Pharmacokinetics and bioequivalence of two brands of metformin 500 mg tablets in Iranian healthy volunteers

The aim of this study was to evaluate the pharmacokinetics (PK) and bioequivalence (BE) of two metformin tablets. For in vitro evaluation, weight variation, assay and dissolution tests were performed. A randomized, single dose, two-period, cross over study in healthy male fasting volunteers was designed. A 2-week washout period separated the two periods. For analysis of PK parameters blood sampling was performed before and after drug administration in various time points up to 12 h. Metformin concentration in plasma was determined using a developed high performance liquid chromatography method. Both formulations passed the assay, content uniformity, and dissolution tests acceptance value. PK parameters, representing the rate and the extent of metformin absorption were calculated and analyzed for two formulations. The 90 % CI obtained by analysis of variance for the ratios of C_max, AUC_0–t, and AUC_0–∞ were 92.14–110.95, 92.72–107.37 and 89.42–110.23 % respectively, meeting the criteria for BE (80–125 %). Administration of a single dose of test and reference formulations did not result in statistically significant differences between in vitro and in vivo BE parameters in healthy Iranian male volunteers. Thus in the case of rate and extent of absorption the test and reference formulations were considered bioequivalent.     

Bioequivalence of Torad tablet 5 mg to Torem tablet 5 mg (torasemide 5 mg)

The purpose of the present study was to evaluate the bioequivalence of two torasemide tablets, Torem (Roche Korea Co., Ltd., Korea, reference drug) and Torad (Samchundang Pharmaceutical Co., Ltd., Korea, test drug) tablet, according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty-eight healthy male Korean volunteers, 23.68 ± 1.79 years in age and 67.59 ± 9.87 kg in body weight, were divided into two groups and received each medicine at the torasemide dose of 10 mg in a randomized 2 × 2 crossover study. After a single administration, blood samples were taken at predetermined time intervals and the serum concentrations of torasemide were monitored by an HPLC–UV. The in vitro dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as AUC_t (the area under the serum concentration–time curve from time zero to 12 h), C_max (maximum serum drug concentration), and T_max (time to reach C_max) were calculated, and computer programs (equiv test and K-BE test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed AUC_t and C_max. The results showed that the differences between two formulation based on the reference drug, ?2.84, ?1.22 and 15.91 % for AUC_t, C_max, and T_max, respectively. No significant sequence effect was found for all of the bioavailability parameters indicating that the crossover design was properly performed. The 90 % confidence intervals using logarithmically transformed data were within the acceptance range of log0.80 to log1.25 (e.g., log0.9305?log1.0043 and log0.9422?log1.0903 for AUC_t and C_max, respectively). Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Torad tablet and Torem tablet are bioequivalent.     

Bioequivalence of Samchundang Berastolin tablet to Jeil Berasil tablet (beraprost sodium 20 μg)

Beraprost sodium, sodium (±)-(1R^*,2R^*,3aS^*,8bS^*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S^*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate), an orally absorbable prostacyclin derivative (PGI₂), has marked ischemic symptom treatments like ulcer and pain with chronic arterial occlusion. The purpose of the present study was to evaluate the bioequivalence of two beraprost sodium tablets, Samchundang Berastolin tablet (Samchundang Pharm. Co., Ltd.) and Jeil Berasil tablet (Jeil Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The in vitro release of beraprost from the two beraprost sodium formulations was tested using KP IX Apparatus II method with various dissolution media. Thirty-two healthy Korean male volunteers, 23.44 ± 1.48 years in age and 65.95 ± 8.94 kg in body weight, were divided into two groups and a randomized 2 × 2 crossover study was employed. After single administration, three tablets containing 20 μg as beraprost sodium, blood samples were taken at predetermined time intervals and the concentrations of beraprost in serum were determined using a LC/MS/MS method with multiple reaction-monitoring. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as AUC_t, C_max and T_max were calculated, and computer programs (Equiv Test and K-BE Test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed AUC_t, C_max and un-transformed T_max. The results showed that the differences between two formulations based on the reference drug, Jeil Berasil tablet, were 2.12, 0.15 and 4 % for AUC_t, C_max, and T_max, respectively. There were no sequence effects between two formulations in these parameters. The 90 % confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8–log 1.25 (e.g., log 0.9114–log 1.0912 and log 0.8471–log 1.1253 for AUC_t and C_max, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Samchundang Berastolin tablet was bioequivalent to Jeil Berasil tablet.     

Bioequivalence of a Highly Variable Drug: An Experience with Nadolol

Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard^® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUC_t, AUC, and C_max in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of C_max. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUC_t and AUC. However, C_max criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the C_max of nadolol is only slightly sensitive to absorption rate and the relatively large variability of C_max reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.     

Pharmacokinetics and Bioequivalence of Two Amoxicillin 500 mg Products: Effect of Food on Absorption and Supporting Scientific Justification for Biowaiver

PurposeAims of this study were to compare the bioequivalence of two formulations of amoxicillin 500 mg capsules under fasted and fed conditions in the same set of healthy volunteers, compare pharmacokinetics of amoxicillin under the two conditions and to assess the possibility of predicting in vivo bioequivalence of the two formulations using in vitro dissolution data.MethodThe innovator product of amoxicillin was used as the reference formulation and a test product, which showed in vitro equivalence after a biowaiver study with the same reference product was used in the bioequivalence study. Altogether 16 subjects were randomized to the reference and test products in the fasted study and 12 of them participated in the fed study. Plasma concentration of amoxicillin was analyzed by a validated Liquid chromatography coupled with two mass spectrometry (LC-MS/MS) method. Noncompartmental analysis was used to determine the pharmacokinetic parameters. Average bioequivalence method was used to evaluate the bioequivalence of the two formulations and statistical significance of the pharmacokinetic parameters were tested to study the effect of food on amoxicillin absorption.ResultsThe Geometric Mean Ratio (GMR) for the test/reference product for the maximum drug concentrations (C_max) was 102.77% and 97.38% in fasted and fed conditions respectively which was within 80.00–125.00% range required to demonstrate bioequivalence. The GMR for test/reference products for the area under the curve (AUC_0-8,) was 100.05% and 96.91% in fasted and fed conditions respectively meeting the bioequivalence criteria. For the reference product, the C_max was 9.38 and 7.61 µg x mL⁻¹(p =0.0224), time to reach maximum concentration (T_max) was 1.73 and 3.02 h (p=0.0005) and AUC_0-8 was 26.02 and 25.54 µg/h⁻¹ mL⁻¹ p = 0.672) under fasted and fed conditions respectively.ConclusionThe test and the reference formulations were bioequivalent under both fasted and fed conditions. Although the C_max was significantly lower and T_max was significantly delayed under fed conditions, it did not affect the AUC. Therefore, being a time dependent antibiotic, clinically significant effect of food on efficacy of amoxicillin is unlikely. As the selected products were equivalent in vitro, these findings support scientific justification for conducting in vitro dissolution studies for solid oral amoxicillin products as a surrogate for in vivo bioequivalence studies.     

Comparison of pharmacokinetics of citalopram in healthy Asian Indian and Mexican volunteers

Randomized, two-way crossover, bioequivalence studies were conducted separately in healthy Mexican and Asian Indian volunteers. One tablet either of test or of reference product was administered after 10?h of overnight fasting. After dosing, serial blood samples were collected for a period of 72?h and 168?h, respectively, for both the studies. Plasma samples were analyzed for citalopram by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC_0–t, AUC_0–72, AUC_0–∞, C_max, and T_max were determined from plasma concentration-time profiles for both the test and reference formulation of citalopram 20?mg tablets, and were compared statistically to evaluate bioequivalence between the two brands of citalopram. In both the studies, the analysis of variance (ANOVA) did not show any significant difference between the test and reference formulations and 90% confidence intervals (CI) were lying within the acceptable range for bioequivalence. The test and reference formulations exhibited comparable pharmacokinetics profiles and were bioequivalent, but high values of both C_max (~ 23%) and AUC (~ 34%) were observed in Asian Indian healthy volunteers as compared to the Mexican volunteers. This may be due to the poor metabolism of Citalopram in the Asian population. This difference in the results of pharmacokinetic parameters of Asian Indian and Mexican volunteers may be attributed to ethnic factors.     

Development and bioequivalence study of potassium chloride extended release tablets

The purposes of this study are to prepare the generic extended release tablet of potassium chloride (PC) 600 mg and to compare the absorption of potassium ion from the experimental tablets to that of Kaleorid® LP 600 mg (Leo Pharmaceutical Products, Denmark). Carnauba wax was used as retardant in the matrix core tablets. The core tablets were coated with blends of ethyl cellulose (EC) and hydroxypropyl methyl cellulose (HPMC) to modulate the drug release. Results of a selective two-level, three-factor experiment design revealed that a blend of 41.75% of EC and 58.25% of HPMC at 4.5% weight gained could produce the coated tablets having dissolution profiles similar to those of Kaleorid®. A two-treatment, two-period, two-sequence crossover bioequivalence study was carried out on 24 healthy volunteers to compare the absorption of potassium ion from experimental tablets to that from Kaleorid®. The potassium ion in the urine was measured by a selective electrode of the ADVIA 1650 system (Bayer) and used to calculate cumulative urinary excretion and urinary excretion rate. Results of 90 percent confidence interval analysis showed that the limits for natural log-transformed cumulative urinary potassium excretion (Ln Ae_0-24) of test product were in the range of 3.73–3.79 mEq, corresponding to 99.08%–100.92% of Kaleorid^®, respectively, and the limits for natural log-transformed maximal potassium excretion rate (R_max) of test product were in the range of 1.72–1.82 mEq/h, corresponding to 97.34%–102.66% of reference product, respectively. Both of them fell within the bioequivalence interval (80%–125%) of reference product, proving that experimental product is bioequivalent to Kaleorid^®.     

Formulation and bioequivalence of two valsartan tablets after a single oral administration

The aim of this study is to assess the quality of Valzan^® tablet (160 mg, valsartan immediate release test formulation) by comparing its pharmacokinetic parameters with Diovan^® tablet (160 mg, valsartan reference formulation). Valzan^® tablets were prepared according to a dry granulation method (roll compaction). To assess the bioequivalence of Valzan^® tablets a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy male volunteers. The selected volunteers were divided into two groups of 12 subjects. One group was treated with the reference formulation (Diovan^®) and the other one with the generic Valzan^®, with a cross-over after the drug washout period of 14 days. Blood samples were collected at fixed time intervals and valsartan concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC_0–48, AUC_0–∞, C_max, T_max, K_e and T_1/2 were determined for both the tablets and were compared statistically to evaluate the bioequivalence between the two brands of valsartan, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on this statistical evaluation it was concluded that the test tablets (Valzan^®) is well formulated, since it exhibits pharmacokinetic profile comparable to the reference brand Diovan^®.     

Pharmacokinetics and bioequivalence of low-dose clopidogrel in healthy Chinese volunteers under fasted and fed conditions

Clopidogrel is an antiplatelet drug whose performance at a low dose (25 mg) have not been evaluated in Chinese patients, who may be subject to different effects from Caucasians. We carried out this evaluation and compared a generic (Taijia) and a reference drug (Plavix^®). We evaluated Taijia and Plavix^® in 128 subjects, with 64 in a fasted state and 64 receiving a high-fat diet, and computed C_max, AUC_0-∞, and AUC_0-t. Reference-scaled average bioequivalence (RSABE) methods and average bioequivalence (ABE) methods were used, and adverse events were assessed. Average maximum plasma concentrations (C_max) of clopidogrel were significantly greater after 25 mg dose under fed conditions compared to fasted. Reference-scaled C_max, AUC_0-t, and AUC_0-∞ were higher than the 0.294 cutoff during fasted, meeting RSABE criteria. Under fed conditions, S_WR for AUC_0-t and AUC_0-∞ were lower than 0.294, permitting use of ABE. The 90% confidence intervals for AUC_0-t and AUC_0-∞ indicated bioequivalence. Pharmacokinetic parameters differed between fasted and fed states. The generic product was bioequivalent to the reference drug, and was safe and well tolerated. This suggests that they can be used interchangeably in a clinical setting.     

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

The aim of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios and ratio of geometric means (GMR) of AUC and C_max of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and C_max of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of C_max, AUC_0–t and AUC_0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94) were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70) and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64) were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for C_max). The RSABE approach was successful in evaluating the bioequivalence of these two formulations.KEY WORDS: Reference-scaled average bioequivalence, Agomelatine, 3-Hydroxy-agomelatine, 7-Desmethyl-agomelatine, Chinese subjects, High variability, Generic drug     

Comparative bioavailability study of capecitabine tablets of 500 mg in metastatic breast cancer and colorectal cancer patients under fed condition

Capecitabine (oral prodrug of 5-fluorouracil) is the first-line treatment for the metastatic breast and colorectal cancer. The objective of the study was to determine the bioequivalence between the test product (capecitabine tablets 500?mg) of Dr. Reddy’s Laboratories Limited relative to that of reference product XELODA^® (capecitabine) 500?mg tablets of Roche Registration Inc. in patients of metastatic breast or colorectal cancer stabilized with twice daily dosing of capecitabine monotherapy. This was an open-label, randomized, single dose, two-way cross-over bioequivalence study under fed conditions. The subjects received either of the treatments (test or reference) 30?min after consumption of a high fat, high calorie breakfast as a single morning dose of 2000?mg on two separate days (days 1 and 2) based on their body surface area. Blood samples were collected up to 10?h post-dose and analyzed for capecitabine using the validated liquid chromatographic mass spectrometric (LC-MS/MS) method. The least square mean ratio and 90% confidence intervals of C_max, AUC_0–t and AUC_0–∞ were within the regulatory acceptance criteria of 80.00–125.00% and considered as bioequivalent.     

Lack of bioequivalence of a generic mefloquine tablet with the standard product

Objective: To assess the bioequivalence between a generic tablet of mefloquine (Mephaquin^®?= M1) with the reference tablet (Lariam^®?=?M2) in healthy volunteers. Methods: This open label, randomized two-way cross-over study was performed in a single centre. Following an overnight fast, eighteen healthy volunteers received a single oral dose of 750?mg mefloquine either in the form of three M1 lactabs or three M2 tablets. Serial blood samples were collected up to 8 weeks after drug administration. Plasma samples were analysed for mefloquine and its carboxylic acid metabolite using liquid chromatography and subsequent tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of mefloquine and its metabolite were estimated by non-compartmental methods. Results: The pharmacokinetics of mefloquine after administration of M1 and M2 tablets were significantly different as reflected by the respective mean values of maximum plasma concentration (C_max 656 vs 1018?ng?·?ml^?1), time to reach maximum concentration (t_max 46 vs 13?h) and area under the plasma concentration-time curve (AUC_0→∞ 338 vs 432?μg?·?h?·?ml^?1). No significant differences existed between the elimination half-lives of the two formulations (394 vs 396?h). The relative bioavailability (M1 vs M2) was 0.78 and ranged from 0.38 to 1.37. Bioequivalence could not be demonstrated for log-transformed data of AUC_0→∞ or AUC_0→last within a predefined range of 80–125% and for C_max within a range of 70–143%. Conclusions: The observed differences in C_max, t_max and AUC are consistent with a slower rate and lower extent of mefloquine absorption after administration of M1. Statistical evaluation of these kinetic data showed that the M1 tablet is not bioequivalent to the M2 tablet. Clinical consequences of this finding cannot be excluded.     

Generic sustained release tablets of trimetazidine hydrochloride: Preparation and in vitro–in vivo correlation studies

The aim of the current work was to develop generic sustained-release tablets containing 35 mg trimetazidine dihydrochloride and to establish an in vitro–in vivo correlation that could predict the bioavailability. The marketed sustained release tablet (Vastarel MR) used as reference, a sustained-release matrix tablet was prepared using hydroxypropyl methylcellulose (HPMC) as matrix by wet granulation and the in vitro dissolution profiles of the self-made tablets were determined in four different dissolution media (0.1 M HCl, pH 4.5 PBS, pH 6.8 PBS and water). A higher similarity between prepared tablets and Vastarel MR was established, with similarity factor (f₂) ranging from 60 to 75 in the four media. The in vivo pharmacokinetics was studied in six healthy beagles. Compared with Vastarel MR, the C_max of self-made tablets was slightly decreased, while the T_max and MRT_0–t were slightly prolonged, but with no significant difference (P > 0.05). The average of relative bioavailability (F) was 102.52% based on AUC_0–t. For log-transformed AUC_0–t and C_max, the upper confidence limit on the appropriate criterion is <0, indicating these two formulations were population bioequivalent. The in vivo–in vitro correlation coefficient obtained from point-to-point analysis of self-made tablets was 0.9720. In conclusion, the prepared tablets were bioequivalent to the marketed tablets, according to both the in vitro release rate and extent of absorption, and a good in vivo–in vitro correlation was established for the self-made tablets that indicated in vitro dissolution tests could be used as a surrogate for bioavailability studies.     

Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects

Background and the purpose of the study

The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated.

Methods

The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC_0–72, AUC_0–8, C_max and T_max. Similarity factor, dissolution efficiency (DE), and mean dissolution time (MDT) was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT) or fraction of the drug dissolved (FRD) vs fraction of the drug absorbed (FRA).

Results

Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC_0–8, and C_max of each two formulations in each bioequivalence studies were within the acceptable range of 80–125%. Differences were not observed between the untransformed T_max values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50) did not reflect their in vivo properties.

Major conclusions

Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in-process quality control of amiodarone tablet formulations.     

Comparative bioavailability of josamycin,a macrolide antibiotic,from a tablet and solution and the influence of dissolution on in vivo release

The bioavailability of josamycin from a tablet formulation (2 × Josacine® 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean C_max of 1.64±0.67 mg L⁻¹ attained at a mean t_max of 0.39±0.08 h. The AUC_0–last was 1.510±0.687 mg h L⁻¹. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration–time profiles were obtained from the tablets and C_max values ranged from 0.05 to 0.71 mg L⁻¹ with a t_max range of 0.33–2.0 h. AUC_0–last values ranged from 0.03 to 0.95 mg h L⁻¹. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2–5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration–time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution–pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0. © 1998 John Wiley & Sons, Ltd.     

RELATIVE BIOAVAILABILITY OF FOUR CLOMIPRAMINE HYDROCHLORIDE TABLET PRODUCTS

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2×25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 2×25 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5×10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 5×10 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable C_max were 31·.3 ng mL⁻¹ for the reference and 31·.6 ng mL⁻¹ for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL⁻¹ and 753 ng h mL⁻¹ for the reference and test, respectively. In study 2, the geometric mean C_max values were 25·.8 ng mL⁻¹ and 23·.9 ng mL⁻¹ for the reference and test respectively; the geometric mean AUC values were 569 ng h mL⁻¹ and 547 ng h mL⁻¹. The 90% confidence intervals for the ‘test/reference’ mean ratios of the plasma clomipramine pharmacokinetic variables C_max and AUC_(0–∞) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80–125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil^®) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.     

Pharmacokinetics,bioequivalence and safety of two formulations of ticagrelor in healthy Chinese subjects: Effects of food

Ticagrelor is the first reversible ADP P2Y12 receptor antagonist approved to treat acute coronary syndrome. To investigate the effects of food on the pharmacokinetics (PK), bioequivalence and safety of ticagrelor tablets in healthy Chinese volunteers, 32 healthy subjects were randomly assigned to an open-labelled, single-centre, two-preparation, two-sequence, two-cycle, double-crossover trial under fasting and fed conditions, with a washout period of 7 days. Plasma concentrations of ticagrelor and AR-C124910XX were determined using LC–MS/MS. The C_max, AUC_0–t and AUC_0–∞ of the reference and test tablets were determined using ANOVA and the USFDA bioequivalence statistical criterion of 90% CI for the 80%–125% range (p ≤ 0.05) of the geometric mean ratios. Adverse events (AEs) were observed and recorded. Food consumption increased the AUC_0–t and AUC_0–∞ (p < 0.01) of ticagrelor, lowered the C_max (p < 0.01) and prolonged the t_12z (p < 0.05) of AR-C124910XX. The effects of food on the reference preparations were comparable. Formulation, time and sequence had no significant effects on the PK parameters (p ≧ 0.05). The test formulation was bioequivalent to the reference formulation as the geometric mean ratios under fasting and fed conditions were within equivalence limits (80%–125%). No serious AEs were reported. Thus, test and reference ticagrelor are bioequivalent in Chinese subjects under fasting and fed conditions.     

Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies

Purpose

The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.

Methods

The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C_max, but not for t_max (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C_max and AUC bioequivalence.

Results

The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C_max non-chiral: 82.77–96.09, sum of enantiomers: 82.19–98.23; 90% CI AUC_t non-chiral: 107.23–115.49, sum of enantiomers: 105.73–121.35). However, the chiral method showed differences in AUC and C_max that resulted in non-bioequivalence for the individual enantiomers (90% CI C_max S-ibuprofen: 76.05–91.36, R-ibuprofen: 87.84–113.05; 90% CI AUC_t S-ibuprofen: 96.67–105.86, R-ibuprofen: 118.86–142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.

Conclusions

Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption.     

A 1‐step Bayesian predictive approach for evaluating in vitro in vivo correlation (IVIVC)

IVIVC (in vitro in vivo correlation) methods may support approving a change in formulation of a drug using only in vitro dissolution data without additional bioequivalence trials in human subjects. Most current IVIVC methods express the in vivo plasma concentration of a drug formulation as a function of the cumulative in vivo absorption. The absorption is not directly observable, so is estimated by the cumulative dissolution of the drug formulation in in vitro dissolution trials. The calculations conventionally entail the complex and potentially unstable mathematical operations of convolution and deconvolution, or approximations aimed at omitting their need. This paper describes, and illustrates with data on a controlled‐release formulation, a Bayesian approach to evaluating IVIVC that does not require convolution, deconvolution or approximation. This approach incorporates between‐ and within‐subject (or replicate) variability without assuming asymptotic normality. The plasma concentration curve is expressed in terms of the in vitro dissolution percentage instead of time, recognizing that this correspondence may be noisy because of the various sources of error. All conventional functions of the concentration curve such as AUC, C_max and T_max can be expressed in terms of dissolution percentage, with uncertainties arising from variability in measuring absorption and dissolution accounted for explicitly. Copyright © 2009 John Wiley & Sons, Ltd.