Bioequivalence Testing Research Articles

Views and perceptions about locally manufactured medicines in Ethiopia: a qualitative study of physicians, patients and regulatory authorities

BackgroundBecause of their cost, the use of locally produced, bioequivalent, generic drugs is universally recommended. In Ethiopia. while the government is committed to raising the market share and use of locally produced drugs, the process is hampered by the lack of a bioequivalence testing centre to strengthen the regulatory environment and deliver quality-assured local medicines. The purpose of this study is to assess the views and perceptions of key regulatory stakeholders, physicians and patients about locally produced generic medicines.MethodsA descriptive qualitative study, using focus group discussions and key informant interviews, was conducted. Five key informant interviews (two senior regulatory authority members and 3 institutional review board members) as well as 4 focus group discussions (2 with physicians and 2 with patients) were held. Data were analysed using an inductive, thematic process.ResultsFour major themes emerged: awareness of lack of bioequivalence profiles associated with local medicines, perceptions about the quality and effectiveness of local medicines, quality and efficacy of imported medicines from developing countries and quality and efficacy of cheaper medicines. All institutional review board members were aware of bioequivalence issues. However, many physicians lacked detailed knowledge about bioequivalence, its clinical relevance and the lack of bioequivalence data for local medicines. All institutional review board members, physicians and male patients, but not female patients, were concerned about the quality and effectiveness of local medicines. Female patients were more confident about the locally produced drugs. In addition, some physicians and patients were not confident about the quality and effectiveness of cheaper drugs and drugs imported from developing countries. Government officials believed that local drugs are reliable.ConclusionThe success of promoting the use of inexpensive local medicines and changing the perception of the community depends not only on increasing the domestic market share held by local companies, but also on the capacity of the regulatory environment and companies to produce quality assured medicines and to overcome misconceptions. Among other initiatives, establishing an accredited bioequivalence centre in the country needs to be addressed urgently.

Bioequivalence study of dihydroartemisinin-piperaquine (DHP) generic formulation in fixed-dose combination, in healthy Indonesian volunteers

Background: Malaria is still considered as a major health problem in the world including in Indonesia, which is regarded as one of the malaria-endemic countries. Since 2006, WHO has recommended the use of artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria. In Indonesia, DHP tablet (combination of dihydroartemisinin and piperaquine) is the first line therapy used in malaria control program, which currently used imported DHP tablet. To produce generic DHP tablet, comparative bioequivalence test between DHP tablet and the drug previously used is needed. Methods: A single dosed, randomized, double-blinded, one-period, and parallel study design was conducted in the present research. Every twenty-four subjects were assigned into two groups, which are test group and comparison group. Results: The results showed that even though in vitro comparison of dissolution test has fulfilled the requirements, in vivo test results has not fulfilled the bioequivalence standards. Obtained geometric mean ratios (90% confidence intervals) of the test drug to comparator drug for dihydroartemisinin were 83.30% (67.06%–103.48%) for AUC0-t, 83.24% (67.10%–103.26%) for AUC0-inf, and 75.67% (61.83%–92.61%) for Cmax. The geometric mean ratios (90% confidence intervals) of the test drug to comparator drug for piperaquine were 97.31% (76.50%–123.80%) for AUC0-t, 94.18% (74.18%–119.59%) for AUC0-inf, and 96.47% (71.80%–129.62%) for Cmax. Conclusions: Therefore, the pharmacokinetic profile of the test drug is concluded to be bio-inequivalent with the comparator drug.

A noniterative sample size procedure for tests based on t distributions.

A noniterative sample size procedure is proposed for a general hypothesis test based on the t distribution by modifying and extending Guenther's approach for the one sample and two sample t tests. The generalized procedure is employed to determine the sample size for treatment comparisons using the analysis of covariance (ANCOVA) and the mixed effects model for repeated measures in randomized clinical trials. The sample size is calculated by adding a few simple correction terms to the sample size from the normal approximation to account for the nonnormality of the t statistic and lower order variance terms, which are functions of the covariates in the model. But it does not require specifying the covariate distribution. The noniterative procedure is suitable for superiority tests, noninferiority tests, and a special case of the tests for equivalence or bioequivalence and generally yields the exact or nearly exact sample size estimate after rounding to an integer. The method for calculating the exact power of the two sample t test with unequal variance in superiority trials is extended to equivalence trials. We also derive accurate power formulae for ANCOVA and mixed effects model for repeated measures, and the formula for ANCOVA is exact for normally distributed covariates. Numerical examples demonstrate the accuracy of the proposed methods particularly in small samples.

Design and inference for 3-stage bioequivalence testing with serial sampling data.

A bioequivalence test is to compare bioavailability parameters, such as the maximum observed concentration (Cmax ) or the area under the concentration-time curve, for a test drug and a reference drug. During the planning of a bioequivalence test, it requires an assumption about the variance of Cmax or area under the concentration-time curve for the estimation of sample size. Since the variance is unknown, current 2-stage designs use variance estimated from stage 1 data to determine the sample size for stage 2. However, the estimation of variance with the stage 1 data is unstable and may result in too large or too small sample size for stage 2. This problem is magnified in bioequivalence tests with a serial sampling schedule, by which only one sample is collected from each individual and thus the correct assumption of variance becomes even more difficult. To solve this problem, we propose 3-stage designs. Our designs increase sample sizes over stages gradually, so that extremely large sample sizes will not happen. With one more stage of data, the power is increased. Moreover, the variance estimated using data from both stages 1 and 2 is more stable than that using data from stage 1 only in a 2-stage design. These features of the proposed designs are demonstrated by simulations. Testing significance levels are adjusted to control the overall type I errors at the same level for all the multistage designs.

Microextraction techniques in antibiotic monitoring in body fluids: Recent trends and future

ABSTRACTThe analysis of drugs in biomedical discipline targets a broad range of aims such as therapeutic drug monitoring, pharmacokinetic study to investigate the drug bioavailability, bioequivalence tests to evaluate the effect of formulation parameters, toxicology, and forensic science. Because of the low levels of typical antibiotics in plasma, blood, urine, exhalation samples, and other biological fluids as well as complex matrix of biological media, adequate sample preparation methods should be implemented for quantification of antibiotics. In this review, developments in well-established microextraction techniques for the clinical analysis of biological samples will be reviewed and discussed. This article presents an overview of microextraction methods for biological samples, focusing especially on antibiotics.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride

Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers.

Controlling the type I error rate in two-stage sequential adaptive designs when testing for average bioequivalence.

In a 2×2 crossover trial for establishing average bioequivalence (ABE) of a generic agent and a currently marketed drug, the recommended approach to hypothesis testing is the two one-sided test (TOST) procedure, which depends, among other things, on the estimated within-subject variability. The power of this procedure, and therefore the sample size required to achieve a minimum power, depends on having a good estimate of this variability. When there is uncertainty, it is advisable to plan the design in two stages, with an interim sample size reestimation after the first stage, using an interim estimate of the within-subject variability. One method and 3 variations of doing this were proposed by Potvin et al. Using simulation, the operating characteristics, including the empirical type I error rate, of the 4 variations (called Methods A, B, C, and D) were assessed by Potvin et al and Methods B and C were recommended. However, none of these 4 variations formally controls the type I error rate of falsely claiming ABE, even though the amount of inflation produced by Method C was considered acceptable. A major disadvantage of assessing type I error rate inflation using simulation is that unless all possible scenarios for the intended design and analysis are investigated, it is impossible to be sure that the type I error rate is controlled. Here, we propose an alternative, principled method of sample size reestimation that is guaranteed to control the type I error rate at any given significance level. This method uses a new version of the inverse-normal combination of p-values test, in conjunction with standard group sequential techniques, that is more robust to large deviations in initial assumptions regarding the variability of the pharmacokinetic endpoints. The sample size reestimation step is based on significance levels and power requirements that are conditional on the first-stage results. This necessitates a discussion and exploitation of the peculiar properties of the power curve of the TOST testing procedure. We illustrate our approach with an example based on a real ABE study and compare the operating characteristics of our proposed method with those of Method B of Povin et al.

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial.

BackgroundAlthough the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.Methods and findingsFrom December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.ConclusionsUsing an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.Trial registrationClinicalTrials.gov NCT01889758.

Lack of Bioequivalence Among Low-dose, Enteric-coated Aspirin Preparations.

Low-dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection; however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory requirements, we carried out bioequivalence tests for two 75 mg enteric-coated aspirin preparations (Caprin and Protek) using Nu-Seals 75 mg aspirin as the comparator. The primary endpoint was serum thromboxane levels after 14 days of treatment. Protek failed to meet bioequivalence, as it was significantly less effective than Nu-Seals. In contrast, Caprin was not bioequivalent with Nu-Seals but as it was more effective it was granted approval. However, 75 mg plain aspirin was found to be more effective than Nu-Seals at inhibiting serum thromboxane production. Thus, there is significant variation in the ability of low-dose aspirin preparations to inhibit serum thromboxane production.

A series of N-of-1 trials to assess the therapeutic interchangeability of two enalapril formulations in the treatment of hypertension in Addis Ababa, Ethiopia: study protocol for a randomized controlled trial

BackgroundHypertension is one of the leading causes of morbidity and mortality in Ethiopia. Treatment usually involves lifelong medication use. Enalapril is a common drug for the treatment of hypertension in Ethiopia. However, the drug is expensive and, therefore, there is limited capacity for people to afford the treatment. Locally produced Enalapril is a cost-effective solution to treat the disease. However, as local medicines regulation does not include bioequivalence tests on locally produced drugs, physicians and patients need assurance about the effectiveness and safety of local generics. Evidence on therapeutic equivalence is needed on these untested local drugs.MethodsThis is a hospital-based, randomized, partially blinded, three-cycle crossover trial in single patients, comparing a locally produced version of enalapril with enalapril imported from Europe. Patients involved in this trial are not blinded, as there is no local facility to produce relatively small numbers of placebos or encapsulated drugs. To ensure blinding of study investigators and data analysts, study medications are prepared by an independent pharmacy unit using opaque medication packaging. The importance of maintaining blinding is also part of patient pre-trial education. Each N-of-1 trial will consist of three successive 14-day treatment pairs, each pair comprising 7 days of 5–20 mg local and 7 days of 5–20 mg imported enalapril taken once daily in the morning. The primary outcome will be the average difference in systolic blood pressure as measured by home blood pressure measurements.DiscussionThe number of locally produced products, such as enalapril, being approved without proof of bioequivalence is dramatically increasing. By bridging the information gap on bioequivalence, the trial will give rigorous evidence on therapeutic equivalence of locally produced enalapril in the treatment of hypertension. If there is no difference, the hypothesized result, then patients can take the local medicine with confidence. This trial will also will determine whether aggregated N-of-1 studies are feasible to evaluate untested generic drugs in resource-limited countries where bioequivalence testing centers are unavailable.Trial registration numberAustralian and New Zealand Clinical Trial Registry, ID: ACTRN12616001088437p. Registered on 12 August 2016.

Testing for bioequivalence of highly variable drugs from TR-RT crossover designs with heterogeneous residual variances.

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR-RTR-RRT and TRTR-RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR-RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR-RT designs. Under the assumption of zero subject-by-formulation interaction, this basic model is comparable to the FDA-recommended model for TRR-RTR-RRT and TRTR-RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real-world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ-based testing procedure that evaluates HV drugs under practical TR-RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ-based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.

A Proton Pump Inhibitor in the Reformulation Setting: Bioequivalence and Potential Implications for Long-Term Safety.

Proton pump inhibitors (PPIs) have become known for both their therapeutic effect and good safety profile. An application was submitted to the US Food and Drug Administration for approval of a reformulated PPI product that failed bioequivalence testing, but was submitted on the basis of the long history of PPI use as a “surrogate” for equivalence. This review evaluates the safety data for PPIs, discuss variability of pharmacokinetic parameters of PPIs in the reformulation setting, and potential implications of those changes for long‐term safety.

Effect of Different Sampling Schedules on Results of Bioavailability and Bioequivalence Studies: Evaluation by Means of Monte Carlo Simulations.

Bioavailability and bioequivalence study is one of the most frequently performed investigations in clinical trials. Bioequivalence testing is based on the assumption that 2 drug products will be therapeutically equivalent when they are equivalent in the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed and becomes available at the site of drug action. In recent years there has been a significant growth in published papers that use in silico studies based on mathematical simulations to analyze pharmacokinetic and pharmacodynamic properties of drugs, including bioavailability and bioequivalence aspects. The goal of this study is to evaluate the usefulness of in silico studies as a tool in the planning of bioequivalence, bioavailability and other pharmacokinetic assays, e.g., to determine an appropriate sampling schedule. Monte Carlo simulations were used to define adequate blood sampling schedules for a bioequivalence assay comparing 2 different formulations of cefadroxil oral suspensions. In silico bioequivalence studies comparing different formulation of cefadroxil oral suspensions using various sampling schedules were performed using models. An in vivo study was conducted to confirm in silico results. The results of in silico and in vivo bioequivalence studies demonstrated that schedules with fewer sampling times are as efficient as schedules with larger numbers of sampling times in the assessment of bioequivalence, but only if Tmax is included as a sampling time. It was also concluded that in silico studies are useful tools in the planning of bioequivalence, bioavailability and other pharmacokinetic in vivo assays.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization–, U.S. Food and Drug Administration–, or European Medicines Agency–recommended method using the innovator as the comparator, and (c) results comply with criteria for “very rapidly dissolving” or “similarly rapidly dissolving.” Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study.

Generic antiretrovirals for the treatment of HIV: a novel challenge for Western countries? .

The introduction of generic antiretroviral medications in developing countries has resulted in significant CD4 cell restoration, HIV viral decline, and a noteworthy reduction in the time to initiation of therapy. Projection models have also predicted significant cost saving associated with the extensive diffusion of generic antiretrovirals in developed countries. However, some uncertainties on generics have recently been raised. These concerns mainly relate to the adequacy of the study design for bioequivalence testing, the potential for uncontrolled switching from one generic to another, and the loss of adherence if patients switched from fixed-dose coformulations to single components in order to incorporate the new generic drugs. In the present review, we deal with current evidence and potential controversial issues regarding generic antiretrovirals and their underlying economic implications and provide some proposals on how to favor the widespread diffusion of generics in HIV medicine. This may be particularly relevant considering that the safe, systematic switch from patented to generic antiretrovirals could potentially guarantee access to therapies for HIV-infected patients worldwide and lead to money savings that would compensate the expenditure increase resulting from new, innovative HIV drugs. .

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate–labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient.

Bioequivalence and Pharmacokinetics Comparison of Two Formulations of Extended-Release Pentoxifylline Tablets in Healthy Subjects after Fasting and Fed Conditions

The pharmacokinetics and bioequivalence of a newly developed extended-released (ER) tablet containing 400 mg pentoxifylline as a test product was compared with the reference brand product Trental® 400 mg ER tablet produced by Sanofi-Aventis. Two separate studies were conducted simultaneously. The first study was conducted under fasting condition, whereas, the second study was conducted under fed condition; using the same batches of the test and reference products in both studies. In each study, both products were administered to 32 healthy male adult volunteers applying a single-dose, two-treatment, two-period, two-sequence, randomized crossover design with one-week washout period between dosing. Twenty two blood samples were withdrawn from each volunteer over 24 hours period. Pentoxifylline concentrations were determined in plasma by a validated HPLC method according to FDA Bioanalytical Method Validation Guidance using UV detection and chloramphenicol as internal standard. The lower limit of quantitation of the drug in plasma was 5 ng/ml and the upper limit of quantitation was 500 ng/ml. From the plasma concentration-time data of each individual, the pharmacokinetic parameters; Cmax, AUC0-t, AUC0-¥, Cmax/AUC0-¥, Tmax, lZ & T0.5; were calculated applying non-compartmental analysis. Data of the test and reference products were statistically analyzed to test for bioequivalence of the two products, using criteria of FDA and EMEA Guidance. The pharmacokinetic parameters mentioned above were statistically analyzed by descriptive statistics, ANOVA test and 90% Confidence Interval (CI). ANOVA test involved the calculation of the effects of: treatment, period, sequence and subjects nested in sequence. According to the above guidance, the primary pharmacokinetic parameters used for bioequivalence testing, namely Cmax, AUC0-t and AUC0-¥ were also statistically analyzed by ANOVA & CI tests using the corresponding Ln-transformed values. The mean values Cmax, AUC0-t , AUC0-¥ , Cmax/AUC0-¥ , Tmax, lZ & T0.5 for the test formula obtained from the fasting study were; 144.4 ng/ml, 845.4 ng.hr/ml, 868.4 ng.hr/ml, 0.186 hr-1, 3.29 hr, 0.561 hr-1 and 1.65 hr, respectively; and the mean values of these parameters for the reference formula were; 150.0 ng/ml, 871.1 ng.hr/ml, 893.7 ng.hr/ml, 0.177 hr-1, 3.70 hr, 0.558 hr-1 and 1.59 hr, respectively. The mean values of the above mentioned parameters for the test formula obtained from the fed study were; 157.8 ng/ml, 826.5 ng.hr/ml, 853.8 ng.hr/ml, 0.198 hr-1, 5.4 hr, 0.458 hr-1 and 2.06 hr, respectively; and the mean values of these parameters for the reference formula were; 162.1 ng/ml, 869.7 ng.hr/ml, 894.8 ng.hr/ml, 0.196 hr-1, 4.1 hr, 0.525 hr-1 and 1.80 hr, respectively. Based on criteria of FDA and EMEA Guidance on Bioavailability and Bioequivalence, the results of the fasting and fed studies demonstrated bioequivalence of the two products under either condition. Accordingly, it is concluded that the newly developed ER tablet containing 400 mg pentoxifylline is bioequivalent to Trental® 400 mg ER tablet produced by Sanofi-Aventis.
 Keywords: Pentoxifylline, Pharmacokinetics, Bioequivalence.

Comparison of non-compartmental and mixed effect modelling methods for establishing bioequivalence for the case of two compartment kinetics and censored concentrations.

Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool was developed with the ability to rapidly compare NCA and NLMEM methods in determining bioequivalence using both R and NONMEM and applied to a drug with two-compartment pharmacokinetics. Concentration-time profiles were simulated where relative bioavailability, random unexplained variability (RUV) at the lower limit of quantification (LLOQ) differed between simulations. NLMEM analyses employed either the M1 or M3 methods for dealing with values below the LLOQ. It was used to elucidate the impact of changes in (i) RUV at the LLOQ, (ii) the extent of censoring data below the LLOQ and (iii) the concentration sampling times. The simulations showed NLMEM having a consistent 20-40% higher accuracy and sensitivity in identifying bioequivalent studies when compared to NCA, while NCA was found to have a 1-10% higher specificity than NLMEM. Increasing data censoring by increasing the LLOQ resulted in decreases of ~10% to the accuracy and sensitivity of NCA, with minimal effects on NLMEM. The tool provides a platform for comparing NCA and NLMEM methods and its use can be extended beyond the scenarios reported here. In the situations examined it is seen that NLMEM is more accurate than NCA and may offer some advantages in the determination of bioequivalence.

A review on drug approval process in US, Europe and India-dossier, bioavailability and bioequivalence studies

Pharmaceutical Regulatory Affairs (PRA) is a vital unit in a pharmaceutical company that successfully drives the Research and Development (RandD) efforts of the company to the market. In the present scenario, countries have different regulatory requirements for approval of a new drug. The single regulatory approach for marketing authorization application (MAA) of a new drug product applicable to various countries (on the basis of single dossier) is utmost difficult. Therefore, the knowledge of exact and detailed regulatory requirements for MAA of each country should be known to establish a suitable regulatory strategy. CTD was developed with the aim to provide a common format for the technical documentation that would significantly reduce the time and resources needed to compile applications for registration of human pharmaceuticals and would ease the preparation of electronic submissions. Bioavailability and bioequivalence testing are essential in the drug development process as they create the foundation for regulatory decision making when evaluating formulation changes and lot-to-lot consistency in innovator products. They also serve as the primary components to demonstrate therapeutic equivalence between generic products and the reference innovator product. This article will focus the similarities and differences in drug approval process and requirements of the documents/CTD specifications to the drug regulatory authorities in the Europe, USA and India also focuses on submission and work flow related to bioavailability and bioequivalence studies.

Comparative pharmacokinetic and bioequivalence evaluation of two formulations of morniflumate 350-mg tablets in healthy male subjects .

Morniflumate is a nonsteroid anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-1, 2 (COX-1, 2). This study aimed to compare the pharmacokinetics (PKs) and assess the bioequivalence of two different formulations of morniflumate 350-mg tablets in healthy Korean male subjects. A randomized, single-dose, two-period, two-sequence crossover study was conducted with 38 subjects. Subjects received a single dose of two tablets of either a test or a reference formulation and the alternated formulation in the next period. Serial blood samples for the PK analysis were collected over 12 hours. PK parameters were determined by a noncompartment analysis. PK parameters, including the maximum concentration (Cmax) and the area under-the-concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) were compared in bioequivalence tests. The Cmax of the test and reference formulations were 985.72 ± 6.80 mg/L and 947.09 ± 6.73 mg/L, respectively, while the AUClast values were 2675.92 ± 7.84 mg×h/L and 2653.06 ± 7.78 mg×h/L, respectively. The geometric mean ratios (90% confidence interval) of the test formulation to the reference formulation for Cmax and AUClast were 1.0715 (0.9469 - 1.2124) and 1.0592 (0.9592 - 1.1695), respectively. The new formulation of morniflumate 350-mg tablet showed a PK profile similar to that of the marketed formulation, and the results of this study fell within in the conventional criteria of bioequivalence. .