Bioequivalence Acceptance Limits Research Articles

Cariprazine Orodispersible Tablet: A New Formulation for Cariprazine.

Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0-72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.

A Bioequivalence Comparison at Steady State between the Newly Developed Once-Daily Extended Release Tablet Formulation and the Approved Twice-Daily Tablet Formulation of Deutetrabenazine (P2-11.015)

<h3>Objective:</h3> To assess the bioequivalence (BE) and relative bioavailability (BA) between a once-daily (QD) extended release formulation of deutetrabenazine and the approved twice-daily (BID) formulation at steady state under fed conditions. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva) in a BID formulation is an approved treatment for tardive dyskinesia and chorea associated with Huntington disease. A QD formulation has been developed. <h3>Design/Methods:</h3> In a phase 1 study (TV50717-BE-10179) using a randomized cross-over design, healthy adult males and females (n=262) received 24 mg QD formulation (test) as a once daily administration and 12 mg BID formulation (reference) as a twice daily administration, each for 7 days in fed state. Safety was assessed throughout the study and pharmacokinetic (PK) blood sampling occurred on days 4–7. Test-to-reference geometric mean ratios (GMRs) and 90%CIs for BE acceptance limits (80.00% to 125.00%) were computed for PK parameters (area under the plasma concentration curve over 24-hours at steady-state [AUC_0–24hr,ss] and maximum plasma concentration at steady-state [C_max,ss]) of deutetrabenazine, active metabolites, deuterated α-HTBZ and β-HTBZ, and total (α+β)-HTBZ. Relative BA was assessed for C_max,ss of the active metabolites (individually and as a total sum). <h3>Results:</h3> The GMRs (90%CIs) for AUC_0–24hr,ss were 115.15% (110.38–120.14%) for deutetrabenazine, 95.40% (94.13–96.69%) for α-HTBZ, 94.13% (92.35–95.94%) for β-HTBZ, and 95.05% (93.67–96.46%) for total (α+β)-HTBZ. GMRs of C_max,ss were 95.09% (90.60–99.80%) for deutetrabenazine, 79.56% (78.21–80.94%) for α-HTBZ, 74.85% (73.13–76.60%) for β-HTBZ and 77.71% (76.26–79.16%) for total (α+β)-HTBZ. No new safety findings emerged in this study. <h3>Conclusions:</h3> At steady state, deutetrabenazine administered as the QD formulation was bioequivalent to the approved BID formulation for both AUC and C_max. The active metabolites at steady state were bioequivalent with regard to AUC between the QD and BID formulation; C_max was slightly lower for the QD formulation compared to the BID formulation. <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gutierrez has stock in Teva. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.

Bioequivalence study of two Esomeprazole40 mg MUPS tablets in healthy adult Bangladeshi human subjects

Background: The primary objective of this study is to investigate the bioequivalence of two formulations (test&amp; reference) of Esomeprazole 40 mg MUPS Tablet in healthy, adult human subjects. Method: In this study, a single dose, two-sequence, two-way crossover randomized design was used to investigate the bioequivalence under fasting conditions. 14 healthy volunteers received the two formulations over the course of two treatment days, each followed by a seven-day washout period. Following the administration of a single dose of 40 mg of each formulation, blood samples were taken at predetermined time points and subjected to a validated LC-MS/MS method for Esomeprazole concentration analysis. The plasma concentration-time profiles of both formulations were used to determine the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Result: Pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ did not show any statistically significant differences. The 90 % confidence intervals of Cmax, AUC0-t, and AUC0-∞ for Esomeprazole was found 89.35% (82.27-97.03%), 107.61% (99.78-116.05%), and 107.72 (99.87-116.20%) respectively which is within predetermined bioequivalence acceptance limits of 80 - 125 %. Conclusion: In terms of absorption rate and extent, the test product of Beximcopharmaceuticals has met the regulatory requirements for bioequivalence with the reference product Nexium MUPS.

Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology.

Marketing authorisation of generic drugs is based on a demonstration of the "average" bioequivalence (ABE), with acceptance limits of 0.8-1.25 for the 90% confidence interval (CI) of the ratio (generic versus reference) of geometric means of exposure (whole blood, serum or plasma drug concentration). However, when interchangeability of reference by one generic is considered during treatment of a given patient, such methodology cannot guarantee the lack of therapeutic impact especially for drugs with narrow therapeutic index. This review article describes the basis and limits of ABE methodology, and the adaptations that have been proposed by regulatory agencies. For highly variable drugs, given their large therapeutic margin, regulatory agencies even allow widening of the bioequivalence acceptance limits. For drugs with a narrow therapeutic index, the average bioequivalence methodology has been amended differently by regulatory agencies. The European Medicine Agency only requires the narrowing of the ABE acceptance limits to the 0.9-1.10 range. The US Food and Drug Administration (FDA) has proposed to narrow the ABE acceptance limits according to the reference within-subject variance. The FDA requires a fully replicate cross-over study (with four periods) which allows one to compare the within-subject variance between generic and reference drug, and to detect any subject-by-formulation interaction. Indeed, any within-subject variance difference or subject by formulation interactionis an obstacle to interchangeability at the individual level. These amendments for the ABE do not fundamentally change the fact that individual ratios of exposure (generic/reference) will vary to a larger extent than the ratio of their means. For these reasons, since true individual bioequivalence studies cannot be performed for practical reasons and statistical issues, one can suggest that, in addition to the usual average bioequivalence criteria, the limits of the 95% confidence interval of the individual generic/reference exposure ratios could be used to allow interchangeability during treatment (at least for narrow therapeutic index drugs). Limit values of such CI for interchangeability acceptance should be scaled to the therapeutic margin of the reference drug. Regulatory agencies could conduct calculations based on real datasets of bioequivalence studies to determine if such criteria could be acceptable to allow interchangeability.

Pharmacokinetics and Bioequivalence of 2 Azithromycin Tablet Formulations: A Randomized, Open-Label, 2-Stage Crossover Study in Healthy Volunteers.

The current study aimed to assess the bioequivalence of a new branded azithromycin with the reference formulation. An open-label, randomized, 2-stage, crossover study design was implemented involving 77 healthy volunteers under fasting conditions. Each volunteer received a single dose of 250-mg azithromycin tablets test and reference formulations separated by a 21-day washout period. Twenty-two samples were collected at pre-dose and until 72hours post-dose. Azithromycin concentrations were analyzed using a high-performance liquid chromatography-mass spectrometry validated method following a solid-phase plasma extraction. Noncompartmental analysis was carried out to estimate the pharmacokinetic parameters, which were compared between the test and reference products using a multivariate analysis of variance. The difference between Cmax and AUC0-72 of the test and reference formulation was not significant. The 94.1% confidence intervals of ln-transformed Cmax and AUC0-72 of azithromycin were within the bioequivalence acceptance limits of 80%-125%, therefore it can be concluded that the tested formulation is bioequivalent to the reference formulation.

Pharmacokinetics and Bioequivalence Evaluation of 2 Formulations of Tenofovir Alafenamide

The study was conducted to compare the pharmacokinetics and safety profiles of 2 brands of tenofovir alafenamide (TAF) fumarate tablets. This research was a 2-preparation, 2-sequence, 4-period crossover, completely replicated study in 68 healthy Chinese subjects under fasting and fed conditions. The mean values of the area under the concentration-time curve from time 0 to the last time point with blood sample collection (AUC0-t ), area under the concentration-time curve from time 0 to infinity (AUC0-∞ ), and maximum concentration (Cmax ) for the test and reference products of TAF were 248.5 and 275.7 ng/mL, 148.1 and 157.8 ng • h/mL, and 148.4 and 158.1 ng • h/mL, respectively, under the fasting condition. On the other hand, the mean value of Cmax , AUC0-t , and AUC0-∞ for the test and reference formulations of TAF were 244.6 and 246.7 ng/mL, 230.4 and 244.9 ng • h/mL, and 233.2 and 246.2 ng • h/mL, respectively, under the fed condition. The 90% confidence intervals for geometric mean ratios of AUC0-t and AUC0-∞ of TAF in fasting and fed states were within the bioequivalence acceptance limits when tested using the average-bioequivalence method. The point estimate value for geometric mean ratio of Cmax in fasting and fed states (88.4% and 95.5%, respectively) were within the bioequivalence acceptance limits as per the reference-scaled average-bioequivalence method. The safety profiles of the 2 formulations were comparable. Pharmacokinetic analysis demonstrated that the test formulations of TAF exhibited bioequivalence to the reference and were well tolerated by healthy Chinese subjects (Study Registry Identification Number: CTR20190086; CTR20190087).

Pharmacogenetic Perspectives in Improving Pharmacokinetic Profiles for Efficient Bioequivalence Trials with Highly Variable Drugs: A Review

Conducting bioequivalence trials under traditional crossover study designs without exposing a large number of healthy volunteers to demonstrate two highly variable (%coefficient of variability greater than 30) test/reference (branded) drug products in different formulations to meet the standard 90% confidence interval criteria of relevant pharmacokinetic metrics between 0.80 and 1.25 and to maintain the consumer risk smaller than 5% has been a challenging task. Genetic polymorphisms encoding key drug-metabolizing enzymes can significantly influence absorption, distribution, metabolism and elimination of many highly variable generic drugs after administration. This article briefly reviews the case studies and examples of utilizing pharmacogenetic screening approaches in the recent literature to alleviate the resources and ethical burden of recruiting larger numbers of subjects in bioequivalence trials needed to perform pharmacokinetic studies for formulations of highly variable drug products without widening the bioequivalence acceptance limits.

Physiologically Based Pharmacokinetic Modeling for Substitutability Analysis of Venlafaxine Hydrochloride Extended-Release Formulations Using Different Release Mechanisms: Osmotic Pump Versus Openable Matrix

A Food and Drug Administration–approved generic oral product of venlafaxine hydrochloride (HCl) extended-release (ER) tablets has used a release mechanism based on an openable matrix, which is different from the push–pull osmotic pump system of its reference-listed drug. In an extreme case, a delay in the bursting of the openable matrix may be considered a product failure mode that alters the intended profile of systemic exposure. A physiologically based pharmacokinetic absorption model was established and verified to simulate the pharmacokinetic profiles after a single-dose oral administration of ER venlafaxine HCl tablets based on an osmotic pump or openable matrix design. This model adequately predicted the observed human mean pharmacokinetic metrics with <20% difference between the predicted and observed data. Based on the modeling and simulation results, Cmax and AUCt of the venlafaxine openable matrix tablets were entirely within the bioequivalence acceptance limits (i.e., 80%-125%) when the lag time varied from 0 to 4 h and using drug-release profiles under most dissolution conditions. The results indicated that a bioinequivalence risk is minimal for a delayed onset of drug release from the approved generic venlafaxine HCl ER tablets with an openable matrix design, supporting its substitutability to the reference product.

Application of New Bioequivalence Testing Procedures To Tacrolimus Formulations in Stable Kidney Recipients: Global Regulatory Impact.

Bioequivalence(BE) studies are an integral component of innovator and generic drug approval processes. Worldwide regulatory bodies have and continue to modify BE testing approaches for narrow therapeutic index(NTI) drugs such as tacrolimus. Modifications of BE approaches for NTI drugs essentially include two approaches 1)Direct tightening of average BE limits and 2) reference scaled average BE(RSCABE) based upon the within subject variability of the innovator product in healthy volunteers. The transplant community has encouraged testing in the transplant population. A recent publication of a prospective, two-center, randomized, two-period, two sequence, crossover, steady-state pharmacokinetic study comparing Sandoz generic tacrolimus (TS) vs Prograf (TP) in stable renal transplants revealed the following. The TS:TP ratio for AUC 0-12 was 1.02 with a 90% CI of 97-108% and Cmax was 1.09 with a 90% CI of 101-118%. Methods: Various BE testing approaches were applied to these data in stable renal transplants including tighter BE limits and RSCABE. Results: In the renal transplant population, tighter average BE limits for most regulatory bodies (Health Canada, South Africa, Asia and Latin America) were met for AUC and Cmax, however the Cmax did not meet 2010 regulatory standards of the EMA and the Danish Medicine Agency due to Cmax CI outside the 90.0-111.11% approval range and by not including 100% respectively. However in 2013, the EMA Efficacy Working Party recommended acceptable Cmax CI for tacrolimus of 80-125%. Calculations for RSCABE resulted in within subject variability of the innovator product (TP) of 14.9% and 24.2% for AUC and Cmax respectively. Using the RSCABE procedure, the 90% CI to meet BE standards for AUC was 86-117% and Cmax was 80-125%. Conclusion: TS in renal transplants met all current FDA and EMA modified bioequivalence criteria. Also, application of RSCABE to the variability of 24.2% of TP Cmax in the renal transplants showed that the confidence interval of 80-125% is acceptable and allows for adjustment to the variability of the innovator product, TP, in transplant recipients. The RSCABE approach dynamically adjusts to the variability of tacrolimus PK parameters of renal transplants, and may be more appropriate than fixed BE acceptance limits. DISCLOSURES:Wiland, A.: Employee, Novartis. McCague, K.: Employee, Novartis.

Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials.

The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior. These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin. The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L⁻¹), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events. Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet.

Linagliptin fixed-dose combination with metformin is bioequivalent to co-administration of linagliptin and metformin as individual tablets.

To demonstrate bioequivalence of linagliptin/metformin fixed-dose combination (FDC) tablets and the corresponding combination of individual tablets taken together, i.e., free-pill (FP) treatment. Three dosing combinations were evaluated in three separate randomized studies: linagliptin 2.5 mg with 500 mg, 850 mg, or 1,000 mg metformin. These studies used a prospective, open-label, randomized, two-way crossover design to evaluate bioequivalence in healthy volunteers (n = 287). After an overnight fast, participants received an FDC tablet once, and on a separate visit received the corresponding FP treatment. The two possible treatment sequences (FDC/FP and FP/FDC) were randomly allocated to the participants. A washout period of 35 days separated the two study treatments. The primary endpoints were maximum plasma concentration (Cmax) of linagliptin and metformin, area under the plasma concentration time curve from 0 to 72 hours (AUC0-72) for linagliptin, and from 0 to infinity (AUC0-inf) for metformin. The 90% confidence intervals of the adjusted geometric mean ratios of Cmax and AUC (calculated as FDC/ FP) were within the bioequivalence acceptance limits of 80 - 125%. The number of participants reporting at least one adverse event following FDC treatments was comparable to, or less than, that following FP treatments. Evaluation of vital signs and clinical laboratory tests revealed no safety issues. FDC tablets of linagliptin and metformin are bioequivalent to individual tablets of respective dose strengths taken together. Both treatments were well tolerated.

Bioequivalence of Glucophage® (Metformin) Tablets from Europe and the United States Tested in Healthy Volunteers

Objectives: To investigate whether Glucophage® (metformin) tablets from Europe are bioequivalent to Glucophage tablets from the United States (US) despite in vitro dissolution differences. Bioequivalence would indicate that global Phase III data collected with either product is valid for the registration of fixed-dose combinations with metformin in both regions. Research design and methods: This study included two parts, both of which were conducted according to a randomised, open-label, single-dose, two-period crossover design. The subjects of Part I (N=28) received the 1000 mg Glucophage products, and the subjects of Part II (N=28) received the 500 mg Glucophage products. Results: At both dose levels (1000 mg and 500 mg), administration of single doses of Glucophage from Europe and the US resulted in comparable exposures, as determined by AUC0-inf and Cmax of metformin. The geometric mean ratios of AUC0-inf and Cmax were close to 100%, and the 90% confidence intervals of AUC0-inf and Cmax were contained within the bioequivalence acceptance limits of 80% to 125%. Incidence of adverse events was low and randomly distributed between treatment groups. Conclusions: Glucophage tablets from Europe and the US were shown to be bioequivalent at doses of 1000 mg and 500 mg. Glucophage tablets from both markets were well tolerated by healthy male and female subjects

International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences

The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1. A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m(2), po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews. The mean values of Cmax, AUC0-t, and AUC0-∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found. The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m(2)) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy fasted Chinese adult males

Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China. Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers. Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C max, T max, t ½, AUC 0−t, and AUC 0−∞), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the logtransformed ratios of AUC and C max of atorvastatin were within the predetermined bioequivalence range (0.80–1.25 for AUC and 0.70–1.43 for C max) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs). Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m 2) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m 2) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C max, AUC 0−t, and AUC 0−∞) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C max, AUC 0−t, and AUC 0−∞) of both atorvastatin (0.73–0.91, 0.92–1.02, and 0.91–1.01, respectively) and ortho-hydroxy-atorvastatin (0.83–1.05, 0.92–1.02, and 0.93–1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug. Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.

The bioequivalence of highly variable drugs and drug products

'Highly variable drugs' have been defined as those drugs for which the within-subject variability (WSV) equals or exceeds 30% of the maximum concentration (Cmax) and/or the area under the concentration versus time curve (AUC). Despite the fact that highly variable drugs are generally safe with flat dose response curves, the bioequivalence of their formulations is a problem because the high variability means that large numbers of subjects are required to give adequate statistical power. Highly variable drug products are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem rather than high innate WSV of the drug itself. A further problem caused by high variability is that a subset of the population may respond differently to the two formulations producing a significant subject x formulation interaction. Practical examples are shown using replicate designs. The methods proposed to deal with the problems posed by highly variable drugs include: (i) Drug regulatory jurisdictions states that the 90% confidence interval (90% CI) around the test to reference geometric mean ratio (GMR) is required to fit with bioequivalence acceptance limits of 0.8 - 1.25 for both Cmax and AUC. The WSV for single point estimation of Cmax is often greater than that for AUC. One strategy therefore is not to require a 90% CI for Cmax of drugs that do not exhibit a toxicity associated with Cmax and merely require the GMR to fall within the acceptance limits. (ii) To arbitrarily broaden the bioequivalence acceptance limits. For example, to permit a sponsor to justify the use of wider limits e.g the 90% CI around the GMR of Cmax values might be required to fit within acceptance limits of 0.75 - 1.33 or even 0.70 - 1.42. (iii) A more systematic approach would be to broaden the acceptance limits by scaling to either the residual variance from a 2-period design or to the WSV of the reference product in a replicate design. Subsequent evaluations of scaling procedures have demonstrated that smaller numbers of subjects are required for bioequivalence studies on formulations of highly variable drugs. A disadvantage of scaling is that the method is less sensitive to differences between the means compared with unscaled treatment, such that the GMR may prove to be unacceptably low or high. This possibility has let to a suggestion that the GMR must fall within acceptance limits of 0.8 - 1.25 in scaled treatments. (iv) A similar method is to scale the metric rather than the acceptance limits. This method was proposed by the United States' Food and Drug Administration in the context of Individual bioequivalence, but may also be applied (v) to average bioequivalence. (vi) To carry out bioequivalence studies at steady state whenever a multiple dose regimen is ethically acceptable for healthy volunteers. This solution is based on the observation that high variability in a single dose study tends to be dampened at steady state, thus increasing statistical power. Drug regulators have not favored this approach on the grounds that bioequivalence testing should be based on the most discriminating test possible. (vii) Finally the use of metabolite data has been proposed since in many (but by no means all) cases, metabolite is less highly variable than that of the parent drug. This subject remains controversial except when the administered substance is a prodrug which converted by metabolism into the active drug.

Some Conceptual Issues in the Evaluation of Average, Population, and Individual Bioequivalence

New approaches to population bioequivalence (PBE) and individual bioequivalence (IBE) have been motivated by the limitations of average bioequivalence (ABE) to handle unequal variances and subject-by-formulation interaction. The criteria for PBE and IBE described in the Food and Drug Administration draft guidance employ aggregate criteria that combine information on differences in bioavailability between formulation means, and differences in bioavailability variation of formulations between and within subjects. Examples from replicate design studies have demonstrated that the trade-off in means offered by the scaled aggregate criterion may result in clinically unacceptable decisions in favor of IBE, although ABE does not hold. Concerning the statistical methods, there are at least three conceptual issues that are still unresolved. First, aggregate hypotheses on the logarithmic scale have no obvious translation into the original scale. Second, scaling corresponds to a modification of the bioequivalence acceptance limits, and is an issue independent of IBE, PBE, and ABE, but is handled differently for IBE and PBE than for ABE. Third, the proposed criteria do not mandate hierarchical testing (first means, then variances, lastly subject-by-formulation interaction). If, despite major clinical reservations, IBE is further pursued, statistical research should focus on disaggregate criteria that allow exact stepwise procedures for evaluating untransformed parameters.

Metrics to Characterize Concentration-Time Profiles in Single- and Multiple-Dose Bioequivalence Studies

In bioequivalence assessment, pharmacokinetic characteristics of concentration-time curves have traditionally been associated with rate and extent of absorption. In the actual context of bioequivalence, however, the similarity of the shapes rather than that of the absorption rates is essential. As a consequence, the following definition of bioequivalence was proposed during Bio-International ‘94 as a more appropriate one: “Two medicinal products are considered bioequivalent if their concentration-time profiles are so similar that they are unlikely to produce clinically relevant differences in therapeutic and/or adverse effects.” In order to quantify the similarity of concentration-time profiles, suitable shape characteristics (metrics) and appropriate bioequivalence acceptance limits (bioequivalence ranges) are needed. Whereas the majority of recent investigations dealt with indirect measures of rate of absorption and their sensitivity to simulated changes in the absorption rate, future research should fo...

An approach for widening the bioequivalence acceptance limits in the case of highly variable drugs.

Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80-125%). This paper examines alternative approaches to establishing bioequivalence. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. We challenge the "one size fits all" current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or "goal posts" which vary in accordance with the intrasubject variability of the reference product.