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Biomedical subjects

V P Shah

Publications and source records attributed to V P Shah.

At least 19 recordsLinked to original sources
PubMed2001

Variability in the bioavailability of phenytoin capsules in males and females.

PURPOSE: To determine inter-lot and intra-subject variability in the bioavailability of the 100 mg extended phenytoin sodium capsules. In addition, to determine the effect of gender and menstrual cycle on phenytoin bioavailability. METHODS: Three different lots of extended phenytoin sodium capsules were given to 12 healthy male and 12 healthy female subjects in a crossover fashion. One of the lots was also given a second time to each subject. Plasma phenytoin was determined, using an HPLC assay, in samples collected over a 73-hr period after each dose. RESULTS: The mean Cmax for the four administrations ranged from 1.71-1.79 microg/ml and mean AUC(0-infinity) values from ranged 53.0-54.1 microg*hr/ml. The elimination half-life was 3 hr shorter, and the AUC(0-infinity) adjusted for the mg/kg dose was 30% lower for females. Average bioequivalence was demonstrated between the three lots for both Cmax and AUC(0-infinity) based on the BE limit of 80-125%. Further, all confidence intervals of AUC(0-infinity) fell within the limit of 90-111%. There were no differences in the confidence limits for Cmax and AUC(0-infinity) determined separately for males and females. Also, there was no difference in the mean Cmax or AUC(0-infinity) for females when analyzed as a function of the week of their menstrual cycle. Individual bioequivalence was demonstrated between three lots of phenytoin using the constant-scaled method, but not the reference-scaled method. CONCLUSIONS: There was very little difference in the bioavailability of the three lots of phenytoin. Females exhibited a lower AUC(0-infinity) than males after adjustment of dose for body weight, but their inclusion in the study did not affect the assessment of bioequivalence. When dose was not adjusted for body weight, no difference in AUC(0-infinity) was seen between males and females.

Adult↗
PubMed2001

Progress in methodologies for evaluating bioequivalence of topical formulations.

Assessment of bioequivalence of topical dermatological formulations is a challenge. Currently, comparative clinical studies are used to establish bioequivalence for most formulations (except corticosteroids). This article reviews different in vivo methodologies for determining bioequivalence, and the progress made in this area. Dermatopharmacokinetics is the term used to describe the pharmacokinetics of topically applied drugs in the stratum corneum. A tape stripping procedure used in dermatopharmacokinetic methodology measures the drug concentration in stratum corneum at the site of application. Various studies have shown dermatopharmacokinetics to be a reliable and reproducible method for determining bioequivalence, and have indicated that it is applicable for all topical dermatological drug products. However, confidence in this methodology needs to be established, particularly regarding its relevance to clinical drug efficacy.

Administration, Topical↗
PubMed2000

Dissolution testing as a prognostic tool for oral drug absorption: dissolution behavior of glibenclamide.

PURPOSE: The dissolution behavior of two commercially available glibenclamide formulations was tested in various media. The aim of the study was to investigate whether the use of biorelevant dissolution media (BDM) would be advantageous over the use of standard media for predicting the in vivo performance of the two formulations. METHODS: The dissolution tests were performed using USP 23 apparatus 2. Conventional buffers and USP media were compared with two BDM containing different amounts of lecithin and sodium taurocholate. RESULTS: The dissolution of two drug powders was highly dependent on wetting, particle size, pH, and the composition of the medium used. In addition, the dissolution behavior of the two glibenclamide formulations showed differences in all media tested. The dissolution results of the two formulations were compared with those from an in vivo bioequivalence study undertaken by the central quality control laboratory of the German pharmacists (ZL). The bioequivalence criterion set by the ZL requires more than 80% drug release within 10 minutes. Results in FaSSIF, one of the BDMs, met the ZL criterion and this medium was also able to discriminate between the two formulations. This was not the case for the other media tested. CONCLUSIONS: The study indicates that BDM are better able to discriminate between glibenclamide formulations than standard dissolution media.

Administration, Oral↗
PubMed2000

Bioequivalence of methylphenidate immediate-release tablets using a replicated study design to characterize intrasubject variability.

PURPOSE: To determine the relative bioavailability of two marketed, immediate-release methylphenidate tablets. The study used a replicated study design to characterize intrasubject variability, and determine bioequivalence using both average and individual bioequivalence criteria. METHODS: A replicated crossover design was employed using 20 subjects. Each subject received a single 20 mg dose of the reference tablet on two occasions and two doses of the test tablet on two occasions. Blood samples were obtained for 10 hr after dosing, and plasma was assayed for methylphenidate by GC/MS. RESULTS: The test product was more rapidly dissolved in vitro and more rapidly absorbed in vivo than the reference product. The mean Cmax and AUC(0-infinity) differed by 11% and 9%, respectively. Using an average bioequivalence criterion, the 90% confidence limits for the Ln-transformed Cmax and AUC(0-infinity), comparing the two replicates of the test to the reference product, fell within the acceptable range of 80-125%. Using an individual bioequivalence criterion the test product failed to demonstrate equivalence in Cmax to the reference product. CONCLUSIONS: The test and reference tablets were bioequivalent using an average bioequivalence criterion. The intrasubject variability of the generic product was greater and the subject-by-formulation interaction variance was borderline high. For these reasons, the test tablets were not individually bioequivalent to the reference tablets.

Adult↗
PubMed2000

The effect of gelatin cross-linking on the bioequivalence of hard and soft gelatin acetaminophen capsules.

PURPOSE: To determine if changes in the in vitro dissolution of hard and soft gelatin acetaminophen capsules, which result from gelatin crosslinking, are predictive of changes in the bioavailability of the capsules in humans. METHODS: Both hard and soft gelatin capsules were "stressed" by a controlled exposure to formaldehyde, resulting in unstressed, moderately stressed and highly stressed capsules. In vitro dissolution studies were conducted using water or SGF with and without pepsin as the media. Separate 24-subject, 3-way crossover human bioequivalence studies were performed on the unstressed and stressed acetaminophen capsules. Plasma acetaminophen was determined by high performance liquid chromatography (HPLC) for 12 hr after each dose. RESULTS: The in vitro rate of dissolution of hard and soft gelatin capsules was decreased by crosslinking. The bioequivalence studies showed that both hard and soft gelatin capsules, which failed to meet the USP dissolution specification in water, but complied when tested in SGF containing pepsin, were bioequivalent to the unstressed control capsules. The capsules that were cross-linked to the greatest extent were not bioequivalent to the unstressed control capsules, based on Cmax. A trend toward an increase in Cmax with increased level of cross-linking was observed, but this was only significant for the severely stressed capsules. CONCLUSIONS: On the basis of this study a two-tier in vitro dissolution test was developed using enzymes to distinguish between bioequivalent and bioinequivalent gelatin capsules.

Acetaminophen↗
PubMed1999

Bioequivalence of immediate-release theophylline capsules.

A three-way crossover study in 18 healthy male volunteers was conducted to evaluate the bioequivalence of three different 200 mg anhydrous theophylline immediate-release (IR) capsules. The products had not been rated as therapeutically equivalent by the US Food and Drug Administration (FDA) owing to a lack of bioequivalence data. Serum samples were obtained from 0 to 34 h after dosing. Mean time of maximum serum concentration (T(max)) ranged from 1.3 to 1.4 h. Mean values for the maximum serum concentration (C(max)) and the area under the serum concentration-time curves (AUC) differed by <5% for the three products. The confidence limits for Ln-transformed C(max) and AUC ranged from >/=89 to </=113%. It was concluded that the three products were bioequivalent. In addition, the rapid in vitro dissolution of these formulations, as well as the reported high solubility and high permeability of theophylline, was predictive of the lack of any bioavailability differences among the three products.

Adult↗
PubMed1999

Assessment of value and applications of in vitro testing of topical dermatological drug products.

The FDA recently issued a guidance covering practices of scaleup and post approval changes with semisolids (SUPAC-SS). This guidance outlines the steps that must be taken by a company to maintain certification of its semisolid dermatological products after quantitative changes have been made in their compositions and/or after changes have been made in the sourcing of their key ingredients, in their processing, in their batch sizes, and/or after their site of manufacture has been relocated. A key element within the guidance is a release test to be used to determine if the diffusional release of a drug found in a formulation is the same after changes have been made to the formulation as it was prior to implementing the changes. The AAPS-FDA sponsored workshop was set up to explore this qualifying test. The stated aims of the workshop were: a) to illustrate the methodology and techniques of in vitro release testing, b) to show the sensitivity of in vitro release with respect to manufacturing variables and to variations in components and composition (of specific formulations), c) to recognize in vitro release testing as a useful procedure for SUPAC documentation, d) to highlight and evaluate other applications of in vitro release testing, e) to explore the degree to which in vitro release testing and bioavailability may be related, and f) to evaluate the role of in vitro release testing of topical dosage forms as a tool to improve product quality.

Administration, Topical↗
PubMed1999

Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling.

BACKGROUND: Dermatologic corticosteroid products produce skin blanching that is related to clinical potency and dose. (For application of the vasoconstrictor assay to bioavailability and bioequivalence assessment, dose is defined in terms of duration of treatment exposure [dose duration], so the terms dose and dose duration have been used interchangeably). The vasoconstrictor assay is the method of choice to assess dermatologic corticosteroid products bioequivalence if dose-response is validated. This article examines dose-response validation to meet objectives of US Food and Drug Administration (FDA) bioequivalence guidance for dermatologic corticosteroid products. METHODS: An exploratory dose-response study was conducted to determine applicability of the empirical maximum effect (Emax) model to the individual subject and population dose-response relationships of six dermatologic corticosteroid product creams that varied from the most to the least potent classes. Products were applied to the skin of 10 healthy subjects in each of two dosing periods for dose durations of 0.5, 1, 2, and 6 hours. Skin blanching was measured by reflectance colorimeter through 24 hours after application. Area under the effect curve (AUEC) was determined for each dose duration. An Emax model was fitted to the AUEC versus dose duration data. A similar analysis was conducted for a bioequivalence study on two formulations of a dermatologic corticosteroid product in 40 healthy subjects. RESULTS: In the exploratory study, the number of individual subject data sets for which the Emax model provided an acceptable fit generally increased with the potency of the dermatologic corticosteroid product. On the basis of population modeling, dose-response data of all products, except the lowest potency cream, were adequately described by the Emax model. Values for population ED50 (the dose duration required to achieve 50% of the fitted AUECmax value) decreased with increase in dermatologic corticosteroid product potency. CONCLUSIONS: Acceptable model fits to all individual subject dose-response data were not achieved for any dermatologic corticosteroid product. However, population dose-responses were adequately described by the Emax model. On the basis of these data, the optimal dose duration used for comparison of multisource dermatologic corticosteroid products is recommended to be equal to the ED50 based on population modeling of pilot dose-response study data.

Adrenal Cortex Hormones↗
PubMed1999

Evaluation of the test system used for in vitro release of drugs for topical dermatological drug products.

The purpose of this research was to evaluate different parameters that can influence in vitro drug release from topical dermatological drug products such as creams, gels, and ointments. In vitro release from topical dermatological drug products was carried out by using a static diffusion cell, a synthetic membrane, and an appropriate receptor medium. The receptor medium was mixed by means of a magnetic bar rotated at 400 rpm. Experiments were designed to evaluate the influence of (i) receptor media, (ii) different lots of synthetic membranes, and (iii) agitation on drug release. Release experiments were also carried out to study inter- and intralot variability. The in vitro release test was used to evaluate the marketed glucocorticoid products. Among the parameters studied, the receptor medium was found to be the most important and critical variable that influenced drug release. The release rate ranged between 0.61 and 2.68 micrograms/cm2/min0.5 for betamethasone dipropionate, depending on the percentage of ethanol in the receptor medium. The drug release was not influenced by agitation or by different lots of synthetic membranes. Very small inter- and intralot variability was observed. These experiments establish the ruggedness of the in vitro diffusion cell test system used for the drug release measurements.

Administration, Topical↗
PubMed1998

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo.

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.

ATP Citrate (pro-S)-Lyase↗
PubMed1998

The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets.

PURPOSE: To determine if three marketed generic carbamazepine tablets were bioequivalent to the innovator formulation, as well as to each other. In addition, to examine in vivo-in vitro relationships among the four formulations. METHODS: Each formulation was given as a single dose to 18 healthy male and female subjects using a crossover design. Blood samples were collected for 169 hr. Carbamazepine was assayed by HPLC with UV detection. RESULTS: In vivo fraction absorbed plots indicated that the three generic formulations were absorbed more rapidly than the innovator product, and the mean time of maximum plasma concentration was 6-7 hr sooner for the generic formulations. The mean maximum plasma concentration ranged from 17-19 percent higher for the generic products compared to the innovator, and the 90% confidence limits for Cmax data ranged from 11 1% to 126%. The mean AUC(0-infinity) for the generic products ranged from 101-104% compared to the innovator, and the confidence limits for AUC ranged from 97-108%. CONCLUSIONS: The generic products were all more rapidly absorbed than the innovator, but simulations of steady-state concentrations indicated that it would be unlikely that these differences would have any significant clinical effect. An excellent association was seen between the Cmax and the percent of drug dissolved in vitro. The correlation was used to accurately predict the Cmax of four other 200 mg tablets evaluated in an earlier study.

Adult↗
PubMed1998

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Adult↗
PubMed1998

In vitro dissolution profile comparison--statistics and analysis of the similarity factor, f2.

PURPOSE: To describe the properties of the similarity factor (f2) as a measure for assessing the similarity of two dissolution profiles. Discuss the statistical properties of the estimate based on sample means. METHODS: The f2 metrics and the decision rule is evaluated using examples of dissolution profiles. The confidence interval is calculated using bootstrapping method. The bias of the estimate using sample mean dissolution is evaluated. RESULTS: 1. f2 values were found to be sensitive to number of sample points, after the dissolution plateau has been reached. 2. The statistical evaluation of f2 could be made using 90% confidence interval approach. 3. The statistical distribution of f2 metrics could be simulated using 'Bootstrap' method. A relatively robust distribution could be obtained after more than 500 'Bootstraps'. 4. A statistical 'bias correction' was found to reduce the bias. CONCLUSIONS: The similarity factor f2 is a simple measure for the comparison of two dissolution profiles. But the commonly used similarity factor estimate f2 is a biased and conservative estimate of f2. The bootstrap approach is a useful tool to simulate the confidence interval.

Chemistry, Pharmaceutical↗
PubMed1998

Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms.

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.

Administration, Oral↗
PubMed1998

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets.

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.

Adrenergic beta-Antagonists↗
PubMed1997

In vitro dissolution profile comparison and IVIVR. Carbamazepine case.

Dissolution data for the immediate or modified release drug products are usually collected as percent dissolved at multiple time points. Once an in-vitro/in-vivo relationship is established on a drug product, the dissolution profile becomes meaningful and important. In that context, if a firm desires to modify its formulation on which the in-vitro/in-vivo association has been established, a meaningful insight into the pharmacokinetics may be obtained by comparing the dissolution profiles of the two lots. In this presentation, we demonstrated a model dependent dissolution profile comparison approach using example of carbamazepine tablet dissolution data. Once a mathematical function was selected to describe the dissolution data coming from various standard lots, a similarity region could be constructed using the model parameter variances. To compare the test and reference lot dissolution profiles, a statistical distance was calculated between the mean parameters. A confidence region generated around the normalized mean statistical distance could then be compared with the similarity region to assess the similarity or dissimilarity of the dissolution profiles.

Biological Availability↗