Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects

This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 microg (2 x 250 microg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N-oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (PE, 1.12; 90% CI, 1.00-1.25), and respective N-oxide AUCs (PE, 0.91; 90% CI, 0.79-1.04; PE, 0.99; 90% CI, 0.92-1.06) occurred. Because roflumilast N-oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.     

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.     

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%).     

Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.     

Effect of food on the pharmacokinetics of osmotic controlled-release methylphenidate HCl in healthy subjects

The effect of a high-fat meal on the pharmacokinetics of OROS(R) (methylphenidate HCl), an osmotic controlled-release formulation of methylphenidate HCl, was investigated in healthy subjects. Mean peak methylphenidate plasma concentrations occurred slightly later and peak methylphenidate plasma concentrations and AUC values were slightly higher (approximately 10-30%) in the presence of food than in the absence of food. There was no difference in the plasma elimination half-life of methylphenidate between the fed and fasted state. Similarly, peak concentrations and AUC values for alpha-phenyl-2-piperidine acetic acid (PPA; ritalinic acid), the major metabolite of methylphenidate, were slightly higher in the presence of food than in its absence. The 90% confidence interval (CI) for the treatment ratio (fed/fasted) for C(max) was 120.6%-140. 0% for the 18-mg dose and 105.4-119.3% for a 36-mg dose. The 90% CI for the treatment ratio for AUC(infinity) was 114.6-125.7% for the 18-mg dose and 115.1-124.6% for the 36-mg dose. PPA levels were measured following the 18-mg dose and the 90% CI of the treatment ratio was 106.8-115.4% for C(max) and 97.9-103.6% for AUC(infinity). These results indicate the absence of dose dumping from OROS (methylphenidate HCl) in the presence of food. Food does not impede drug absorption and OROS (methylphenidate HCl) may be administered in the fed or fasted state. There were no differences in the adverse event profile between the fed and fasted state.     

Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers

The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food. Copyright (c) 2007 John Wiley & Sons, Ltd.     

Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers

OBJECTIVE: To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks. METHODS: Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings. RESULTS: The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration. CONCLUSIONS: Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.     

Comparative bioavailability of two cefadroxil formulations in healthy human volunteers after a single-dose administration

OBJECTIVE: To compare the bioavailability of two cefadroxil capsule (500 mg) formulations (Cefadroxila from Eurofarma Laboratórios Ltd, Brazil, as test formulation and Cefamox from Bristol-Myers Squibb, Brazil S.A. as reference formulation) in 24 volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with randomized two-period crossover design and a 1-week washout period. Plasma samples were obtained over a 12-h interval. Cefadroxil concentrations were analysed by combined reversed-phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using a selected ion monitoring method. From the cefadroxil plasma concentration versus time curves the following pharmacokinetic parameters were obtained: AUC(last), AUC(0-infinity) and C(max). RESULTS: Geometric mean of Cefadroxila/Cefamox 500 mg individual percent ratio was 103.97% for AUC(last), 104.08% for AUC(0-infinity) and 95.23% for C(max). The 90% confidence intervals (CI) were 98.14-110.16%, 98.37-110.12%, and 85.59-105.96%, respectively. CONCLUSION: Since the 90% CI for C(max), AUC(last) and AUC(0-infinity) were within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that the Cefadroxila 500 mg capsule was bioequivalent to the Cefamox 500 mg capsule, according to both the rate and extent of absorption.     

Pharmacokinetic bioequivalence of enfuvirtide using a needle-free device versus standard needle administration

STUDY OBJECTIVES: To compare the relative bioavailability of enfuvirtide, a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, injected with the Biojector 2000 (B2000) needle-free device versus a 27-gauge half-inch needle-syringe; and to assess safety, tolerability, and patient preference for the two devices. DESIGN: Open-label, randomized, two-period crossover bioequivalence evaluation. SETTING: Clinical research center. PATIENTS: Twenty-seven adults with HIV-1 viral loads below 1000 copies/ml. INTERVENTION: Each patient received enfuvirtide 90 mg subcutaneously with the B2000 and with the needle-syringe, with a 1-week washout between treatments. MEASUREMENTS AND MAIN RESULTS: Twenty-six and 27 patients were included in the bioequivalence and safety analyses, respectively. Plasma enfuvirtide concentrations were measured at baseline and at several intervals after each injection. The B2000:needle-syringe ratios of maximum concentration (C(max)), area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)), and AUC from time zero to tau (dosing interval) (AUC(0-tau)) served as criteria for bioequivalence determination. The two drug delivery systems were considered bioequivalent if the 90% confidence intervals (CIs) for the ratios were within 0.8-1.25. Safety and tolerability were evaluated based on documentation of adverse events, graded laboratory toxicities, and local injection-site reactions. Patient surveys provided feedback on device preference. Ratios of C(max), AUC(0-infinity), and AUC(0-tau) were 0.95 (90% CI 0.84-1.09), 0.99 (90% CI 0.93-1.05), and 0.99 (90% CI 0.93-1.05), respectively. The frequency of injection-site reactions was low, and severity was generally mild for both devices. Survey results showed 18 patients (69%) had a positive overall impression of the B2000 and 14 (54%) felt safer injecting with this device. Overall, 17 patients (65%) preferred the B2000 over the needle-syringe. CONCLUSION: Bioavailability of enfuvirtide with the B2000 and needle-syringe was equivalent based on C(max), AUC(0-tau), and AUC(0-infinity). Safety profiles and injection-site reactions were comparable between the devices, but patients preferred the B2000. Delivery of enfuvirtide with the B2000 is a feasible alternative to standard needle administration and warrants further evaluation.     

Food does not affect the pharmacokinetics of tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist

Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.     

The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers

The pharmacokinetics and tolerability of a new putative non-benzodiazepine type anxiolytic compound deramciclane was studied in two consecutive studies. An open dose-escalation design was used to study doses from 0.2 to 50 mg in 18 healthy male volunteers. In the second study doses from 50 to 150 mg were investigated in 14 healthy males in a double-blind, placebo-controlled, dose escalation study. Deramciclane was rapidly absorbed from the GI-tract and T(max) was 2-4 h. The elimination half-life increased from about 20 h to about 32 h with the increasing dose. Nevertheless, the AUC(0-infinity) values increased linearly within the studies over the dose ranges of 3-50 and 50-150 mg. However, the increase was more than the ratio of the dose over the total dose range of 3-150 mg. Therefore, non-linear pharmacokinetics of deramciclane at high doses cannot be excluded. N-desmethyl deramciclane, which is the active metabolite of deramciclane, was determined in plasma. C(max) was reached at about 6 h. The AUC(0-48 h) for the N-desmethyl metabolite was about one third of the AUC(0-infinity) of the parent compound and the ratio remained constant at each dose level. Deramciclane was safe, and was well tolerated at each dose level.     

Bioequivalence evaluation of cefdinir in healthy fasting subjects

A simple and sensitive HPLC method was developed to determine cefdinir (CAS 91832-40-5) in human plasma. The method was validated by investigating the accuracy and precision for intra- and inter-day runs in a linear concentration from 0.05-2.0?μg/ml. The object of this study was to compare the bioavailability of cefdinir capsule (reference) and cefdinir granule (test) containing 100?mg of cefdinir. A randomized, open-label, single-dose, 2-way crossover bioequivalence study in 20 healthy, Chinese, male subjects was conducted. A 1-week wash-out period was applied. Blood samples were collected before and with 10?h after drug administration. The formulations were compared using the following pharmacokinetic parameters: AUC0-t, AUC0-∞ and C max. The 90% confidence interval (CI) of the ratios of log-transformed AUC0-t and AUC0-∞ were used to assess bioequivalence between the 2 formulations using the equivalence interval of 80 and 125%. The results showed that the 90% CI of the ratios of AUC0-t, AUC0-∞ and C max were 102.5% (94.7-111.0%), 103.4% (94.8-112.7%) and 106.4% (97.0-116.7%), respectively, which indicated 2 formulations of cefidinir are bioequivalent. Both treatments showed similar tolerability and safety.     

A randomized study of the effects of food on the pharmacokinetics of once-daily extended-release hydromorphone in healthy volunteers

This randomized, open-label, crossover study investigated the influence of food on the pharmacokinetics of extended-release hydromorphone in 30 healthy volunteers. Participants received extended-release hydromorphone 16 mg in the fasted state and immediately after a high-fat breakfast. In addition, the pharmacokinetics of a 16-mg dose of extended-release hydromorphone and a 16-mg daily dose (4 mg qid) of immediate-release hydromorphone in the fasted state were compared. Treatments were separated by washout periods of 7 to 14 days. Naltrexone was given throughout each treatment period to block the opioid effects of hydromorphone. The 90% confidence intervals (CIs) of the ratios of geometric means for maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC) for extended-release hydromorphone in the fed and fasted states were within the bioequivalence criteria range of 80% to 125%. In the fasted state, the 90% CIs of the ratios of AUC geometric means for extended-release hydromorphone and immediate-release hydromorphone were also within the bioequivalence range. Both hydromorphone treatments were well tolerated. This study shows that the bioavailability of extended-release hydromorphone is not affected by food and that the bioavailability of extended-release hydromorphone under fasting conditions is comparable with that of the immediate-release formulation when administered at the same total daily dose.     

Comparative bioavailability study of two preparations of letrozole in healthy subjects

The bioavailability of a new letrozole (CAS 112809-51-5) preparation was compared with the reference preparation of the drug in 25 healthy volunteers, aged between 18 and 33. A single dose of 2.5 mg was given orally in the fasted state, using a randomized two-way, cross-over protocol. A washout period of two weeks separated both treatment periods. Blood samples were obtained at regular time intervals, until 312 h after drug administration. After solid phase extraction (SPE) letrozole plasma levels were measured by high pressure liquid chromatography that was validated before the start of the study (UV detector, fluoroletrozole as an internal standard). The limit of quantification was 1.4 nmol/ml. The following pharmacokinetics parameters were calculated from letrozole plasma concentrations: AUC(0-infinity), AUC(0-t), Cmax, tmax, F(rel), MRT, t(1/2), k(el). The confidence intervals for the statistical calculations of AUC(0-infinity), Cmax, tmax were 95 % and AUC(0-t), MRT, t(1/2), k(el) were tested by means of the unpaired t-tests procedure and after logarithmic transformation for overall significant differences using analysis of variance--three-way ANOVA. The AUC(0-infinity) ratio test/reference and the 90 % confidence interval were 99.52 %, and 94.05-107.31%, respectively. The Cmax ratio test/reference and the 90 % confidence interval were 89.18 %, and 84.48-98.60%, respectively. AUC(0-infinity) and Cmax ratios (90 % CI) were within the 80-125 % interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new letrozole preparation is therapeutically equivalent to the reference preparation for both the extent and the rate of absorption after single dose administration in healthy volunteers.     

Bioequivalence study of two brands of enalapril tablets after single oral administration to healthy volunteers

OBJECTIVE: To compare the relative bioavailability and bioequivalence of 2 enalapril tablet formulations in healthy volunteers under fasting conditions. METHODS: An open-label, single-dose, randomized, two-period, crossover trial with a 1-week washout period in 24 healthy volunteers. The 2 enalapril 20 mg tablet formulations used were Antiprex (Elpen, Greece) as test and Renitec (Vianex, Greece) as reference preparation. Serial blood samples were collected at 19 points for 36 h. Plasma samples were analyzed for enalaprilat, the pharmacologically active metabolite of enalapril, by a validated GC/MS assay. Pharmacokinetic parameters, such as AUC(0-infinity), AUC(0-t), C(max) T(max), t1/2 and MRT were calculated from plasma concentrations for both formulations. Statistical comparisons (ANOVA and 90% confidence intervals) of AUC(0-infinity), AUC(0-t) and C(max) data were evaluated after logarithmic transformation, and differences of T(max) were tested non-parametrically. RESULTS: The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 88.0 - 117.6% (point estimate: 101.8%) for AUC(0-infinity), 88.7 - 118.9% (point estimate: 102.7%) for AUC(0-t), and 91.0% - 123.4% (point estimate: 106.0%) for C(max) No statistically significant differences were found between the 2 preparations for T(max) t1/2 and MRT values. CONCLUSIONS: From the results of the present study, it is concluded that the test and reference tablet formulations of enalapril are bioequivalent for both the extent and the rate of absorption and therefore the 2 products can be considered to be interchangeable in clinical practice.     

Influence of food intake on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase

The objective of this study was to investigate the effect of food on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. Twenty-four healthy male (n = 9) and female (n = 15) subjects were treated in a randomized, 2-way crossover design with a single oral dose of 100 mg miglustat with or without food. Consumption of a standard high-fat breakfast within 30 minutes before administration of miglustat significantly reduced peak exposure but did not significantly affect the extent of systemic exposure to miglustat. The peak plasma concentration (C(max)) decreased by 36% on average following administration with food. Area under the plasma concentration-time curve (AUC(0-infinity)) showed a modest (14%) decrease with food, but the 90% confidence interval was within the acceptance limit of 80% to 125%. The median (min-max) time to C(max) (t(max)) was prolonged from 2.5 (1.0-4.0) hours in the fasted state to 4.5 (1.5-8.0) hours in the fed state, whereas the apparent terminal half-life was approximately 8 hours and not affected by food. In conclusion, the intake of food has an effect on some pharmacokinetic parameters such as C(max) and t(max) but does not affect the extent of exposure to miglustat. The observed effects of food intake on the pharmacokinetics of miglustat are not considered to be of clinical relevance.     

Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status

We have investigated the pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under fed and fasted conditions in eight healthy volunteers. The volunteers were administered a single oral dose of mixed tocotrienols (300 mg) under fed or fasted conditions. The bioavailability of tocotrienols under the two conditions was compared using the parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC(o-infinity)). A statistically significant difference was observed between the fed and fasted logarithmic transformed values of Cmax (P < 0.01) and AUC(0-infinity) (P < 0.01) for all three tocotrienols. In addition, the 90% confidence intervals for the ratio of the logarithmic transformed AUC(0-infinity) values of alpha-, gamma- and delta-tocotrienols under the fed state over those of the fasted state were found to lie between 2.24-3.40, 2.05-4.09 and 1.59-3.81, respectively, while those of the Cmax were between 2.28-4.39, 2.31-5.87 and 1.52-4.05, respectively. However, no statistically significant difference was observed between the fed and fasted Tmax values of the three homologues. The mean apparent elimination half-life (t(1/2)) of alpha-, gamma- and delta-tocotrienols was estimated to be 4.4, 4.3 and 2.3 h, respectively, being between 4.5- to 8.7-fold shorter than that reported for alpha-tocopherol. No statistically significant difference was observed between the fed and fasted t(1/2) values. The mean apparent volume of distribution (Vd/f) values under the fed state were significantly smaller than those of the fasted state, which could be attributed to increased absorption of the tocotrienols in the fed state.     

Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast

OBJECTIVE: Objective of the study was the comparison of two nifedipine sustained-release products marketed in Europe. Maximum plasma concentration (C(max)) and area under the plasma-concentration curve (AUC) values were derived after administration of single doses (60 mg) of test product and reference product, both approved for once-a-day administration, to 24 healthy male volunteers either after an overnight fast or immediately after a high-fat American breakfast. The study was performed with a randomised, non-blinded, four-period crossover design. Within- and between-product comparisons were determined for fed versus fasted administration considering bioavailability and tolerability of all treatments. Furthermore, in vitro dissolution characteristics of both products were evaluated.METHODS: Plasma samples were assayed using a liquid chromatography-mass spectrometry method, and resulting pharmacokinetic parameters were determined model independently according to international requirements and the current European guidelines.RESULTS: Under fasted conditions the comparison of test and reference products showed a similar extent of bioavailability with a mean ratio of AUC((0-)(infinity)()) of 99% [95% confidence interval (CI) 86%, 114%], but significantly higher C(max) values resulting in a mean ratio of 169% (95% CI 139%, 206%). Accordingly, mean residence time and half-value duration values were smaller for the test product than the reference product. Under fed conditions, a pronounced food effect could be observed for the test product resulting in a pronounced increase of C(max) values. The affiliating point estimate was calculated as 340% with a 95% CI of 279%, 413%. However no remarkable influence of food intake was observed for the reference product.CONCLUSION: Under fasting conditions the modified-release characteristics of the test product are less pronounced than the reference product. No relevant impact of food intake could be observed for the reference product when switching from fasted to fed state, whereas a significant loss of modified-release characteristics could be detected for the test product under fed conditions resulting in much higher maximum concentrations. Such a phenomenon has been described in literature as "dose-dumping effect".     

Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers

The bioavailability of drotaverine (CAS 14009-24-6) was investigated after oral administration of a drotaverine capsule preparation (20 mg Droxa mite) and compared to that of a reference tablet preparation. The preparations were investigated in 23 healthy volunteers, aged between 20 and 27 years, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of drotaverine plasma concentrations were collected at pre-defined time points up to 30 h following drug administration. A washout period of two weeks separated both treatment periods. Drotaverine plasma concentrations were determined by means of a validated HPLC method (UV detector, imipramine HCl salt as an internal standard). The limit of detection was 6 ng/ml. Values of 1593.92 +/- 949.70 ng x h/l (95% confidence interval (CI): 1183.20-2004.60) for the test and 1705.48 +/- 737.78 ng x h/l (95% CI: 1386.40-2024.50) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax of 121.89 +/- 37.03 ng/ml (95% CI: 104.05-139.80) and 121.85 +/- 37.97 ng/ml (95% CI: 107.09-135.74) and time to reach maximum plasma concentration--Tmax of 1.29 +/- 0.42 h (95% CI: 1.11-1.48) and 1.14 +/- 0.34 h (95% CI: 0.99-1.29) achieved for the test and reference preparations did not differ significantly. The relative bioavailability (AUC(0-infinity) ratio test/reference) and Cmax ratio test/reference were 103.15% (90% CI: 81.68-124.60) and 103.74% (90% CI: 94.10-113.38), respectively. AUC was calculated using two different methods. There were no significant differences between the obtained values. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the European Agency for the Evalution of Medicinal Products (CPMP) and the Food and Drug Administration, it is concluded that the new drotaverine capsule formulation is therapeutically equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.