Evaluation of Truncated Areas in the Assessment of Bioequivalence of Immediate Release Formulations of Drugs with Long Half-Lives and of Cmax with Different Dissolution Rates

Purpose. To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for drugs with long half-lives and to study the relationship between Cmax and in vitro dissolution rates. Methods. Monte-Carlo simulations were conducted using actual mean plasma concentrations of five long half-life drug products. The simulations were based on a catenary pharmacokinetic system in which the drug disposition in the body was represented by a one-or two-compartment model, characterizing the observed mean profiles. The influence of dramatic changes in the in vitro dissolution rate constant k_d, was simulated in scenarios consisting of 20 crossover trials with 24 subjects per trial, comparing a fast dissolving reference and a hypothetical, slow dissolving test formulation. Results. The AUC's truncated after the completion of distribution phase were found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the Cmax measure was insensitive to the changes in the in vitro dissolution rate. The Cmax measure was found to be useful in the bioequivalence assessment since it reflected both the rate and extent of absorption. (Cmax/AUCt) measure was specific to absorption rate. Conclusions. For the bioequivalence determination of long half-life drug products, (1) the use of truncated AUC's after completion of the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may be insensitive to input rate changes, if the absorption rate is not constrained by the input rate in relation to the distribution or elimination rate.(3) (Cmax/AUCt) may be more specific to k_a differences, but Cmax reflects differences in both rate and extent of absorption.The views expressed in this paper are professional opinions and perspectives of the authors and do not represent the official policy of the U.S. Food and Drug Administration at this time.     

The Role of Metabolites in Bioequivalency Assessment. III. Highly Variable Drugs with Linear Kinetics and First-Pass Effect

Purpose. Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CL_INT) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%. Methods. Simulated PK studies were done using a linear first-pass model with CL_INT values ranging from 15 L/HR to 900 L/HR. Test/Reference absorption rate constants (Ka) and fraction absorbed (Fa) ratios of 1.0 or 1.25 were used for all simulations. The impact of the value of CL_INT and its intrasubject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fraction metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75. Results. When CL_INT values were raised above those for liver blood flow, the frequency of trials in which bioequivalence was correctly declared decreased when parent AUC was used as a bioequivalence criterion. Only when CL_INT exceeded liver blood flow did the metabolite become important in assessing extent of absorption. Conclusions. The Cmax for the parent drug provided the most accurate assessment of bioequivalence. The Cmax for the metabolite was insensitive to changes related to rate of input, and when CL_INT exceeded liver blood flow, evaluation of the metabolite Cmax data may lead to a conclusion of bioequivalence for products that were not.     

Evaluation of Bioequivalence of Highly Variable Drugs Using Clinical Trial Simulations. II: Comparison of Single and Multiple-Dose Trials Using AUC and Cmax

Purpose. Evaluating of the effects of high intrasubject variability in clearance (CL) and volume of distribution (V), on 90% confidence intervals (CIs) for AUC (Area Under the concentration Curve) in single and multiple-dose bioequivalence studies. The main methodology was Monte Carlo simulation, and we also used deterministic simulation, and examination of clinical trials. The results are compared with those previously observed for Cmax (maximum concentration.) Methods. The time course of drug concentration in plasma was simulated using a one-compartment model with log-normal statistical distributions of intersubject and intrasubject variabilities in the pharmacokinetic parameters. Both immediate-release and prolonged-release products were simulated using several levels of intrasubject variability in single-dose and multiple-dose studies. Simulations of 2000 clinical bioequivalence trials per condition (138 conditions) with 30 subjects in each crossover trial were carried out. Simulated data were compared with data from actual bioequivalence trials. Results. The current simulations for AUC show similar probabilities of failure for single-dose and multiple-dose bioequivalence studies, even with differences in the rate of absorption or fraction absorbed. AUC values from prolonged-release scenario studies are more sensitive to changes in the first order absorption rate constant ka, and to variability in CL and V than AUC from studies of immediate-release studies. Conclusions. We showed that multiple-dose designs for highly variable drugs do not always reduce intrasubject variability in either AUC or Cmax, although the behavior of AUC differs from Cmax. Single dose AUC to the last quantifiable concentration was more reliable than either single dose AUC extrapolated to infinity, or multiple dose AUC during a steady-state interval. Multiple-dose designs may not be the best solution for assessing bioequivalence of highly variable drugs.     

Effects of Food on the Pharmacokinetics of Methylphenidate

Purpose. To test the hypothesis that the pharmacokinetics of d-meth- ylphenidate (d-MPH) would be altered by food ingested before administration of an immediate release formulation (dl-MPH- IR) but not when food is ingested before a slow release formulation (dl-MPH-SR). Methods. A randomized, four-phase, open label, crossover design was conducted in 24 healthy men who each received, on separate occasions, dl-MPH-IR and dl-MPH-SR taken after an overnight fast and 15 min after a standardized breakfast (20% protein, 21% fat, 59% carbohydrate). Plasma MPH levels were monitored by a validated, stereoselective, GLC-ECD method. Results. For plasma d-MPH, there were significant differences (ANOVA) between dl-MPH-IR and dl-MPH-SR in tmax, Cmax (peak exposure), and Cmax/AUC (sensitive to rate of absorption). Dl-MPH-SR on average delayed tmax from 2.3 to 3.7 h and lowered Cmax 34%. There was no significant difference between the formulations in AUC (extent of absorption). For dl-MPH-IR, food significantly increased Cmax (23%) and AUC (15%) and for dl-MPH-SR the corresponding increases were Cmax (17%) and AUC (14%). After dl-MPH-IR, food delayed average tmax from 2.0 to 2.5 but had no effect on tmax after dl-MPH-SR. There was no effect of food on Cmax/AUC (rate of absorption). Conclusions. Food caused a significant increase in extent of absorption but had no effect on rate of absorption of d-MPH after either dl-MPHIR or dl-MPH-SR.     

Why Rate of Absorption Inferences in Single Dose Bioequivalence Studies are Often Inappropriate

Purpose. Peak drug concentration (C_max) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). C_max serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of C_max, not the time to Cmax(Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to C_max(T_max) instead of C_max. Methods. We have previously redirected attention to T_max as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts T_max easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for T_max treatment differences. Three separate BE studies are then analyzed by both methods. Results. By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended analysis of BE studies. First, C_max, a continuous variable peak-height or extent measure has usurped T_max's function and performs erratically as a substitute measure for the rate of absorption. Second, T_max, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, C_max), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.     

Bioequivalence evaluation of two oral formulations of quetiapine fumarate in healthy volunteers

One bioequivalence study was carried out in healthy volunteers in order to compare the rate and extent of absorption of two oral formulations of quetiapine fumarate (CAS 111974-72-2) 25 mg film-coated tablet. Thirty subjects were administered quetiapine fumarate film-coated tablet of test and reference formulation in an open-label, randomised, fasting, two-period, two-sequence, crossover study. Blood samples were taken before and within 48 h after drug administration. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUC and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUCo-t, and Cmax were within the bioequivalence acceptance range of 80-125%. It may be therefore concluded that the test formulation of quetiapine fumarate 25 mg film-coated tablet is bioequivalent to the reference product and can be prescribed interchangeably.     

Comparison of two microemulsion of cyclosporine A in healthy volunteers

This study evaluated the bioequivalence of a new Cyclosporine A microemulsion formulation in comparison to the reference market standard. Twenty-four adult healthy volunteers were randomised to receive the two Cyclosporin A microemulsion formulations, at a dose of 2.5 mg/kg, according to a cross-over design. Blood samples were taken before drug administration and at 12 points within 24 hours. Cyclosporine A whole blood concentrations were determined by HPLC. The pharmacokinetic parameters AUC0-t and AUC0-infinity were calculated by the trapezoidal rule, Cmax and Tmax were obtained directly from blood data. AUCs and Cmax were tested for bioequivalence after log transformation of data, differences for Tmax were evaluated by the rank test of Wilcoxon for paired data. The 90% confidence interval ratio between tested/reference drug was 0.98 for AUC0-t, 0.96 for AUC0-infinity and 1.01 for Cmax. All of them were within the range of bioequivalence. Tmax was 1.60 +/- 0.44 hours after test drug and 1.67 +/- 0.48 after reference drug (p = 0.27, Wilcoxon test). According to these results the two Cyclosporine A microemulsion formulations can be considered bioequivalent.     

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).     

Truncated Area Under the Curve as a Measure of Relative Extent of Bioavailability: Evaluation Using Experimental Data and Monte Carlo Simulations

Purpose. The use of truncated areas under the curve (AUCs) could be a significant advantage for bioequivalence studies of drugs with long half-lives. The purpose of this study was to evaluate the performance of truncated AUCs as measures of relative extent of bioavailability using a large database of experimental data and Monte Carlo simulations. Methods. The experimental data consisted of 123 single-dose, 2-treatment, crossover studies with at least 18 subjects/study. Monte Carlo techniques were also used to simulate studies that reflected a wide variety of experimental conditions. AUCs were calculated over different time intervals and the standard two one-sided t tests procedure was used to assess bioequivalence. Results. The experimental data showed that conclusions concerning bioequivalence were identical between AUCs truncated at four times the time of peak concentration (Tmax) and AUCs extrapolated to infinity (AUC_inf) in 120/123 or 97.6% of studies. There was little change in the intra-subject CVs for AUCs truncated at 3*Tmax or later. The results of Monte Carlo simulations were generally consistent with the experimental data and showed that AUCs truncated at 72 hours (AUC_0–72) performed well compared to AUC_inf as measures of bioequivalence for drugs with long half-lives. Conclusions. Based on both the experimental and simulated data, AUCs truncated after the absorption phase perform well as measures of relative extent of bioavailability. Truncated AUCs offer a particular advantage for drugs with long half-lives and these results indicate that it would be reasonable to limit the sample collection period to 72 hours in bioequivalence studies of oral formulations.     

Absorption Rate Vs. Exposure: Which Is More Useful for Bioequivalence Testing?

Purpose. The goals were to evaluate the usefulness of C_max/AUC_lqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption. Methods. The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and elimination was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using C_max/AUC_lqc, AUC_lqc, and C_max as bioequivalence measures. Results. The outcome of a bioequivalence trial was shown to depend on the measure. C_max/AUC_lqc reflected changes in ka, but not in F. AUC_lqc showed dependence on F, but virtually no dependence on ka. For C_max, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes. Conclusions. It was concluded that use of C_max/AUC_lqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of exposure rather than rate and extent of absorption concepts is encouraged.     

High Variability in Drug Pharmacokinetics Complicates Determination of Bioequivalence: Experience with Verapamil

Purpose. For the assessment of bioequivalence it is assumed that drug clearance in each subject on each of the study days is the same and any observed differences in AUC and/or Cmax between a brand and generic formulation are due to differences in bioavailability. We hypothesized that this assumption was invalid for highly variable drugs such as verapamil and tested it by comparing bioavailability for the brand vs itself. Methods. To avoid any contribution from potential formulation differences, we evaluated bioavailability for Isoptin SR 240 mg tablets in 9 healthy volunteers on 2 occasions separated by 1 week as part of a larger study. A validated HPLC assay was used to measure serial blood samples over 36 hours. Results. The AUC_0–t varied 3.8 fold among subjects and 5/9 subjects had >30% difference in AUC_0–t on the 2 days. After log transformation, the mean AUC_0–t ± %cv (ng·h/mL) on Occasion 1 (878 ± 38) was 23% greater (p = 0.031) than on Occasion 2 (713 ± 41). The 90% confidence interval of Occasion 1/Occasion 2 was 106–143%. The Cmax varied >9 fold (30–278 ng/mL) among subjects. The intra-subject difference between days ranged from –46% to +298%. The 90% confidence interval was 72–152% for Cmax. Since the same lot of Isoptin was used in the same subjects on 2 occasions, the observed differences must be due to biological variability in verapamil pharmacokinetics, not formulation differences. Conclusions. The intra-subject biological variability complicates bio-equivalence assessment and can lead to an erroneous assumption of bioinequi valence.     

Sensitive and Specific Determination of the Equivalence of Absorption Rates

Purpose. To develop a new method for the direct, sensitive evaluation of the equivalence of absorption rates in linear kinetic systems. Methods. Concentrations are obtained before the earlier peak. Ratios of concentrations adjusted for the corresponding ratio of AUCs (area under the curve contrasting plasma concentration with time), or their logarithm, are extrapolated by linear regression to the time of drug administration. The intercept estimates the ratio of absorption rate constants (k_a), or its logarithm. Results. The intercept metric assesses the equivalence of absorption rates with very favourable characteristics. The metric reflects the k_a-ratio specifically (i.e., not affected by other kinetic parameters), is approximately linear to it, exhibits high kinetic sensitivity and excellent statistical properties. With many observations, the intercept metric has near-ideal features, including high power for determining bioequivalence and the ability to detect a 25% difference between k_a values. With only 3 or 4 measurements before the earlier peak, the performance of the metric depends on the preset regulatory conditions. Reasonably good power is noted if the bioequivalence limits determine a 50% difference between two metrics and, approximately, between two k_a values. The intercept metric shows very high power with a wider bioequivalence range. The power declines only moderately with increasing intraindividual variation of k_a. The equivalence of absorption rates is assessed with much higher power by the intercept metric than by C_max. Conclusions. The excellent kinetic and statistical properties of the intercept metric enable the specific and sensitive determination of the equivalence of absorption rates.     

The Duration of Measuring Partial AUCs for the Assessment of Bioequivalence

Purpose. To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (k_aT/k_aR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUC_pT/AUC_pR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared. Results. The power for stating bioequivalence was high when AUC_P was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUC_P was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUC_p was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction. Conclusions. The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.     

Bioequivalence study of 2 orodispersible formulations of ondansetron 8 mg in healthy volunteers

This study was designed to compare the rate and extent of absorption of 2 oral formulations of ondansetron (CAS 99614-02-5) 8?mg orodispersible tablets in healthy volunteers. 22 subjects were administered ondansetron orodispersible tablets of test and reference formulation in a single-dose, 2-period, 2-sequence, fasting, open-label, crossover and randomised study. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline [1] it may be therefore concluded that test formulation of ondansetron 8?mg orodispersible tablet is bioequivalent to the reference formulation.     

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus

Objective Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine.Methods In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing.Results Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77–0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83–0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%.Conclusions Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.     

Metrics Comparing Simulated Early Concentration Profiles for the Determination of Bioequivalence

Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC _P) the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I _{L /H}), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (M _log). For comparison, also properties of C _maxand an ideally evaluated measure (Id) were determined. Results. M _logshowed generally the highest statistical power and KS, and also the largest SE, closely followed by I _{L /H}. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C _max. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M _loghad the highest statistical power, closely followed by I_{L /H}and then by partial AUC.     

Relationship Between Gelation Rate of Controlled-release Acetaminophen Tablets Containing Polyethylene Oxide and Colonic Drug Release in Dogs

Purpose. We hypothesized that sufficient gelation of orally administered hydrophilic matrix tablets before they reach the colon could, as a result of continuous erosion of the gelated matrix, prevent the decrease in colonic drug release which normally occurs here. The purpose of this study was to elucidate the effect of gelation of hydrophilic matrices containing polyethylene oxide on colonic drug release in dogs using controlled-release (CR) acetaminophen tablets. Methods. Two types of CR tablets were prepared, a slow gelling tablet (SG) and a rapid gelling tablet (RG) containing an extra highly water soluble filler. In vitro and in vivo performance were examined. Results. SG and RG showed similar drug release behavior in vitro. In oral administration to dogs, the two formulations showed similar gastrointestinal transit, reaching the colon within 2–4 h after oral dosing. Further, they showed similar maximum plasma levels (Cmax) and time to Cmax (Tmax). In contrast, however, the two tablets produced different plasma levels from 2 h post-dosing, with plasma levels of RG higher than those of SG and with smaller individual variation. Directly observed colonic drug release behavior of RG was similar to in vitro drug release, whereas that from SG was suppressed. Conclusions. Colonic drug release is closely related to the gelation of hydrophilic matrix, and rapid gelation provides continuous in vivo drug release.     

Acute Gastrointestinal Toxic Effects of Suspensions of Unencapsulated and Encapsulated Ibuprofen in Rats

Purpose. The study examined the gastrointestinal (GIT) toxicity effects of suspensions of encapsulated and unencapsulated ibuprofen in male Wistar rats. Methods. Rats were randomly divided into four experimental groups and four control groups, and dosed with suspensions of encapsulated and unencapsulated ibuprofen (17 mg/kg and 44 mg/kg). Bethanechol chloride, a cholinomimetic agent (5 mg/kg), was administered 30 minutes after the dosing, to induce gastric irritation. Blood plasma concentrations were monitored in another set of rats for 12 hours using the encapsulated and unencapsulated systems, to establish drug release and exposure to the mucosa. Results. Evaluation of the upper GI segments after 7 hours revealed that the 44 mg/kg dose of the encapsulated drug significantly reduced the number of lesions present compared to the unencapsulated drug (p < 0.05). At 17 mg/kg, the encapsulated drug reduced toxicity, but not significantly compared to the unencapsulated ibuprofen. Necrosis of the mucosa was observed histopathologically in the unencapsulated drug at both doses, whereas the encapsulated drug treatment revealed preserved mucosa. The encapsulated system had a maximum plasma concentration, Cmax, and time taken to reach Cmax, (Tmax) of 26.7 µg/ml ± 1.5 and 3.6 ± 0.2 hr, respectively. The area under the plasma concentration-time curve, (AUC_0–12), was 158.8 ± 23.5 µg·h/ml, confirming drug release and absorption. Conclusions. Encapsulation of ibuprofen significantly reduced gastrointestinal toxicity especially at the higher dose level and drug was released enough to subject the GI mucosa to irritation, but without the usual toxic effects.     

Bioequivalence study of two capsule formulations containing diacerein 50 mg in healthy human subjects

This study presents the results of a two-way, two-period, two-treatment crossover investigation in 12 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 50 mg of diacerein (CAS 13739-02-1). Both formulations were administered orally as a single dose separated by a one-week washout period. The content of diacerein in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax, values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.63% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.     

Bioequivalence Comparison of Pediatric Dasatinib Formulations and Elucidation of Absorption Mechanisms Through Integrated PBPK Modeling

SPRYCEL^® (Dasatinib) is a Biopharmaceutical Classification System II weakly basic drug that exhibits strong pH-dependent solubility. Dasatinib is currently presented in 2 drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension. A bioequivalence study comparing the formulations in adult healthy subjects found that overall exposure (AUC_0-24) from suspension treatments was ～9% to 13% lower, Cmax was similar, and median Tmax from powder for oral suspension was ～30 min earlier. To understand the mechanism contributing to this behavior, a combination of biorelevant dissolution studies and physiologically based pharmacokinetic modeling was used to simulate in vivo performance. In vitro biorelevant dissolution confirmed that the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 min). Physiologically based pharmacokinetic parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC_0-24 was simulated for tablet dosage forms with 10 to 15 min longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence.