Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics.

This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

A modern view of excipient effects on bioequivalence: case study of sorbitol.

PURPOSE: To examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs. METHODS: Two single-dose, replicated, crossover studies were first conducted in healthy volunteers (N=20 each) to compare the effect of 5 Gm of sorbitol and sucrose on bioequivalence of 150 mg ranitidine or 50 mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (N=24) to determine the threshold of sorbitol effect on bioequivalence of 150 mg ranitidine in solution. RESULTS: Ranitidine Cmax and AUC0-infinity were decreased by approximately 50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC0-infinity. An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC0-infinity, as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25 Gm or greater. CONCLUSIONS: As exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other 'common' excipients that may have unintended influence on bioavailability/bioequivalence.

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.

Predictive ability of level A in vitro-in vivo correlation for ringcap controlled-release acetaminophen tablets.

PURPOSE: The goal of this study was to establish and validate an in vitro-in vivo correlation (IVIVC) for two sustained-release formulations (i.e., a matrix tablet and a RingCap banded matrix tablet) containing 750 mg of acetaminophen. METHODS: The in vitro dissolution and in vivo disposition of these formulations were examined by using a USP type III dissolution apparatus and a single-dose, three-way, crossover study that included an immediate-release acetaminophen dosage form, respectively. An IVIVC was established by using the mean fraction dissolved (FD) and mean fraction absorbed (FA) and used to simulate the plasma concentration-time profile of acetaminophen after administration of the matrix tablet (i.e., internal validation) and RingCap banded matrix tablet (i.e., external validation). RESULTS: A statistically significant relationship (r2 = 0.997, P < 0.001) existed between the FD and FA for matrix tablets and was best described by the equation (FA) = 0.984 x (FD) + 0.0133. The percent predictions errors in CMAX and AUCL were <10% when predicting the plasma concentration-time profiles for the two formulations, validating the internal and external predictability of the IVIVC. CONCLUSIONS: The data (i) show that in vitro dissolution data are a good predictor of in vivo fraction absorbed for acetaminophen, (ii) support the general use of in vitro dissolution data for readily soluble and readily absorbed drugs, (iii) suggest that acetaminophen may serve as a model drug for evaluating novel sustained-release delivery systems, and (iv) provide a tangible example of the limitations of current methods for predicting and validating IVIVC.

Carbamazepine level-A in vivo-in vitro correlation (IVIVC): a scaled convolution based predictive approach.

A method is presented for prediction of the systemic drug concentration profile from in vitro release/dissolution data for a drug formulation. The method is demonstrated using four different tablet formulations containing 200 mg carbamazepine (CZM), each administered in a four way cross-over manner to 20 human subjects, with 15 blood samples drawn to determine the resulting concentration profile. Amount versus time dissolution data were obtained by a 75 rpm paddle method for each formulation. Differentiation, with respect to time, of a monotonic quadratic spline fitted to the dissolution data provided the dissolution rate curve. The dissolution curve was through time and magnitude scaling mapped into a drug concentration curve via a convolution by a single exponential, and the estimated unit impulse response function. The method was tested by cross-validation, where the in vivo concentration profiles for each formulation were predicted based on correlation parameters determined from in vivo-in vitro data from the remaining three formulations. The mean prediction error (MPE), defined as the mean value of 100% x(observed-predicted)/observed was calculated for all 240 cross-validation predictions. The mean values of MPE were in the range of 10-36% (average 22%) with standard deviations (S.D.s) in the range of 9-33% (average 13%), indicating a good prediction performance of the proposed in vivo-in vitro correlation (IVIVC) method.

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.

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.

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

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

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.

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.

Delivery of dehydroepiandrosterone to premenopausal women: effects of micronization and nonoral administration.

OBJECTIVES: This single-dose study compares three dehydroepiandrosterone delivery methods (oral crystalline steroid, micronized steroid, and vaginal administration) to ascertain whether physiologic levels of circulating dehydroepiandrosterone and dehydroepiandrosterone sulfate can be obtained while increases in testosterone are minimized. STUDY DESIGN: Two randomized, double-blind, placebo-controlled single-dose comparisons were made. For oral micronized versus crystalline dehydroepiandrosterone 300 mg doses of micronized or crystalline dehydroepiandrosterone were administered, followed by 6 hours of blood sampling (n=7). Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels were measured; areas under the curve and mean peak values were analyzed by Student-Newman-Keuls tests. For oral versus vaginal micronized dehydroepiandrosterone 150 mg oral or vaginal doses of micronized dehydroepiandrosterone were administered, followed by blood sampling over 12 hours (n=5). Data analysis was as described. RESULTS: Oral micronized and unmicronized dehydroepiandrosterone resulted in increases in serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. Micronization increased the area-under-the-curve ratios for dehydroepiandrosterone sulfate/dehydroepiandrosterone and dehydroepiandrosterone sulfate/testosterone. Vaginal administration provided equivalent serum dehydroepiandrosterone; however, it failed to increase dehydroepiandrosterone sulfate or testosterone over placebo. CONCLUSION: Micronization of oral dehydroepiandrosterone diminishes bioconversion to testosterone. Vaginal dehydroepiandrosterone delivers equivalent dehydroepiandrosterone but substantially diminishes dehydroepiandrosterone bioconversion.

Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women.

OBJECTIVE: To demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles. DESIGN: Oral micronized DHEa (50 mg/d) was administered in 3-week treatments to 11 postmenopausal women in a prospective, placebo-controlled, randomized, blinded, crossover trial with an interarm washout. After dose (23 hour) serum DHEA, DHEAS, T, and cortisol levels were measured, as were fasting lipoproteins, oral glucose tolerance tests (OGTT), T-lymphocyte insulin binding and degradation, and urine collagen cross-links. Morphometric changes were determined by hydrostatic weighing. RESULTS: Dehydroepiandrosterone sulfate, DHEA, T, and free T increased up to two times premenopausal levels with treatment. Fasting triglycerides declined; no change in collagen cross-links or morphometric indexes was noted. Oral glucose tolerance test parameters did not change, but both T-lymphocyte insulin binding and degradation increased with DHEA. CONCLUSION: Fifty milligrams per day of oral DHEA gives suprahysiologic androgen levels; 25 mg/d may be more appropriate. Dehydroepiandrosterone enhanced tissue insulin sensitivity and lowered serum triglycerides. Rationale is provided for postmenopausal replacement therapy with this androgen.

Pharmacokinetic comparison of a once-daily and twice-daily theophylline delivery system.

The steady-state pharmacokinetics of a formulation of a 24-hour extended-release theophylline preparation (Uni-Dur) were compared with a twice-daily formulation (Theo-Dur) in healthy volunteers. Eighteen healthy, adult, male volunteers received both treatments (600-mg dose of Uni-Dur every morning for 5 doses or 300 mg every 12 hours for 10 doses of Theo-Dur) in a randomized, two-way crossover design with no washout period between treatments. Blood samples were collected just before doses 3, 4, and 5 of Uni-Dur and before doses 5, 7, and 9 of Theo-Dur, as well as at 2-hour intervals for 24 hours following doses 5 of Uni-Dur and doses 9 and 10 of Theo-Dur. The mean serum theophylline concentration-time curves were similar for both formulations from 2 to 18 hours postdose, and the maximum serum theophylline concentrations were comparable (7.66 micrograms/mL for Uni-Dur compared with 7.78 micrograms/mL for Theo-Dur). Fluctuations in serum theophylline concentrations were greater with Uni-Dur (139 +/- 85% compared with 72 +/- 25% normalized to trough serum concentrations; 77 +/- 22% compared with 53 +/- 13% normalized to average steady-state serum concentrations). Based on the area under the curves, the extent of absorption of Uni-Dur was 91.42 +/- 14.24% of Theo-Dur. These findings suggest that the clinical response in patients treated with once-daily Uni-Dur may be equivalent to Theo-Dur given every 12 hours. Furthermore, because of the similar serum concentration over time profiles of the two formulations, it is unlikely that additional monitoring of serum levels during a conversion will be necessary.

Comparative steady-state bioavailability of Theo-24 and Theo-Dur in healthy men.

This study was designed to compare the steady-state theophylline serum concentrations produced by 800 mg daily doses of Theo-24 and Theo-Dur in normal, healthy men administered according to each product's recommended dosing instructions. Sixteen subjects with theophylline clearances ranging from 0.39 to 0.95 mL/min/kg (average, 0.60 mL/min/kg) and theophylline elimination half-lives ranging from 5.1 to 10.5 hours (average 7.9 hours) completed the study. They were all nonsmokers, who ranged in age from 18 to 44 years and were within 10% of normal weight for their height and build. Theo-24 demonstrated a high extent of absorption (89%, range 54% to 115%) relative to Theo-Dur. Both formulations demonstrated similar times to maximum theophylline concentration (11.3 hours for Theo-24 and 11.5 hours for Theo-Dur), similar peak to trough concentration ratios relative to the trough concentration (74% for Theo-24, 62% for Theo-Dur) and similar periods of time within 5 to 15 mg/L (25.2 to 75.7 mumol/L; 21.4 hours for Theo-24, 19.4 hours for Theo-Dur). No "dose dumping" was demonstrated. The results indicate that Theo-24 dosed at least one hour prior to a high-fat breakfast produces serum theophylline concentrations in a range similar to Theo-Dur administered every 12 hours.

Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women.

OBJECTIVE: This study tests the hypothesis that dehydroepiandrosterone or its metabolic products are immunomodulatory in postmenopausal women with relative adrenal androgen deficiency. STUDY DESIGN: A prospective, randomized, double-blind, crossover study of 11 subjects with 3-week treatment arms separated by a 2-week washout period was performed. Immunologic evaluation at the beginning and end of the treatment arms consisted of flow cytometry to delineate T-cell populations, in vitro T-cell mitogenic response and cytokine production, and natural killer cell cytotoxicity. Statistical analysis was based on a split-plot design with analysis of variance with repeated measures. RESULTS: Dehydroepiandrosterone supplementation decreased CD4+ (helper) T cells and increased CD8+/CD56+ (natural killer) cells. Although T-cell mitogenic and interleukin-6 responses were inhibited, natural killer cell cytotoxicity increased dramatically. CONCLUSIONS: These data provide the first in vivo evidence in human for an immunomodulatory effect of dehydroepiandrosterone. The salutary immune changes could account for clinical and experimental evidence of antioncogenic effects of this steroid. This study provides a strong rationale for further clinical studies on dehydroepiandrosterone supplementation in adrenal androgen-deficient states.

Biopharmaceutical factors in seizure control and drug toxicity.

Problems related to bioequivalence and bioavailability for four antiepileptic drugs (AEDs) are reviewed. Bioequivalence and bioavailability of AEDs can be affected by many factors, including physicochemical characteristics of the agent, the dosage form, and physiological condition of the patient. In 1988, breakthrough seizures prompted an FDA investigation of one company's generic carbamazepine tablets. Results indicated that the manufacturer had changed its source of carbamazepine, which led to a wide range of dissolution characteristics for different lots of tablets. In two separate studies, clonazepam was shown to be more rapidly absorbed in patients with a normal gastric pH than in those with a higher-than-normal gastric pH. With phenytoin, which exhibits nonlinear pharmacokinetics, differences in the rate and extent of absorption can adversely affect the bioavailability of this agent. Finally, the bioequivalence of generic primidone was contested in an adolescent girl who appeared to experience more frequent seizures with a generic product than with a trade formulation. The effectiveness of a drug depends on complex interactions involving the drug, the drug product formulation, and the patient. Minimizing variability in the absorption process is particularly important with AEDs, because of their narrow therapeutic range.

The effect of gastric pH on the absorption of controlled-release theophylline dosage forms in humans.

The bioavailability of three marketed controlled-release dosage forms and a reference solution of theophylline was studied in eight subjects with normal gastric fluid acidity and seven subjects who were achlorhydric. Gastric pH was monitored with a Heidelberg capsule. One of the controlled-release dosage forms dissolved more rapidly in vitro when exposed to acid conditions, one dissolved more rapidly in pH 7.5 media, and the third dissolved at a rate independent of pH. Using a crossover design, each subject received each dosage form twice. Blood was sampled for up to 47 hr after each dose, and serum was assayed for theophylline by HPLC. The product which dissolved more rapidly under acid conditions in vitro exhibited a 3 hr longer Tmax in the achlorhydrics compared to the normal subjects. The product which dissolved more rapidly in the pH 7.5 media exhibited a relatively higher AUC(0-infinity) in the achlorhydric subjects than in normal subjects after the AUC data were normalized for clearance differences between the two subject groups. The in vivo bioavailability of these dosage forms could be related to the in vitro dissolution characteristics for some parameters. However, with the exception of the mean Tmax values, the mean bioavailability parameters differed by less than 20% between the two subjects groups.

The bioinequivalence of carbamazepine tablets with a history of clinical failures.

The bioavailability of three lots of a generic 200-mg carbamazepine tablet, which had been withdrawn from the market, was compared to the bioavailability of one lot of the innovator product in 24 healthy volunteers. Fifty-three lots of the generic product had been recalled by the manufacturer because of concerns over reports of clinical failures for several of the lots. The three generic lots tested in this study exhibited a wide range of bioavailability, as well as large differences in the in vitro dissolution rates. The mean maximum carbamazepine plasma concentrations for two of the generic lots were only 61-74% that of the innovator product, while the third lot was 142% of the innovator. The mean areas under the plasma concentration-time curve for the three generic lots ranged from 60 to 113% that of the innovator product. The results clearly indicate a significant difference in the rate and extent of absorption of the generic products compared to the innovator, as well as among the generic lots. A good relationship was found between the in vivo parameters and the in vitro dissolution results for the four dosage forms.