Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles.

The bolus (or oblet) is a dosage form that can be used for the oral administration of pharmaceutical compounds to ruminating species. Unlike traditional tablets, oral boluses may contain quantities of drug on the order of grams rather than milligrams. Due to its size, it is only recently that USP-like in vitro dissolution methods have been developed for this dosage form. However, whether or not these dissolution tests can predict product in vivo performance has yet to be determined. The importance of this issue is apparent when the U.S. Food and Drug Administration Center for Veterinary Medicine is faced with the decision of whether to require additional in vivo bioequivalence study data to support the approval of changes in product chemistry or manufacturing method. The current study was undertaken to determine whether an in vivo/in vitro correlation can be established for bovine sulfamethazine oral boluses and to acquire insight into the magnitude of changes in in vitro product performance that can occur before corresponding changes are seen in in vivo blood level profiles. Based upon the results of this investigation, it is concluded that marked changes in in vitro sulfamethazine bolus performance can be tolerated before resulting in altered in vivo blood level profiles. However, the data also suggest that rumenal absorption may occur for some compounds. Therefore the degree to which variation in product in vitro dissolution profiles can be tolerated may be compound specific.

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.

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 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.

Effect of dietary fat content on the bioavailability of a sustained release quinidine gluconate tablet.

Quinidine gluconate 324 mg sustained release tablets (Quinaglute) was administered as a single dose to 15 healthy male subjects following an overnight fast, immediately following a high fat (HF) breakfast or immediately following a low fat (LF) breakfast. Serum samples were obtained over a 48 h period and analyzed for quinidine content using a high performance liquid chromatographic assay. Under the conditions of the study, both the rate and extent of quinidine bioavailability was significantly affected by food. The extent of bioavailability was statistically significantly greater (p less than 0.05) following both the HF and LF meals as compared to that in the fasted state. Rate of bioavailability was significantly enhanced following the LF meal as compared to that of the other two treatment groups. Although peak concentrations were greater and time to peak concentrations somewhat later following the HF meal versus those under fasting conditions, these differences were not statistically significant. In addition, the characteristics of the serum concentration-time profile (as defined by the number, magnitude, and time of occurrence of the multiple absorption maxima) was unique for each of the three treatment groups. Possible mechanisms underlying these results are explored.

Bioequivalency and dose proportionality of three tableted promethazine products.

Data from a five-way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were administered as a single oral dose. The five objectives of the study were to investigate bioequivalency, to estimate dose proportionality at two dose levels, to establish validity of a reference production solution for future bioequivalency studies, to estimate intersubject variation, and to compare bioavailability/tablet dissolution data. Blood samples were collected at given intervals over a 24-hour period and analysed for promethazine using an HPLC technique. Pharmacokinetic parameters were calculated using standard procedures and a two-way analysis of variance (ANOVAR) was used to assess whether the differences were statistically significant. The AUC0----infinity data from the ANOVAR analysis showed that the 50 mg innovator and generic products and the 50 mg solution were not significantly different. However, the innovator product had a significantly lower Cmax and longer tmax than the solution. The generic product did not differ significantly from the solution. Promethazine was found to exhibit linear dose proportionality in the range and product studied. Intersubject variation was high for all parameters (23 to 63 per cent) and the in vivo and in vitro data showed a positive relationship.

Stable-isotope methodology in the bioavailability study of 17 alpha-methyltestosterone using gas chromatography-mass spectrometry.

The application of a stable-isotope coadministration technique for estimating the relative bioavailability of 17 alpha-methyltestosterone is described. Eight healthy male subjects were administered orally a single 10-mg 17 alpha-methyltestosterone tablet together with a 10-mg 17 alpha-methyltestosterone-d3 solution. The serum concentrations of 17 alpha-methyltestosterone and 17 alpha-methyltestosterone-d3 were determined by gas chromatography-mass spectrometry with selected ion monitoring using 17 alpha-methyltestosterone-d6 as an internal standard. The extent of absorption from the tablet formulation was comparable to that from the oral solution. The stable-isotope methodology was compared with the conventional cross-over method for evaluating the bioavailability of 17 alpha-methyltestosterone.

In vitro and in vivo bioequivalence of commercial prednisone tablets.

The purpose of the study was to examine the bioequivalence of five commercially available oral prednisone products. The in vivo study utilized 18 healthy males, each of whom was administered 20 mg of prednisone as a reference solution or as a tablet in a 6-week, six-way crossover design. Blood was collected and serum was assayed, using an HPLC procedure specific for prednisone and prednisolone. Mean pharmacokinetic parameters (t 1/2, ke, Cmax, tmax, and AUC) were determined. ANOVA was performed on the prednisone and prednisolone data (F-test, p less than 0.05) as well as Duncan's multiple range analysis. Dissolution tests were also performed on each of the five products in order to test the relationship between dissolution and bioequivalence among prednisone products. The in vitro study consisted of a standard USP dissolution test which included tablets from the same lots as the tablets used in the in vivo study. The data showed no statistical difference in any of the pharmacokinetic parameters among tableted products, subjects, or dosing periods in the study. There was also no statistical difference in the dissolution study among the five commercial tablet forms.

High-dose methotrexate with leucovorin rescue in patients with unresectable non-small cell carcinoma of the lung.

Thirty-one patients with unresectable non-small cell carcinoma of the lung (19 adenocarcinoma, 7 large cell carcinoma, 4 squamous cell carcinoma, 1 mixed histology) were treated with one of two intravenous infusion schedules of high dose methotrexate with leucovorin rescue. First, 14 patients received methotrexate in escalating doses from 1.5 to 12 g/m2 over 6 hours followed immediately with leucovorin 15 mg/m2 for 12 doses every 6 hours; there were no complete or partial responses among these 14 patients. Then, 17 patients were treated with a loading bolus of 50 mg/m2 intravenous methotrexate followed by a 30-hour continuous infusion of 1.5 g/m2. Leucovorin 15 mg/m2 every 6 hours for 12 doses was begun at the end of the infusion. There were 3 partial responses among the 17 patients in this group. The results demonstrate that both 6- and 30-hour infusions of high-dose methotrexate regimens can be given safely to middle aged adult patients, but the overall 10% response rate does not appear to be significantly different than the results with standard-dose methotrexate.

Lack of efficacy of high-dose methotrexate by 30-hour infusion in patients with progressive small cell carcinoma of the lung.

Seventeen patients with small cell carcinoma of the lung (SCCL) refractory to at least one combination chemotherapy regimen were treated with a high-dose methotrexate (HDMTX) program consisting of 1500 mg/m2 of MTX by iv infusion at a constant rate over 30 hrs following a priming dose of 50 mg/m2 of MTX iv. Administration of calcium leucovorin was begun at the end of the infusion. Treatment was repeated every 2 weeks. No complete or partial responses were observed, and the median time to tumor progression was 4 weeks. Hematologic toxicity was much more severe than anticipated, with five patients having thrombocytopenic bleeding requiring platelet transfusions. This HDMTX regimen was both ineffective and unexpectedly toxic in our heavily pretreated patients with SCCL. Literature review discloses little evidence that HDMTX programs have superior activity to standard doses of MTX in this disease.

Multicompartment pharmacokinetic model of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) in humans.

The formation and elimination of the metabolite of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) (I) were studied in seven patients with advanced cancer who received I intravenously. The plasma concentration-time data best fit a triexponential equation. The volume of the metabolite compartment (27.5 liters) was calculated as a fraction of the extrapolated volume. A larger body clearance (111.7 ml/min) of metabolite as compared to the renal clearance (31.3 ml/min) indicates that the metabolite is lost from the plasma equivalent space by another elimination route. The combination of metabolite data presented here with previously published data for unchanged I leads to a multicompartment model for the distribution, metabolism, and excretion of I and its metabolite. A comparison of algebraically derived model transfer constants with those evaluated by computer fitting the system of differential equations is presented.

Pharmacokinetics of nafcillin in patients with renal failure.

Nafcillin, a pencillinase-resistant penicillin, is frequently used for treatment of staphylococcal infections in hemodialysis patients. Despite its widespread use, there is a paucity of available data regarding the pharmacokinetics of nafcillin in hemodialysis patients. Therefore, sodium nafcillin, 25 mg/kg, was given intravenously over a 5- to 15-min period to 12 hemodialysis patients. Eleven patients were studied during dialysis, and eight of these were studied again during the interdialysis period. The initial serum half-life for nafcillin was 0.208 h during dialyses and 0.278 h between dialyses. The terminal half-life was 1.48 h during dialyses and 1.89 h between dialyses. There was no statistically significant difference between these values. These data indicate that renal failure does not appreciably affect the serum half-life of nafcillin, and hemodialysis does not accelerate the rate of clearance of nafcillin from the blood. Therefore, no modification of the usual nafcillin dosage is necessary when using this drug in hemodialysis patients.