Comparative bioavailability of suprofen after coadministration with food or milk

Suprofen is a nonsteroidal analgesic with demonstrated efficacy in the treatment of mild to moderate pain associated with a variety of clinical conditions. Because nonsteroidal analgesic agents may cause gastrointestinal side effects, they are frequently prescribed with food or milk. The purpose of this study was to evaluate the effects of a standard meal and milk alone on the rate and extent of absorption of suprofen. In a randomized three-way cross-over study, 24 healthy volunteers each received a single 200-mg oral dose of suprofen in the fasted state half an hour after a standard meal or half an hour after an 8-ounce glass of milk. The influence of food and milk was greater on the rate than on the extent of absorption of suprofen as illustrated by a more pronounced effect on Cmax than on AUC. In addition, food had a greater influence on the bioavailability of suprofen than milk. Food decreased the mean Cmax to 44% and the mean AUC to 81% relative to the fasted state, whereas milk decreased the mean Cmax to 74% and the mean AUC to only 87% of the respective parameters in the fasted state. Symmetrical confidence intervals demonstrated that the mean AUCmilk was within only 19% and the mean AUCfood was within only 25% of the mean AUC in the fasted state, with 95% confidence.     

Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects

The effect of food on the oral bioavailability of sunitinib malate (SU11248, an oral, multi-targeted tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activities) was assessed in a randomized open-label, two-way crossover study. A 50-mg dose of SU11248 was administered to 16 healthy subjects after a 10-h fast in one period and after a high-fat, high-calorie meal in the other period. The 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were within the 80-125% bioequivalence range, indicating the absence of a food effect. SU11248 exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-infinity both 112%). There was a delay in the formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC0-last and AUC0-infinity were within 80-125%). These results indicate that SU11248 can be administered with or without food.     

Linezolid absolute bioavailability and the effect of food on oral bioavailability.

Linezolid is a novel oxazolidinone antibiotic that has a spectrum of activity encompassing a variety of Gram-positive bacteria. The objectives of this study were twofold: (1) to compare the absorption of linezolid tablets given immediately following a high-fat meal with the absorption of tablets administered while fasting, and (2) to assess the bioavailability of a 375-mg oral dose given while fasting relative to a 375-mg dose of linezolid sterile solution given intravenously. Venous blood samples were taken over the 48 h following the single dose administration of both the oral and intravenous (IV) treatment. Samples were subsequently frozen for the determination of linezolid concentrations by HPLC. The only statistically significant difference between the fasted and the fed treatment was in peak plasma concentration, with the mean C(max) for fasted subjects being 23% greater than that for subjects after consumption of a high-fat meal. Comparable AUC(0-infinity) values were measured under both conditions, indicating that the overall extent of absorption is the same. Therefore, the difference in C(max), while statistically significant, should not affect the therapeutic efficacy of linezolid when it is administered with food. There were no statistically significant differences in AUC(0-infinity), CL or half-life between the fasted oral treatment and the intravenous treatment. As expected, C(max) was statistically different between the two treatments. However, the mean absolute bioavailability (F) of the tablet, using the IV sterile solution as the reference treatment, was 103% (+/-20%).     

Effect of a standardized meal on the bioavailability of a single oral dose of tibolone 2.5 mg in healthy postmenopausal women

STUDY OBJECTIVE: To assess the effect of food on absorption and pharmacokinetic disposition of tibolone. DESIGN: Open-label, randomized, crossover study with a 1-week washout period. SETTING: Institut für Klinische Pharmakologie, Hohenkirchen-Siegertsbrunn, Germany SUBJECTS: Twenty-four healthy, early postmenopausal women. INTERVENTION: Single doses of tibolone 2.5 mg were administered after subjects consumed a high-fat meal or fasted. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of tibolone and its three primary metabolites, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone, were assayed by gas chromatography with mass spectrometry. Peak plasma concentration (Cmax), time to Cmax, area under the plasma concentration versus time curve from time zero to infinity (AUC(0-infinity)), and elimination half-life were calculated, and food effects were evaluated. Plasma concentrations of tibolone and delta4-tibolone were too low to estimate AUC(0-infinity) and half-life. Absorption or formation of 3alpha-hydroxytibolone and 3beta-hydroxytibolone was slower in fed participants than in fasting participants, but this was of no clinical relevance because of the long-term nature of tibolone treatment. Meal consumption did not affect AUC(0-infinity) or half-life for 3alpha-hydroxytibolone and 3beta-hydroxytibolone. CONCLUSION: Food consumption decreased and delayed Cmax but had no effect on the exposure of tibolone and its metabolites. Tibolone therefore can be administered irrespective of meal timing.     

Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults

AIMS: This randomized, crossover, single-dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal. METHODS: This was a randomized, open-label, four-way crossover, single-dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high-fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 x 100 mg) administered with a high-fat meal. RESULTS: The posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h) = 137% (90% confidence interval (CI) 119%, 156% and Cmax = 123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and Cmax values were about 400% when administered with a high-fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; Cmax 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in Cmax of 296% (90% CI 250%, 350%) relative to the fasted state. CONCLUSIONS: The suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.     

Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects

The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600-mg oral dose administered with and without a high-fat/high-calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high-fat/high-calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.     

Influence of food on the bioavailability of trimoprostil: an overview

The influence of food on the bioavailability of trimoprostil , a new antiulcer prostaglandin E2 derivative, was investigated in healthy male volunteers in four separate studies. Doses of 0.75, 1.5, and 3.0 mg were administered orally in both the presence and absence of food followed by serial blood sampling through 24 hours. Plasma trimoprostil concentrations were determined by a gas chromatograph-negative chemical ionization-mass spectrometric method for pharmacokinetic evaluation. Food decreased the absorption rate of trimoprostil as indicated by a later tmax (P less than 0.01) and corresponding lower Cmax at each dose. However, the food effect on tmax diminished as the dose increased. Although Cmax was reduced, food did not alter the extent of absorption, indicated by similar AUC (P greater than 0.05) between fed and fasted states. Both Cmax and AUC increased proportionately with an increase in dose. The harmonic mean half-lives of elimination were similar (P greater than 0.05) across all doses and ranged from 27 to 55 minutes.     

Influence of food on the oral bioavailability of moxonidine.

Moxonidine is a new centrally acting anti-hypertensive with a very low adverse drug reaction profile. Among others, the aim of the study presented here was to determine the influence of food on the pharmacokinetics of moxonidine. Single oral moxonidine doses of 0.2 mg fasting and 0.2 mg non-fasting were administered in a randomized cross-over study. Eighteen subjects participated in the study, all of whom completed the study according to the protocol. Three sets of analytical plasma data could not be evaluated pharmacokinetically giving a total number of 15 evaluable cases. Renal excretion was evaluated for all 18 subjects. Food intake had no influence on the pharmacokinetics of moxonidine. The relative bioavailability of moxonidine administered under non-fasting conditions reached 94% of the bioavailability after fasted administration. Food intake resulted in a slight decrease of Cmax and a minimal increase of tmax as compared to the fasted treatment. The absorption half-life t1/2a showed a minor prolongation. These differences were not statistically significant in any of the parameters. For t1/2 lambda 2, CLtot and Ae(24h) no statistically significant differences were found between the fasting and non-fasting treatment. The amount of moxonidine excreted unchanged in urine accounted for about 46% of the dose administered after both treatments.     

The effect of food on the absorption of oral ziprasidone

Oral ziprasidone bioavailability is increased when taken with food. Here we describe two pharmacokinetic studies to quantify the impact of food on ziprasidone absorption in healthy volunteers. The first, an open-label, six-way crossover study, investigated ziprasidone absorption in eight healthy men. Subjects received oral ziprasidone (20, 40, and 80 mg) after an 8-hour fast or immediately following a US Food and Drug Administration standard meal (50% fat). In this study, area under the serum concentration- time curve (AUC) was greater in fed than in fasting states at each dose (20 mg, +48%; 40 mg, +87%; 80 mg, +101%). Under fasting conditions, increases in AUC and maximum drug concentration (Cmax) were less than dose-proportional; under fed conditions, they were dose-proportional. The second, an open-label, randomized, three-way crossover study, explored the impact of dietary fat on ziprasidone absorption in 14 healthy subjects. Subjects received ziprasidone (40 mg) under three conditions: fasting, with a high-fat meal (60% fat), and with a moderate-fat (30% fat) meal. AUC and Cmax under fed conditions increased by 104% and 84% (60%-fat meal) and 79% and 98% (30%-fat meal) , respectively, relative to the fasting state. There was no clear difference in ziprasidone bioavailability between the fed groups, suggesting that meal fat content is not a major determinant of bioavailability. Less pharmacokinetic variability was observed in the fed state, suggesting more consistent absorption of ziprasidone. These results demonstrate that administration of ziprasidone with food is crucial to ensure optimal, reliable dose-dependent bioavailability and thus predictable symptom control and tolerability.     

食物对两种桂利嗪胶囊人体生物利用度的影响(英文)

目的比较食物对两种桂利嗪胶囊(A和B)人体生物利用度的影响。方法用HPLC紫外检测法测定健康受试者分别在禁食及餐后一次口服50mg桂利嗪胶囊A或B后血清药物浓度。结果胶囊A的Cmax 及AUC不受食物影响 ,胶囊B的吸收受食物影响 ,禁食后的Cmax 和AUC显著低于餐后的Cmax 和AUC。结论胶囊A的制剂优于胶囊B的制剂 ,其人体生物利用度不受食物影响     

Pharmacokinetics and bioavailability of ergoloid mesylates

The pharmacokinetics and bioavailability of ergoloid mesylates following single administrations of various dose levels (3-9 mg), dosage forms (oral swallow and sublingual tablets, solution) and under different dosing conditions (fasted, with meal) were studied in young healthy volunteers. Male and female subjects showed a similar rate and extent of bioavailable ergoloid after drug treatment. The absorption of ergoloid using either the tablet dosage forms or the drug administered as a solution was rapid, with peak levels of about 60-80 pg ml-1 mg-1 dose achieved after 0.6 to 1.3 h. The elimination half-life for ergoloid in plasma was 2-5 h. Administration of drug with food had no effect on the extent of absorption (AUC) but lowered the absorption rate. This resulted in a reduction of (by 25 per cent) and delay in (by 1 h) achieving peak levels (Cmax). Increasing the ergoloid dose caused a proportional increase in the AUC, but a smaller than proportional increase for Cmax. The tablet formulations provided similar AUCs as the solution; the objective of the sublingual tablet formulation to provide improved bioavailability over the swallow tablet via circumvention of first-pass metabolism was therefore not realized. Transient decreases in blood pressure after ergoloid treatment paralleled the plasma level profiles. Higher ergoloid levels were paired with the larger pressure decreases.     

Absorption of vitamin K2 by dogs after oral administration of a soft gelatin capsule formulation containing a new emulsion-type vehicle

This study has evaluated the performance of a newly developed vehicle for administration of a drug in a soft gelatin capsule. The absorption of vitamin K2 in dogs after oral administration of the vitamin in a soft gelatin capsule containing the newly developed vehicle was compared with absorption after administration of a control formulation prepared by encapsulating the contents of a commercially available vitamin K2 capsule (Glakay capsules 15 mg) in the same type of soft gelatin. Under non-fasted conditions the profile of the plasma concentration of vitamin K2 against time for the test formulation was comparable with that for the control formulation in non-fasted dogs. Under fasted conditions, however, both the maximum concentration (Cmax) and the area under the plot of concentration against time (AUC) were significantly smaller for the test formulation than for the control formulation. The Cmax and AUC for the test formulation were about 10 times larger for non-fasted dogs than for fasted dogs whereas values for the control formulation were about twice as large. These results suggest that both formulations might require the presence of food or digestive fluid components, or both, for better absorption of vitamin K2. It seems that although the performances of the test and control formulations were comparable in the presence of these components, the control formulation works better in their absence. It should be also noted that, in contrast with the results from the absorption tests, the dispersibility of the test vehicle in water was much better than that of the control vehicle. This suggests that dispersibility does not significantly affect vitamin K2 absorption. In conclusion, although the new vehicle did not perform better than the control vehicle in terms of vitamin K2 absorption, the performance of the control formulation was comparable for non-fasted dogs. Because the new vehicle contains considerably less surfactant than the vehicles currently used in soft gelatin capsules, it could be a safer alternative for use under non-fasted conditions.     

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.     

Pharmacokinetics of TJ-8117(Onpi-to), a drug for renal failure (II): effects of food, repeated administration and renal failure to plasma concentration of [3H]-(-)epicatechin 3-O-gallate in rats.

TJ-8117 (Onpi-to) is a herbal medicine extracted from mixture of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active compounds of TJ-8117, was labeled with tritium and spiked to TJ-8117. Effects of food, renal failure and repeated administration to pharmacokinetics of ECG-related radioactivity in the plasma were investigated after oral administration of TJ-8117 containing [3H]ECG ([3H]TJ-8117) in male rats. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in non-fasted rats was higher than that in fasted rats. AUC(0-72 h) and Cmax in the non-fasted was 123% and 248% of those in the fasted. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in 5/6 nephrectomized rats was higher than that in sham-operated rats. AUC(0-72 h) and Cmax in 5/6 nephrectomized was 332% and 236% of those in sham-operated. After repeated administration of TJ-8117 for 6 days, [3H]TJ-8117 was administered on 7th day. Radioactivity in plasma in first day was similar to that in 7th day. The pharmacokinetic parameters were not significantly different between single and repeated administration.     

An evaluation of the effect of food on the oral bioavailability of sustained-release morphine sulfate tablets (ORAMORPH SR) after multiple doses.

The effect of food on the oral bioavailability of sustained-release morphine sulfate tablets (ORAMORPH SR; Roxane Laboratories, Inc., Columbus, OH; OSR) was examined in an open-label, randomized, two-period crossover study. Healthy male volunteers received a 30-mg OSR tablet orally every 12 hours for seven doses during both the fasted and fed states. Dosing periods were separated by a 14-day washout. Volunteers in the fasted group received all doses either 2 hours before or after meals. Volunteers in the fed group received all doses immediately after meals. All meals were standardized. Serial blood samples were collected for analysis of plasma morphine concentration by radioimmunoassay. Pharmacokinetic parameters were calculated using plasma concentration data collected after the last dose at 72 hours of each dosing period. The two one-sided t analysis indicated confidence intervals between 80% and 120% for maximum peak plasma concentration (Cmax), AUC72-84hr, Cavg, and Cmin. The relative bioavailability of OSR administered after meals was 90.2% of that administered in the fasted state. As compared with the fasted condition, morphine bioavailability was essentially unchanged when multiple oral doses of 30-mg OSR tablets were given after meals.     

Food increases the bioavailability of isotretinoin

Twenty healthy male subjects received 80 mg (2 X 40 mg SEG capsules) oral isotretinoin separated by two-week washout periods in an open randomized crossover design. Isotretinoin was administered during a complete fast, 1 hour after a standard breakfast, with a standard breakfast, or 1 hour before a standard breakfast. Blood samples were obtained at specific times over a 72-hour period. Isotretinoin blood concentrations were determined by a specific HPLC method. The relative bioavailability (AUC) of isotretinoin was found to be approximately 1.5 to 2 times greater when the dose was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was given during a complete fast. In addition, because the Cmax value is lower when the dose is administered with food rather than 1 hour after a meal, coadministration of isotretinoin with food may be the best method of administration.     

The effects of food on the bioavailability of fenofibrate administered orally in healthy volunteers via sustained-release capsule

OBJECTIVE: To examine the effects of food on plasma concentration and bioavailability of fenofibrate administered as a sustained-release capsule. METHODS: Twenty-four healthy Korean volunteers were enrolled in a randomised, open-label, balanced, three-treatment, three-period, three-sequence, single oral dose, crossover pharmacokinetic study. A single dose of fenofibrate (250 mg sustained-release capsule) was administered on three occasions -- after overnight fasting, after consumption of a standard breakfast and after a high-fat breakfast. Serial blood samples were collected for the next 72 hours. Plasma fenofibric acid concentrations were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. RESULTS: The pharmacokinetic parameters were significantly affected by food intake. The high-fat breakfast affected the rate of absorption of fenofibrate more than the standard breakfast and fasted conditions. Specifically, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and peak plasma concentration (C(max)) increased 2.45-fold and 2.89-fold, respectively, between the fasted and standard-fed conditions (p < 0.01). In addition, the high-fat meal caused 3.34-fold and 3.82-fold increases compared with the fasted condition in AUC(infinity) and C(max), respectively. A one-compartment open model with lag time successfully described the plasma concentrations of fenofibric acid. CONCLUSION: In healthy volunteers, AUC(infinity) and C(max) of fenofibrate, when administered via sustained-release capsules immediately after the consumption of food, was increased significantly from the fasting conditions (p < 0.01). The greatest AUC(infinity) and C(max) occurred when the capsules were taken after a high-fat breakfast.     

Dose-dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL

AIMS: Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P-glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose-dependently in vivo by cremophor EL, an 'inactive' pharmaceutic aid known to inhibit PGP in vitro. METHODS: In a randomized, placebo-controlled, double-blind, four phase cross-over design single doses of oral saquinavir (Invirase, 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (Cmax), time to reach Cmax (tmax) and terminal elimination half-life (t(1/2)). RESULTS: Cremophor EL dose-dependently increased Cmax, AUC(0,4 h), and AUC(0,infinity) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13-fold for both Cmax and AUC(0,4 h) and 5-fold for AUC(0,infinity). The terminal half-life and the time to reach Cmax (tmax) were unchanged. CONCLUSIONS: Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.     

Food increases the bioavailability of acitretin

Eighteen healthy male volunteers received 50 mg oral doses of acitretin on two occasions, according to a random crossover design. Acitretin was administered during a complete fast or following a moderate breakfast. Plasma samples were obtained at various times and the concentration of acitretin and its 13-cis isomeric metabolite (Ro 13-7652) were quantified by a specific HPLC assay. The AUC0-15 for acitretin was increased when administered with food for all subjects (except one) with a mean increase of 90% (from 1175 to 2249 ng/ml.hr). The maximum plasma concentration of acitretin (Cmax) was increased by 70% when administered with food (from 245 to 416 ng/ml), while the time to reach Cmax was unaffected. The ratio of AUC of Ro 13-7652 to acitretin was the same for both the fasted and fed conditions; therefore, the formation of metabolite was not influenced by concomitant ingestion of food. The presence of food increases the apparent bioavailability of acitretin. A likely mechanism behind this observation is an increase in acitretin solubility in addition to an increase in the lymphatic absorption and a prolonged residence time of the drug in the gastrointestinal tract.