracy and precision of measurements. The assay exhibited a linear dynamic range of 2.0-400 ng/mL for losartan and 1.85-370 ng/mL for losartan acid. A run time of 3.5 min for each sample made it possible to analyze more than 200 samples per day. The validated method has been successfully used to analyze human plasma samples for application in bioavailability/bioequivalence studies.

Comparative bioavailability of two estazolam tablet formulations in Indonesian healthy volunteers.

AIM: To compare the bioavailability of two estazolam (CAS 29975-16-4) tablet formulations (Estalin 2 mg tablets as test formulation and 2 mg tablets of the originator product as reference formulation). METHODS: The study was conducted according to an open label, randomized two-way cross-over design with a two-week washout period. Twenty-four subjects received each of the two estazolam formulations. Blood samples for pharmacokinetic profiling were taken up to 72 h after drug administration in fasting condition. Plasma concentrations of estazolam were determined with a validated HPLC method with ultraviolet detection. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. RESULTS: The mean AUC(0-t), AUC(0-infinity) and Cmax were 2581.38 ng x h/mL, 2934.37 ng x h/mL and 95.25 ng/mL, respectively for the test formulation and 2835.75 ng x h/ mL, 3207.73 ng x h/mL and 99.32 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1 h. The point estimates and 90% confidence Intervals for AUC(0-t), AUC(0-infinity) and Cmax were 91.03% (87.48-94.72%), 91.48% (86.67-96.55%) and 95.90% (92.60-99.31%) respectively, satisfying the bloequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two formulations of estazolam are bioequivalent and, thus, may be prescribed interchangeably.