Correlation between pharmacokinetic parameters of rifampicin and its biologically active metabolite as related to estimation of the relative bioavailability of the antibiotic

In the bioavailability studies with drugs biotransformed to biologically active metabolities only the concentrations of the parent drug (PD) are usually taken into account even when the pharmacokinetic data on the metabolite(s) (M) are available. However, such data may be useful as an alternative source for the bioavailability determination. Moreover, the clinical outcomes often depend on both the PD and M concentrations. The aim of the study performed with two rifampicin formulations, tablets and dragee, was to correlate the pharmacokinetic parameters of the PD and 25-O-deacetylrifampicin, a microbiologically active M of rifampicin, and to examine whether the bioavailability parameters based on the PD and M concentrations were compatible. The serum concentrations of the PD and M were determined in 8 healthy volunteers by HPLC. Despite different patterns of the PD and M pharmacokinetic profiles the PD peak concentration (Cmax) and especially the AUC correlated with Cmax or the AUC of the M (r = 0.76 and 0.92 respectively). Moreover, the extent of the absorption expressed as the AUC ratio for the PD correlated with the AUC ratio for the M (r = 0.86). However, neither the time to reach the maximum (tmax), nor the Cmax/AUC ratio, a measure of the absorption rate, based on the PD pharmacokinetic data correlated with the respective parameters calculated with using the M concentrations. Thus, only the estimates of the extent of the absorption and not of the absorption rate based on the PD and M data may be considered as compatible.     

Bioequivalence of a highly variable drug: an experience with nadolol

PURPOSE: To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC infinity, and Cmax in bioequivalence determinations. METHODS: Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. RESULTS: Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC infinity. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. CONCLUSIONS: Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.     

A single and multiple dose bioavailability study with carbamazepine 400 mg retard tablets with reference to enzyme autoinduction and circadian time differences

Both single and multiple dose bioequivalence studies are required to assess the quality of modified release formulations of drugs. In bioequivalence studies of drugs with enzyme autoinducing properties such as carbamazepine (CBZ), the standard multiple dose study design must be modified to guarantee equivalence of drug elimination. This problem was considered with regard to carbamazepine 400 retard AWD (test) whose bioavailability relative to a listed reference (Tegretal 400 retard) was studied in 2 randomized, open, crossover studies both with 18 healthy volunteers of Caucasian origin (20-36 years, 61.5-92 kg, 172-195 cm). The single dose study was done with 400 mg CBZ. Serum concentration time profiles of CBZ and its active metabolite CBZ-10,11-epoxide were determined until 144 h after administration. The multiple dose study was performed with 400 mg CBZ b.i.d. for 15 days (first 2 days: 200 mg b.i.d.) followed by a 7-day study with the alternative investigational product. 24-hour serum concentration time profiles of CBZ and its metabolite were measured on days 15 and 22 of the study. The quantitative drug analysis was done with an HPLC method the quality of which fulfilled the requirements of bioequivalence studies. Test was considered bioequivalent to reference with regard to the extent of absorption, if the 90% confidence intervals of the AUC0-infinity ratio (single dose) and AUC0-24h ratio (multiple dose) were within the range of 0.80-1.25, and with regard to rate of absorption if the 90% confidence intervals of the Cmax/AUC ratio (single dose) or AUCF0-24h ratio were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratio (test/reference) of CBZ were 0.979 (0.94, 1.02) for the single and 1.01 (0.947, 1.076) for the multiple dose comparison. The point estimator (90% confidence limits) of the Cmax/AUC ratio was 0.989 (0.959, 1.020) and of the AUCF0-24h ratio 1.066 (0.937, 1.212). There were no circadian time differences in any pharmacokinetic parameter. In conclusion: Carbamazepine 400 retard AWD tablets were bioequivalent to reference with regard to extent and rate of absorption after both single and multiple dose administration.     

Comparative bioavailability of two atenolol tablet formulations in healthy male volunteers after a single dose administration

The bioavailability of 2 atenolol tablet formulations (Angipress from Laboratórios Biosintética, and Atenol from Wellcome ICI Laboratory, Brazil) were compared in 18 healthy male volunteers who received a single 50 mg dose of each atenolol formulation. The study was conducted following an open randomized 2-period crossover design with a 14-day washout interval between doses. Plasma samples were obtained over a 24-hour interval and atenolol concentrations were determined by HPLC with fluorimetric detection. From the plasma atenolol concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(zero-24) (area under the concentration vs time curves from 0-24 h), ke (terminal elimination constant), t1/2 (terminal first order elimination half-life), AUC (area under the concentration vs time curves extrapolated to infinity), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax) and Cmax/AUC. All these variables were analyzed using both parametric and nonparametric statistics. Geometric mean Angipress/Atenol individual percent ratios were 99.6% for AUC(zero-24), 99.7% for AUC, 98.0% for Cmax, 102.8% for t1/2, 97.2% for ke and 97.8% for Cmax/AUC, with all their 90% confidence intervals within the bioequivalence range 80-125%, thus showing similar patterns of absorption and disposition. Arithmetic mean for individual Tmax differences was 0.8 h, and the 90% confidence interval did not include the zero value. Based on these results and in accordance with the European Union and the US Food and Drug Administration bioequivalence requirements we conclude that both atenolol formulations are bioequivalent for both the extent and the rate of absorption.     

Influence of food on the oral bioavailability of loratadine and pseudoephedrine from extended-release tablets in healthy volunteers

The effect of a high-fat breakfast on the bioavailability of the components of an extended-release tablet containing 10 mg loratadine in the immediate-release coating and 240 mg pseudoephedrine sulfate in the extended-release core was studied in 24 healthy male volunteers in a single-dose, two-way crossover study. The drug was administered after a 10-hour overnight fast or within 5 minutes of consuming a standardized high-fat breakfast. Serial blood samples were collected over a 48-hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCzero-infinity) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner-Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration-time profiles and values for Cmax and AUCzero-infinity of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax (53%) and AUC from time zero to the final quantifiable sample (AUCif) (76%). However, the resultant Cmax and AUC of loratadine under fed conditions were well below those previously obtained at steady-state after multiple-dose administration of loratadine (40 mg/day) that were shown to be safe and well-tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended-release tablet is not likely to be clinically significant.     

Does AIDS impair the absorption of antituberculosis agents?

SETTING: Case reports of low serum concentrations of antituberculosis drugs, with resultant treatment failure and emergence of drug-resistant organisms in patients with the acquired immune-deficiency syndrome (AIDS), have prompted suggestions that therapeutic drug monitoring (TDM) may be indicated in patients co-infected with the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. OBJECTIVE: To test whether the bioavailability of antituberculosis drugs is altered in HIV-infected patients with tuberculosis. METHOD: Twenty-seven hospitalized tuberculosis patients (13 with AIDS, 14 HIV-negative) were entered into a pharmacokinetic trial. Following the supervised administration of standardized doses of isoniazid, rifampicin and pyrazinamide, the plasma concentrations of the drugs were measured repeatedly over 12 hours and the following parameters were derived for each agent: maximum measured drug concentration (Cmax), time-to-maximum measured drug concentration (Tmax) and area-under-the-concentration-time curve to 12 hours (AUC). RESULTS: No significant differences emerged between the two groups in Cmax, Tmax, and AUC for isoniazid and pyrazinamide. For rifampicin the AIDS patients showed a greater AUC (P < 0.01) than the controls, but there were no significant differences in Cmax and Tmax. CONCLUSION: There was no evidence that HIV infection reduced the plasma concentrations of antituberculosis drugs.     

The bioequivalence of a new amitriptyline tablet formulation in comparison with a reference preparation

An investigation of the bioequivalence of a new tablet formulation (amitriptylin 25 von ct) with 28.3 mg amitriptyline hydrochloride (CAS 549-18-8) was performed in a two-way cross-over study with 18 subjects. The relative bioavailability with respect to a reference preparation for AUC related to amitriptyline (CAS 50-48-6) was 99.3% and for Cmax 100.4%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters related to amitriptyline and the metabolite nortriptyline (CAS 72-69-5), respectively tmax showed no difference. The new formulation was bioequivalent to the reference.     

Bilateral isolated metastases of malignant melanoma to the cerebellopontine angle

PURPOSE: Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, 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 Cmax (Tmax) instead of Cmax. METHODS: We have previously redirected attention to Tmax 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 Tmax 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 Tmax 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, Cmax, a continuous variable peak-height or extent measure has usurped Tmax's function and performs erratically as a substitute measure for the rate of absorption. Second, Tmax, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, Cmax), 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 alpha 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.     

Comparative studies of quality and bioavailability of methotrexate in Thai patients with rheumatoid arthritis

The bioavailability of the two generic methotrexate oral preparations (Emtrexate, Pharmachemie Company, Holland and Methotrexate Remedica, Remedica, Cyprus as the test preparations), were compared to the innovator (Methotrexate Lederle, Lederle, U.S.A. as the reference) in 10 patients with rheumatoid arthritis. A single 7.5 mg oral dose of each preparation was given to the subjects in a randomized, double-blind, three-period crossover design with a 1 week washout period. Serum methotrexate concentrations were determined by using Fluorescence Polarization Immunoassay (Abbott TDx). No significant differences in pharmacokinetic parameters (AUC, Cmax, and Tmax) were observed between the test and reference preparations. The mean and 90 per cent CI of the ratio Emtrexate/Methotrexate Lederle and Methotrexate Remedica/Methotrexate Lederle of the Cmax, AUC0-8, and AUC0-alpha were 0.93 (0.87-1.00), 0.9 (0.82-0.98), 0.88 (0.79-0.99) and 0.97 (0.93-1.02), 0.95 (0.90-0.99), 0.94 (0.86-1.02), respectively. These values were well within the acceptable bioequivalence range of 0.8-1.25. The mean and 90 per cent CI of Tmax difference between Emtrexate-Methotrexate Lederle and Methotrexate Remedica-Methotrexate Lederle also overlapped the stipulated bioequivalence range of the Tmax differences of +/- 0.25 hour. Thus, Emtrexate and Methotrexate Remedica were considered bioequivalent to the reference Methotrexate Lederle regarding the rate of absorption and the extent of absorption.     

Genotypically dependent effects of cyromazine on reproduction and offspring development in the Australian Lucilia cuprina (Diptera: Calliphoridae)

Various factors may influence bioavailability and blood concentrations of cyclosporine, a problem that may be compounded by diseases such as cystic fibrosis in which impaired absorption through the gastrointestinal tract is common. Neoral, a microemulsion formulation of cyclosporine, has improved bioavailability and more stable blood concentrations than earlier formulations. We conducted a prospective, open, crossover study to examine whether these findings held true in 12 clinically stable patients with cystic fibrosis who had undergone lung transplantation at least 6 months earlier. In the first arm, patients continued their usual dosage of cyclosporine twice/day. In the second arm they received Neoral for at least 1 week before having blood studies. For each arm whole blood trough concentrations were drawn for 7-10 successive days, together with a pharmacokinetic study with concentrations drawn at times zero, 1, 2, 3, 4, 6, 12, and 24 hours. Variance was assessed from morning concentrations. Area under the curve from zero to 12 hours (AUC12), maximum concentration (Cmax), and time to Cmax (Tmax) were calculated for each arm. Eleven subjects completed the protocol. The daily variance for Neoral was significantly less than for cyclosporine (p=0.04). The AUC12 for Neoral and cyclosporine were 4164+/-1467 and 5318+/-1670 microg x L/hour (p=0.09), respectively. Respective Cmax were 613+/-242 and 931 +/-458 microg/L (p=0.08) and relative Cmax and AUC12 were 1.91 and 1.47 (p<0.05). Thus Neoral had a superior pharmacokinetic profile and less day-to-day variability in patients with cystic fibrosis who had undergone lung transplantation.     

Comparative pharmacokinetics and bioavailability of two cotrimoxazole preparations

The objective of this study was to assess both pharmacokinetic properties and bioavailability of a newly developed cotrimoxazole preparation (Bioprim tablets, 80 mg of trimethoprim/400 mg sulfamethoxazole), in comparison with a reference preparation commercially available (Bactrim tablets, 80 mg of trimethoprim/400 mg of sulfamethoxazole). The pharmacokinetics and bioavailability of cotrimoxazole from these preparations were compared in an open randomized crossover study in 12 healthy males. Plasma concentrations of trimethoprim and sulfamethoxazole were measured by HPLC after protein precipitation. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The obtained pharmacokinetic values (Cmax, tmax, beta, t1/2 beta, CL, Vd, AUC36, AUC infinity) of both trimethoprim and sulfamethoxazole determined in our study agreed with values reported in the literature. Westlake's and Nonparametric probability tests with the 90% confidence intervals, for both trimethoprim and sulfamethoxazole gave the differences within 80 and 120%, for all necessary measures (Cmax, tmax and AUC infinity). Statistical analysis of the data has shown that the preparations have similar pharmacokinetic profiles and therefore can be considered equally bioavailable.     

Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two-period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model-dependent calculation of the first-order absorption rate constant, and a model-independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O-demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50-mg tablet. A standard, medium-fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration-time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the Cmax of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found.     

Steady state disposition of 5-aminosalicyclic acid following oral dosing

In 18 healthy volunteers the steady state disposition of 5-aminosalicylic acid (5-ASA, mesalazine, CAS 89-57-6; 500 mg tid) was evaluated following the last oral dose in form of slow release tablets (Salofalk) either containing 500 mg or 250 mg 5-ASA. In none of the pharmacokinetic parameters of 5-ASA characterizing bioavailability (e.g. AUC approximately 6 ug/ml x h; Cmax approximately 1.7 micrograms/ml; tmax approximately 5 h; Cminss approximately 0.5 micrograms/ml; Cavss approximately 0.75 microgram/ml) differences between both forms were observed and the calculated 90% confidence intervals and point estimates indicated bioequivalence. Following the delayed absorption 5-ASA was rapidly eliminated (t1/2 = 1.4 +/- 0.5 h).     

Bioavailability of dextromethorphan (as dextrorphan) from sustained release formulations in the presence of guaifenesin in human volunteers

A multiple dose bioavailability study with six healthy male human volunteers was conducted. The bioavailability of an experimental sustained release tablet containing dextromethorphan hydrobromide (DXP-HBr), was compared with a marketed sustained release DXP-HBr suspension in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analysed for the major metabolite of dextromethorphan (DXP), dextrorphan (DX), using a specific HPLC method with fluorescence detection. The bioavailability parameters; area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), and time to peak (Tmax), were obtained from the plasma concentration-time data. Additionally, pharmacokinetic parameters such as mean residence time (MRT), accumulation factor (R), fluctuation index (Fi), total body clearance (Cl), and the average concentration (C) were estimated by using model independent kinetics approach. Analysis of variance of the data revealed that the presence of guaifenesin in the test formulation does not appear to have a statistically significant (p > 0.05) effect on the bioavailability of dextromethorphan as dextrorphan. The relative bioavailability of the tablet dosage form with respect to the suspension was found to be 113% on Day 1 and 110% on Day 6.     

Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets

Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were studied in a single-dose, three-way (test and reference products administered after consumption of standard breakfast, as well as test product in fasting condition), cross-over, food effect bioequivalence study. According to the results, the test product--which, in a former study proved to be bioequivalent with the reference product in fasting state--is bioequivalent with the reference product under feeding conditions and the food intake influenced the pharmacokinetics of the test tablets.     

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies

PURPOSE: While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. METHODS: We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. RESULTS: Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.     

The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.     

Extracellular neurofibrillary tangles are immunopositive for the 40 carboxy-terminal sequence of beta-amyloid protein

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption.     

Bioequivalence of controlled-release calcium antagonists

In this review, several deficiencies of published bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care. A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test: reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made. With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. Some bioequivalence studies of calcium antagonists are deficient in this respect. To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. Some calcium antagonists, such as verpamil, show stereo-selective pharmacokinetics, so that enantiomers may have to be investigated. Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory.