The Effect of Food on Gastrointestinal (GI) Transit of Sustained-Release Ibuprofen Tablets as Evaluated by Gamma Scintigraphy

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of ¹⁷⁰Er₂O₃ (>96% ¹⁷⁰Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable ¹⁷⁰Er to radioactive ¹⁷¹Er (t _1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 µCi of ¹⁷¹Er. Dosage form position was reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7–12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and T _max were unaltered and C _max was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.     

Steady-State Bioavailability and Day-to-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in C _max and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.     

Influence of food on the disposition of the monoamine oxidase-A inhibitor brofaromine in healthy volunteers

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross-over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat- and proteinrich breakfast. Mean (± SD) areas under the plasma concentration-time curves (AUC) were 9.66 (2.35) μmoll^?1 h when given to the fasted volunteers and 11.82 (3.78) μmoll^?1 h (p = 0.0413) when given after a substantial breakfast. Mean (± SD) maximum plasma concentrations (C_max) were 0.71 (0.13) μmoll^?1 when given to the fasted volunteers and 0.85 (0.22) μmoll^?1 (p > 0.05) when given after breakfast. Thus, both the average AUC and C_max were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when C_max was reached (t_max) as well as the elimination half-lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter-subject variability of the plasma levels.     

Application of Dual Radiotelemetric Technique in Studying Drug–Drug Interaction Between Diclofenac Sodium and Ranitidine HCl in Volunteers

Drug–drug interaction between a commercial diclofenac sodium enteric-coated tablet (Voltaren; V) and a ranitidine HCI tablet (Zantac; Z) was evaluated using a dual radiotelemetric technique according to a randomized three-way Latin-Square crossover design balanced for carryover effects. V and Z were given either alone or in combination (Treatment V, Z, V/Z), with a 14-day washout period between treatments. Eighteen fasted subjects swallowed a tethered Heidelberg pH capsule to provide continuous gastric pH. Then the assigned treatment drug and another Heidelberg pH capsule were given simultaneously. The free pH capsule provided information regarding gastric residence time (GRT). Serial blood samples were obtained for up to 12 hr after dosing and drug levels were determined by validated HPLC methods. Treatment effects on AUC, C _max, T _max, T _lag, T _max–T _lag, and T _1/2 were not significant except C _max, which differed slightly for both V and Z when given in combination as compared to alone. Gastric residence times were 46, 33, and 51 min for Treatments V, Z, and V/Z, respectively. Gastric exposure of the enteric-coated tablet of diclofenac was estimated by pH values obtained from the tethered capsule. Median pH values at 3 and 15 min prior to gastric emptying were 3.8 and 4.9 for the combination treatment versus 2.1 and 2.7 for diclofenac alone. The results of this study indicated that there was minimal drug–drug interaction between diclofenac and ranitidine. The gastric pH range resulting from this study did not influence the oral absorption of enteric-coated diclofenac.     

Effects of sensory (teasing) exposure to food on oral propranolol bioavailability

In order to further examine the mechanism of the increase in the plasma propranolol concentration versus time curve (AUC) caused by ingestion of propranolol with food, we administered R, S-propranolol tablets (0.5mg kg^?1) orally to healthy human volunteers and dogs in the presence and absence of sensory exposure to food without ingestion (teasing). Six healthy human volunteers were fasted on one occasion and on the other they were presented with an appetising meal, without eating it (teasing protocol). There was a strong trend to a greater propranolol AUC in the teasing protocol (139.54 mg mL^?1 h^?1 fasting, 178.105 mg mL^?1 h^?1 teasing; p=0.1), and time of peak concentration (t_max) was significantly prolonged (80.22min and 120.32 min, respectively; p<0.03). Further studies were carried out in dogs who received R-propranolol (2 mg kg^?1) as an oral solution by gavage tube on four different occasions: fasting, following intragastric administration of a high-value liquid meal, following teasing with food in the animal house at normal feeding time (high-intensity teasing), and following teasing with food at a time and place not associated with feeding (low-intensity teasing). There were no significant differences in pharmacokinetic parameters between the fasting and intragastric food protocols. Low-intensity teasing resulted in significantly lower AUC and peak concentration (C_max) compared with fasting (p<0.05), confirming food effect patterns known to occur in dogs. High-intensity teasing resulted in significantly greater AUC and C_max compared with fasting (p<0.05), reproducing in dogs the increase in propranolol AUC known to occur with food ingestion in humans. These findings suggest that the mechanism of the ‘food effect’ may involve physiological responses to the sight and smell of food additional to mechanisms activated by ingestion.     

Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling

Since the rate-determining step to the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial changes in GI physiology, in addition to any specific interactions between drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs. In this study, in vitro dissolution testing using biorelevant media coupled with in silico physiologically based pharmacokinetic (PBPK) modeling was applied to the prediction of food effects on the absorption of a poorly soluble drug, celecoxib, from 200 mg capsules. A PBPK model was developed based on STELLA^® software using dissolution kinetics, solubility, standard GI parameters and post-absorptive disposition parameters. Solubility, dissolution profiles and initial dissolution rate from celecoxib 200 mg capsules were measured in biorelevant and compendial media. Standard GI parameters (gastric emptying rate and fluid volume) were varied according to the dosing conditions. Disposition parameters were estimated by fitting compartmental models to the oral PK data, since intravenous data are not available for celecoxib. Predictions of food effects and average plasma profiles were evaluated using the AUC and C_max and the difference factor (f₁). An approximately 7-fold difference in the maximum percentage dissolved was observed in in vitro dissolution tests designed to represent the fed and fasted states. By contrast, the food effect estimated by simulating the plasma profiles with the PBPK model predicted only a slight delay in the peak plasma level (1 h), and modest increases in the C_max and AUC of 1.9-fold and 1.3-fold in the fed state, respectively. The PBPK approach, combining in silico simulation coupled with biorelevant dissolution test results, thus corresponds much better to the food effect observed for celecoxib in vivo. Additionally, point estimates of AUC and C_max as well as f₁ calculations demonstrated clear advantages of using results in biorelevant rather than compendial media in the PBPK model.     

Effect of the timing of food intake on the absorption and bioavailability of carbamazepine immediate-release tablets in beagle dogs

The effect of dosing time on the bioavailability of carbamazepine immediate‐release (IR) tablets was investigated when administered to beagle dogs who were fasting, with co‐administration of food (Co‐food), and 0.5 h before food and 2 h after food. The study was conducted using a single dose of 200 mg (tablets/solution) with a 2 week washout period in a crossover design. Food intake significantly increased the rate and extent of tablet absorption. The C_max (µg·ml^?1, 8.13/3.65) and t_max (h, 1.83/0.92) were increased more than two‐fold and the AUC_0‐24 (µg·h·ml^?1, 20.09/8.19) was 2.5 times that of the values obtained under fasting conditions. The bioavailability of the tablets under fasting conditions was 91.2%, but increased to 223.5%, 182.8% and 148.4% in the Co‐food, 0.5 h before food and 2 h after food groups, respectively (p < 0.05). Although there was no significant difference in the C_max or AUC_0‐24 between the treatments with food, the absorption appeared to be reduced to some extent when the tablets were given 2 h after food. The oral bioavailability of CBZ IR tablets was significantly affected by the timing of the food intake. This is maybe favored by the fluctuations in the level of bile salts with the timing of food intake. To obtain acute therapy for a drug with narrow therapeutic window, attention should be given to the dosing time and food intake interactions. Copyright © 2012 John Wiley & Sons, Ltd.     

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 AUC_t, AUC, and C_max 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 C_max. 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 AUC_t and AUC. However, C_max 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 C_max of nadolol is only slightly sensitive to absorption rate and the relatively large variability of C_max reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.     

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 (C_max), and time to peak (T_max), were obtained from the plasma concentration–time data. Additionally, pharmacokinetic parameters such as mean residence time (MRT), accumulation factor (R), fluctuation index (F_i), 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. Copyright © 1998 John Wiley & Sons, Ltd.     

The effect of colestipol and cholestyramine on ibuprofen bioavailability in man

The purpose of this study was to determine whether a concomitant single oral dose of one of the anion exchange resins colestipol hydrochloride (10 g) or cholestyramine (8 g) administered with ibuprofen (400 mg) would alter the bioavailability of this non-steroidal anti-inflammatory agent. The study was performed according to a randomized three-way crossover design in six healthy male volunteers. After dosing, serial blood samples were collected for a period of 10 h. Plasma harvested from blood was analysed for ibuprofen by a sensitive high-performance liquid chromatographic method. There were no significant differences between colestipol treatment and control for peak plasma concentration (C_max), time to peak concentration (T_max), area under the plasma concentration—time curve (AUC), mean residence time (MRT), elimination rate constant (K_el), or elimination half-life (t_1/2). Cholestyramine treatment resulted in a significant decrease in AUC (26%, p< 0.05) and C_max (34.4%, p <0.01) and a significant increase in T_max (80%, p < 0.01) and MRT (20.2%, p < 0.05). Cholestyramine administration showed no significant effect on the K_el and t_1/2 values. A significant correlation was obtained between the increase in MRT and the increase in T_max. The confidence intervals (90%) of the mean values of the pharmacokinetic parameters (AUC_O–∞ and C_max) for the colestipol : control ratio were well within the acceptable range of 100 ± 20, whereas those for the cholestyramine : control ratio were outside it. Colestipol treatment was found to be bioequivalent to the control treatment by Schuirmann's two one-sided t tests, while cholestyramine treatment was found to be bioinequivalent. The results indicate a lack of interaction between ibuprofen and colestipol and a potential significant interaction (decrease in rate and extent of absorption of ibuprofen) between cholestyramine and ibuprofen in patients receiving concurrent therapy.     

Metabolism and disposition of EXP631—A novel antidepressant analgesic

EXP631, 4-(3-thienyl)-α,α, 1-trimethyl-4-piperidinemethanol hemi-fumarate salt ( I ), is a centrally acting non-opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5–20 mg kg^?1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92–131%. The pharmacokinetics was dose independent as measured by either C_max or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N-desmethyl metabolite ( II ) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.     

The effect of antacid,metoclopramide, and propantheline on the bioavailability of metoprolol and atenolol

Concomitant administration of antacid increased the maximum concentration (Cp_max) and the area under the plasma concentration-time curve (AUC) of 100 mg oral dose of metoprolol by 25 per cent (p< 0.05) and 11 per cent (p < 0.1) respectively. For atenolol the opposite effect was observed and Cp_max and AUC were decreased by 37 and 33 per cent respectively (p< 0.02). In both cases the antacid did not affect the time-course of the drug in the plasma. Pretreatment with metoclopramide did not affect the time-course of atenolol in the plasma or its bioavailability. Propantheline prolonged the absorption phase of atenolol and the time of peaking (t_max) was shifted from 2.1 to 4.5 h. Cp_max of atenolol was essentially unchanged by propantheline pretreatment while the AUC was increased by 36 per cent. It is concluded that the negative effect of the antacid on the bioavailability of atenolol is caused by a reduction in the in vivo dissolution rate due to increased gastric pH. The positive effect of propantheline might be due either to more efficient absorption of atenolol in the upper part of the intestine or more extensive dissolution of the drug as a result of prolonged contact with gastric juice or a combination of these factors.     

Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet

Objective: To compare the pharmacokinetic profiles of diclofenac potassium liquid-filled soft gelatin capsules (DPSGC) using patented ProSorb^® dispersion technology with an immediate-release, diclofenac potassium 50-mg comparator tablet in two open-label, single-dose, randomized, crossover relative bioavailability studies in healthy volunteers. Methods: In Study 1, volunteers (n = 21) received DPSGC 50 mg or a diclofenac potassium 50-mg comparator tablet in two inpatient study periods. In Study 2 (n = 54), volunteers received DPSGC 25 mg, DPSGC 50 mg, or a diclofenac potassium 50-mg comparator immediate-release tablet in three inpatient study periods. Results: In both studies, DPSGC 50 mg displayed a significantly shorter T_max and higher C_max than the 50-mg diclofenac potassium comparator tablet. DPSGC 25 mg (Study 2) produced a shorter T_max (0.45 h) and an equivalent C_max (1125 ng/ml) to the 50-mg comparator drug. Plasma diclofenac concentration–time courses for the diclofenac potassium 50-mg comparator tablet showed many low, delayed, or multiple peaks compared with DPSGC treatments. Conclusions: DPSGC 25 mg and 50 mg were more rapidly and consistently absorbed than diclofenac potassium 50-mg comparator tablets. The C_max of DPSGC 25 mg was equivalent to the 50-mg diclofenac potassium comparator tablet. These characteristics may be beneficial when fast, consistent drug absorption is needed.     

Pharmacokinetics and dose-dependency of LB30870 in rats, dogs, and monkeys

This study was to examine the pharmacokinetics of LB30870, a thrombin inhibitor, after IV and oral administration to rats, dogs, and monkeys. In rats and dogs, LB30870 showed linear pharmacokinetics after IV and oral administration. The oral bioavailability (BA) in rats was about 30 % with high inter-subject variability in the time to reach peak plasma concentration (T_max). Oral absorption of a solution and prototype tablet formulations of LB30870 were tested in dogs. T_max was 30 min and the BA values were 40.8–43.1 % with solution formulation. BA values after oral administration of the two tablet formulations at the dose of 100 mg/dog were 27.0 and 30.8 %. T_max were 60 min in the tablet formulation, indicating that the disintegration and dissolution of tablets caused delay in T_max compared to solution formulation. After IV administration of LB30870 to monkeys, the plasma concentrations decreased bi-exponentially and BA was 15.0 % after oral (20 mg/kg) dosing. In summary, linear pharmacokinetics of LB30870 were observed in both rats and dogs. The differences in BA among species could be due to difference in absorbed fraction and/or the first pass extraction (pre-systemic elimination) of LB30870.     

Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch

Abstract

1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson’s disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration.

2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1?mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5?mg (2 and 4?cm²) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t_1/2), time to peak plasma-concentration (T_max), mean residence time (MRT), area under the curve (AUC_(0–t)) were significantly (p?<?0.05) different between transdermal and oral administrations.

3. The plasma half-life (t_1/2) of rasagiline (1.25?mg patch: 11.8?±?6.5?h, 2.5?mg patch: 12.5?±?4.7?h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1?mg tablet: 4.7?±?2.5?h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5?mg patches compared with 1?mg rasagiline tablet. The prolonged t_1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet.     

Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t_1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and C_max, as well as a slightly shorter T_max, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters C_max, T_max, and AUC, suggesting that the Coltramyl^® tablets have an adequate in vivo dissolution profile.     

IN VIVO/IN VITRO CORRELATIONS FOR FOUR DIFFERENTLY DISSOLVING KETOROLAC TABLETS

This study assesses whether in vitro immediate release ketorolac tablet dissolution profiles (utilizing the recently proposed USP dissolution test for ketorolac tablets) can be correlated with in vivo plasma pharmacokinetic parameters. Four batches of ketorolac tablets were utilized: a ketorolac tablet batch that demonstrated a rapid dissolution rate during USP in vitro dissolution testing, two tablet batches that were manufactured such that they dissolved at moderate rates, and a tablet batch that was manufactured such that it dissolved at a distinctly slow rate. The single-dose mean pharmacokinetic characteristics and relative bioavailability of the four different 10 mg ketorolac tromethamine tablets were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The amount dissolved of the various tablets at 10, 20, and 30 min was in the order of fast-dissolving tablets > medium-1-dissolving tablets=medium-2-dissolving tablets > slow-dissolving tablets. In general, the profiles of the average plasma concentrations for ketorolac were similar for the fast- and the two medium-dissolving tablet batches (even though a statistically significant difference was found between the t_max of the fast-dissolving tablet and one of the medium-dissolving tablet batches). The mean plasma concentrations for the slow-dissolving tablet, however, reached peak levels much later, with the peak also being significantly smaller. There were no statistically significant differences in the total AUC or in the mean plasma half-lives among the four formulations. Good correlations were obtained for mean t_max versus the percentage dissolved at 20, 30, and 45 min. Correlations were generally weaker for percentage dissolved versus C_max or percentage bioavailability. This indicates that in vitro dissolution testing for immediate release ketorolac tablets can be a useful indicator of in vivo time to maximum plasma concentration when comparing similarly formulated tablets. Further, the proposed USP dissolution test and specification would have appropriately failed the slow-dissolving tablet batch, which demonstrated a significantly slower rate of absorption as per t_max and C_max.     

Pharmacokinetics,Bioavailability, and Safety of Montelukast Sodium (MK-0476) in Healthy Males and Females

Purpose. The safety, tolerability, and pharmacokinetics of intravenous (i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. Methods. This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1–3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. Results. In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_1/12), and mean residence time in the body (MRT^i.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (C_max), time when C_max occurred (T_max), apparent t_1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng · hr/ml, 385 ng/ml, 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, V_ss, t_1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, C_max, T_max, apparent t_1/2, MAT and F were 2270 ng·hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. Conclusions. The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.     

Bioavailability of fluvoxamine given with and without food

The influence of concomitant food intake on plasma concentrations of the antidepressant drug fluvoxamine maleate was investigated in a two-way, crossover study design. Eight male and four female healthy, young volunteers received a single oral dose of fluvoxamine maleate (50 mg, tablet) on two occasions: after an overnight fast and immediately after a breakfast. Food did not affect maximum fluvoxamine plasma levels (C_max), or the time to reach C_max (t_max). The plasma AUC of fluvoxamine was on average 7 per cent lower in the fed than in the fasted state. It is concluded that the effect of food on the pharmacokinetics of fluvoxamine is negligible.