Effect on bioavailability of admixing the contents of lansoprazole capsules with selected soft foods.

OBJECTIVE: This study was designed to compare the bioavailability of lansoprazole when administered as an intact capsule and when the contents are admixed with various soft foods. BACKGROUND: Patients sometimes cannot swallow or have difficulty swallowing intact capsules such as lansoprazole. To enable them to ingest the drug, the contents of the capsule can be admixed with small amounts of soft foods. METHODS: Twenty-four healthy adult volunteers participated in this single-dose, 4-period crossover study by ingesting the contents of a 30-mg lansoprazole capsule that had been emptied into either a tablespoon of yogurt (regimen A), Ensure pudding (regimen B), or cottage cheese (regimen C), or given as an intact capsule (regimen D) during the first study period. The regimen assignments were rotated at weekly intervals so that each subject received each regimen. Blood samples were obtained over the 12-hour period after administration of each regimen, and pharmacokinetic parameters were determined. RESULTS: Of the 23 subjects who completed all 4 periods of the study, 18 were male and 5 were female. Their mean (+/- SD) age was 33.3+/-11.6 years, and their ages ranged from 19 to 52 years. No statistically significant differences between regimens were detected in mean maximum concentration, area under the curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity (AUC0-infinity) using analysis of variance. A statistically significant difference was detected in the time to maximum concentration between regimens C and D at 2.1 and 1.5 hours, respectively (P < or = 0.05). Bioavailability was assessed by the two 1-sided tests procedure using a 90% CI for the AUC0-infinity ratio of test-to-reference regimens. The 90% CIs were all within an acceptable equivalence range of 0.80 to 1.25. CONCLUSION: These results indicate similar bioavailabilities between the regimen in which the lansoprazole capsule was emptied and administration of the intact capsule. However, they may have limitations in predicting the results in ill, elderly, or very young patients.

Lansoprazole: administration of the contents of a capsule dosage formulation through a nasogastric tube.

A single-dose, open-label, randomized, crossover bioavailability study was conducted in 24 healthy adult male volunteers to assess an alternative method of administration of lansoprazole capsules. The results of 22 subjects were analyzed. Subjects received regimen A (granules from a 30-mg capsule mixed with apple juice and administered through a nasogastric tube) or regimen B (an intact 30-mg capsule) during the first study period. The regimens were reversed during the second period 1 week later. Blood samples were obtained over 12 hours and pharmacokinetic variables were determined. No statistically significant differences in mean time elapsed to peak concentration, mean peak concentration, area under the curve (AUC)0-t, and AUC0-infinity were detected between regimens by using analysis of variance. Bioavailability was assessed by the 90% confidence interval of the two one-sided tests on the natural logarithm of AUC. The 90% confidence interval for the AUCzero-infinity ratio was 0.955 to 1.140 for regimens A to B. These results indicate similar bioavailabilities between the two regimens and demonstrate that lansoprazole capsules may be administered by mixing the capsule contents with apple juice for administration through a nasogastric tube.

Lansoprazole: an alternative method of administration of a capsule dosage formulation.

A single-dose, open-label, randomized, fasting, two-period, crossover bioavailability study was conducted in 24 healthy adult men to assess an alternative method of administration of lansoprazole capsules. Half of the subjects received regimen A (contents from a 30-mg capsule placed in a tablespoonful of applesauce), and the other half received regimen B (an intact 30-mg capsule) during period 1 of the crossover study. The regimens were reversed during the second period 1 week later. Blood samples were obtained over 12 hours and pharmacokinetic parameters were determined. Mean time elapsed to peak concentration (Tmax) was less than 2 hours for each regimen. The ratio (regimen A:regimen B) of peak concentration (Cmax) means and area under the curve (AUC)0-infinity means were 0.889 and 0.944, respectively. (AUC0-infinity is the sum of AUC0-t and AUCt-infinity, where AUC0-t is the area under the plasma concentration-time curve from time 0 to the time of the last measurable or nonzero concentration as computed by using the trapezoidal rule, and AUCt-infinity is computed as the last nonzero concentration divided by the terminal phase rate constant.) No statistically significant differences (P < or = 0.05) in Tmax, Cmax, and AUC0-infinity were detected between regimens. These data indicate similar bioavailabilities between the two regimens. Lansoprazole granules contained in a standard capsule dosage formulation may be removed and placed directly into applesauce and administered to appropriate patients.

Bioavailability of valproic acid under fasting/nonfasting regimens.

Valporic acid absorption was faster from a syrup than from a capsule form. Peak serum levels occurred with an hour with the syrup formulation. The drug was absorbed more rapidly when administered fasting and immediately before meal compared with immediately after meal. The extent of absorption from each formulation and for each meal regimen was similar. Pharmacokinetic evaluation of the data indicate a serum half-life of 12 hours.

Pentobarbital absorption from capsules and suppositories in humans.

Serum pentobarbital levels following administration of the sodium salt as a 100-mg capsule orally and as two 120-mg suppository formulations (A and B) rectally were measured. From these data and previously determined kinetic constants after intravenous administration, the absorption rates and bioavailability of pentobarbital from each dosage form were determined. All three dosage forms were 100% absorbed. Peak serum pentobarbital levels occurred at 1, 4, and 10 hr for the capsule, Suppository A, and Suppository B, respectively. In vitro studies agreed with the serum data in that Suppository A released drug in an in vitro aqueous pH 1.4 system at a much greater rate that Suppository B. The capsule and Suppository A both appeared to be absorbed by simple first-order processes; however, Suppository B had a complex absorption pattern, which was modeled using sequential zero-order and first-order absorption.

Bioavailability of erythromycin ethylsuccinate in pediatric patients.

A parallel treatment group bioavailability study was undertaken in children 6 to 65 months of age, comparing fasting and nonfasting erythromycin serum levels after a single oral dose of erythromycin ethylsuccinate granules. Results demonstrated significantly higher levels in the nonfasting than in the fasting state, while fasting state levels were comparable to those found in studies of adult subjects receiving recommended doses of the same compound.

Effect of antacids on absorption of clorazepate.

The effect of a magnesia and alumina antacid suspension on the absorption of clorazepate dipotassium was studied in 15 normal healthy adult subjects who ingested a 15-mg dose of clorazepate alone or with single or multiple doses of antacid. The results of this three-period randomized complete crossover study showed a trend of initially slower absorption and lower peak nordiazepam plasma levels when administered with the antacid suspension. However, there were no significant differences among treatments in the extent of absorption as measured by the area under the plasma level-time curves. Clorazepate plasma levels were of relatively short duration and similar for all treatments. The urinary excretion pattern was likewise comparable with conjugated oxazepam, the major species measured. Plasma elimination half-lives of nordiazepam and clorazepate were not affected by the antacid treatments.

Determination of pentobarbital in serum by electron-capture GLC.

A GLC method was developed for pentobarbital in serum. After extraction from serum, a pentafluorobenzyl derivative was prepared and quantitated by electron-capture detection. The method has a sensitivity of 0.1 microng/ml of serum, and the amount detectable is less than 0.2 ng/injection. Hexethal was used as the internal standard. Derivatives of other barbiturates were also made. NMR and mass spectrometric analyses confirmed the proposed structure of the 1,3-bis(pentafluorobenzyl) derivative of pentobarbital. The procedure was successfully applied to measurement of serum pentobarbital levels in humans.

Steady-state bioavailability of two clorazepate dipotassium dosage forms.

A specially designed tablet dosage form of the benzodiazepine clorazepate dipotassium (Tranxene) was developed for once-a-day administration. The drug was administered at a dose of 22.5 mg as (1) the tablet, (2) three 7.5 mg capsules, or (3) one 7.5-mg capsule given every 6 hours. Peak serum levels from the tablet were intermediate between those of the single- and divided-dose capsule regimens. The desired decrease in magnitude of peak levels was obtained without affecting the extent of absorption. Pharmacokinetic analysis of the data according to a two-compartment open model with first-order absorption indicated that the serum half-life (t0.5beta) of nordiazepam, the major biotransformation product present in serum, was about 48 hours and served as a basis for the design of a multiple-dose steady-state study. Multiple-dose administration of the tablet and divided-capsule regimen to two groups of subjects for ten days indicated each dosage form yielded similar minimum steady-state serum levels of about 0.6 micrograms/ml which plateaued following seven days of drug administration. The dosage forms were crossed over between the groups on day 11 and administered for an additional four days. The minimum serum levels obtained with the tablet and capsule were not statistically different. Additionally, the peak serum level and area under the curve (pi=24 hours) at steady state were equivalent between the dosage forms. Good agreement was obtained between model-predicted and observed serum levels during multiple-dose administration for both the tablet and capsule regimens. The serum half-life of nordiazepam following 14 days of clorazepate dipotassium administration was similar to that found after a single dose. These results indicate that a single daily dose of drug as the tablet produced serum levels equivalent to a divided-capsule regimen.

Paramethadione and metabolite serum levels in humans after a single oral paramethadione dose.

A GLC method was developed to determine quantitatively paramethadione and its major metabolite, 5-ethyl-5-methyl-2,4-oxazolidinedione, in serum. The method was reproducible and sensitive to 0.2 mug/ml. After administering a single 300-mg oral dose to human subjects, the average paramethadione serum levels of 6.0 mug/ml occurred at 1 hr and decreased to 0.3 mug/ml after 48 hr. Metabolite serum levels gradually increased to 8.4 mug/ml at 32 hr and were still at this level at 48 hr, which was the last sampling point.

GLC determination of plasma drug levels after oral administration of clorazepate potassium salts.

Plasma nordiazepam levels resulting from the oral administration of clorazepate potassium salts were determined by a sensitive GLC assay. Nordiazepam and the internal standard (diazepam) were selectively extracted into ether at pH 9.2, hydrolyzed to their respective benzophenones, and quantified by electron-capture detection. The assay was used in a comparative bioavailability study of single equimolar oral doses of monopotassium and dipotassium salts of clorazepate in dogs. Both clorazepate salts were rapidly absorbed and exhibited mean peak total drug levels after 1 hr. Clorazepate levels accounted for about 50% of the total drug levels present. No statistical difference in the plasma drug levels of clorazepate mono- and dipotassium salts and the metabolite was found in dogs.