Randomized Comparative Bioavailability of a Novel Three-Dimensional Printed Fast-Melt Formulation of Levetiracetam Following the Administration of a Single 1000-mg Dose to Healthy Human Volunteers Under Fasting and Fed Conditions.

BACKGROUND: Rapidly disintegrating or 'fast-melt' oral formulations have been developed recently to facilitate drug intake among patients. Even though these formulations have helped to improve therapy adherence, some of their limitations include: the dissolution time, their facility to be swallowed, and the dosage strengths that may be accommodated. To overcome these limitations, a novel, porous, quickly disintegrating, and easier-to-swallow fast-melt formulation based on powder-liquid, three-dimensional printing (3DP) technology has been developed. OBJECTIVE: To determine and compare the relative bioavailability of a novel 3DP fast melt containing levetiracetam in healthy male and female subjects. METHODS: This study included 33 subjects in a three-way crossover design. The 3DP fast-melt formulation was compared against the conventional immediate-release tablet of levetiracetam (Keppra(®)) after a single 1000-mg dose administration under fasting conditions following the bioequivalence criteria used by the US Food and Drug Administration. This study also evaluated the food effect on the bioavailability of the levetiracetam 3DP fast melt. A small sip of liquid was used to administer the fast-melt formulation. RESULTS: The novel 3DP fast melt showed rapid oral disintegration (mean duration of 11 s from a sip of water to completion of swallowing) following its administration, and did not affect the pharmacokinetic profile of levetiracetam. A lower absorption peak was observed after administration of the 3DP fast melt under fed conditions, as expected. In addition, time of maximum measured plasma concentration was delayed by approximately 3.5 h under fed conditions. These effects are unlikely to be of clinical significance with long-term administration, and may help reduce the adverse events and facilitate compliance. Finally, no change in the oral mucosa was observed with the 3DP fast melt while being as safe and well tolerated as the standard levetiracetam tablet. CONCLUSION: This study quantified the rapid disintegration of the 3DP levetiracetam fast melt and confirmed its equivalent rate and extent of absorption to the conventional immediate-release tablet in the fasted state, using standard bioequivalence criteria.

Single-Dose, Randomized, Open-Label, Two-Way, Crossover Bioequivalence Study of Two Formulations of Pregabalin 300 mg Hard Capsules in Healthy Volunteers Under Fasting Conditions.

AIMS: This bioequivalence study was conducted to assess the bioequivalence of two formulations, test and reference, of pregabalin 300 mg hard capsules, under fasting conditions. METHODS: This was a single-center, randomized, single-dose, open-label, laboratory-blinded, two-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected prior to and up to 36 h after dosing. Pregabalin plasma concentrations were determined, using a validated method, by reversed phase high performance liquid chromatography coupled to a tandem mass spectrometry detector (LC-MS-MS). Pharmacokinetic metrics used for bioequivalence assessment were the AUC(0-t) (area under the plasma concentration-time curve from time zero to time of last observed non-zero plasma concentration) and the C max (maximum observed plasma concentration). These parameters were determined from the pregabalin plasma concentration data using noncompartmental analysis. RESULTS: Forty healthy subjects, age ranging from 18 to 43 years old, were enrolled and randomized, of whom 39 completed the study. The ratio of geometric least square means for C max was 99.29 % (90 % confidence interval [CI] 93.29-105.67). The ratio of geometric least square means for AUC(0-t) was 101.54 % (90 % CI 100.13-102.98). The 90 % CIs were within the predefined range (80.00-125.00). CONCLUSIONS: Bioequivalence between test and reference formulations, under fasting conditions, was concluded both in terms of rate and extent of absorption.

The impact of new partial AUC parameters for evaluating the bioequivalence of prolonged-release formulations.

To demonstrate bioequivalence (BE) between two prolonged-release (PR) drug formulations, single dose studies under fasting and fed state as well as at least one steady-state study are currently required by the European Medicines Agency (EMA). Recently, however, there have been debates regarding the relevance of steady-state studies. New requirements in single-dose investigations have also been suggested by the EMA to address the absence of a parameter that can adequately assess the equivalence of the shape of the curves. In the draft guideline issued in 2013, new partial area under the curve (pAUC) pharmacokinetic (PK) parameters were introduced to that effect. In light of these potential changes, there is a need of supportive clinical evidence to evaluate the impact of pAUCs on the evaluation of BE between PR formulations. In this retrospective analysis, it was investigated whether the newly defined parameters were associated with an increase in discriminatory ability or a change in variability compared to the conventional PK parameters. Among the single dose studies that met the requirements already in place, 20% were found unable to meet the EMA's new requirements in regards to the pAUC PK parameters. When pairing fasting and fed studies for a same formulation, the failure rate increased to 40%. In some cases, due to the high variability of these parameters, an increase of the sample size would be required to prove BE. In other cases however, the pAUC parameters demonstrated a robust ability to detect differences between the shapes of the curves of PR formulations. The present analysis should help to better understand the impact of the upcoming changes in European regulations on PR formulations and in the design of future BE studies.

Safety, tolerability and pharmacokinetics of trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) in a randomized phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers.

PURPOSE: Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. METHODS: GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m(2). The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. FINDINGS: The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, Tmax of trimebutine ranged from 1.0 to 1.5 hours. Cmax and AUCT were linear (nonlinearity P ≥ 0.05) and proportional (P < 0.05) over the studied dose range. Food increased the Cmax and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84-234) and 174% (138-221), respectively. In the MAD study portion, the Tmax of trimebutine ranged from 0.5 to 2 hours and AUCτ increased from 38 to 170 ng · h/mL. AUCτ and Cmax were linear and proportional over the studied dose range. IMPLICATIONS: GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.).

Health professionals' beliefs related to parental involvement in ambulatory care: an international inquiry.

Changes in health care delivery in Canada and Europe, especially the shift to ambulatory care, have modified the care that children and parents receive and have prompted the need for a partnership alliance. The objectives of this exploratory study were to identify Canadian and Belgian health professionals' beliefs and attitudes towards parental involvement in their child's ambulatory care and to determine if these beliefs varied according to cultural background. Health professionals from both countries generally were in favor of parental involvement in their child's care, but are uncertain about its advantages and disadvantages. Facilitators and barriers mentioned by the health care providers were related to parents' abilities or their attitudes toward partnership, and they also expressed a need for more education on the subject. Results of this study indicate that health professionals working in ambulatory care are not fully ready to utilize parents as true partners in their interventions with children and families. Staff education is an important step towards the establishment and maintenance of a real partnership.

Effects of food and formulation on the relative bioavailability of bismuth biskalcitrate, metronidazole, and tetracycline given for Helicobacter pylori eradication.

AIMS: To evaluate the effects of food and formulation on the pharmacokinetics of bismuth biskalcitrate, metronidazole and tetracycline when combined in a new 3-in-1 single capsule (BMT) for eradication of Helicobacter pylori. METHODS: In a randomized, 3 x 3 cross-over design, 23 healthy males received one dose of BMT in the fed and fasting states and equivalent doses of the three drugs given together but as separate capsules while fasting. Bioequivalence was evaluated according to 90% confidence intervals (CIs) of ratios of geometric least square means for C(max), AUC(t), and AUC(infinity). RESULTS: With respect to food, none of the three drugs met bioequivalence guidelines. Bismuth had lower limit CIs ranging from 12% for C(max) to 25% for AUC(infinity). The corresponding values for tetracycline were 59% and 51%. Metronidazole had a lower limit CI of 74% for C(max). With respect to formulation, bismuth had lower limits of CIs ranging from 39% for C(max) to 50% for AUC(t) and higher limits of 146% for AUC(t), metronidazole met bioequivalence guidelines, and tetracycline had lower limits of CIs between 72% for AUC(t) and 74% for AUC(infinity). CONCLUSIONS: Food significantly decreased the relative bioavailability of each drug but formulation was without effect. This decrease may be beneficial when a local gastric action is needed, as confirmed by a near 90% eradication rate when this combined capsule is administered with food to treat gastro-duodenal local infection by H. pylori.

Influence of omeprazole on bioavailability of bismuth following administration of a triple capsule of bismuth biskalcitrate, metronidazole, and tetracycline.

The objective of this study was to determine the impact of omeprazole on bismuth (Bi) bioavailability when given in a three-in-one capsule containing bismuth biskalcitrate, metronidazole, and tetracycline. Thirty-four healthy volunteers were randomly assigned to receive three capsules (each containing bismuth biskalcitrate 140 mg + metronidazole 125 mg + tetracycline 125 mg) qid alone x 6 days or the same treatment + omeprazole (OM) 20 mg bid. Blood was drawn at intervals for 24 hours after the last dose. After the last dose, mean (CV) C(min) for plasma bismuth was 2882 pg/mL (36%) and 1195 pg/mL (23%) (p< 0.001), with and without OM, respectively. Mean (CV) C(max) was 25493 pg/mL (69%) and 8061 pg/mL (28%) (p < 0.001) with and without OM, respectively. AUC(0-24) increased by 2.9 in presence of OM (p < 0.001). Adverse events in both groups were usually mild and of a gastrointestinal nature, and all had resolved by the end of the trial. This study confirms an interaction between Bi biskalcitrate and OM. Risk of Bi toxicity, seen after long-term use of Bi compounds, is minimal here because plasma levels of Bi remained well below the toxic levels of 50 microg/L, and the treatment period with this triple capsule + OM is only 10 days, a substantially lower number of days compared to that which might produce Bi toxicity.

Effects of first and second generation calcium channel blockers on diastolic function of the failing hamster heart: relationship with coronary flow changes.

Calcium channel blockers (CCBs) have variable efficacy in the treatment of heart failure. We hypothesized that modulation of left ventricular diastolic pressure (LVDP) may play a role in the variable efficacy of CCBs in this condition. Isolated perfused hearts from 200- to 250-day-old UM-X7.1 cardiomyopathic hamsters (failing hearts) and age-matched Syrian hamsters (normal hearts) were studied. After recording of heart rate, coronary flow (CF), LVDP and left ventricular systolic pressure (LVSP), hearts were exposed either to verapamil or diltiazem (1 nM-10 microM), mibefradil (1 nM-1 microM) or clentiazem (1 nM-10 microM). Mechanical increase in CF (+2 to +10 ml/min) was carried out using a roller pump. Mechanically-augmented flow led to an increase in coronary perfusion pressure (+40 to +90 mm Hg), LVSP (+5 to +40 mm Hg) and LVDP (+5 to +25 mm Hg). CCBs-induced increment of coronary flow led to a difference in their cardiac response. In normal hearts, the negative inotropic response was more important with diltiazem and verapamil. Failing hearts did not demonstrate increased inotropic sensitivity to first-generation CCBs. On the contrary, at clinically relevant concentrations, verapamil resulted in the most pronounced impairment of LVDP followed by diltiazem while mibefradil and clentiazem, at clinically relevant concentrations, preserved LVDP. Such findings provide an additional explanation for the variable efficacy of CCBs in heart failure.

Effects of lercanidipine on coronary reactivity and myocardial remodeling in transition to heart failure in cardiomyopathic hamsters.

AIM: Lercanidipine is a new vasoselective dihydropyridine calcium channel blocker with a short plasma half-life, long duration of action, and demonstrated cardioprotective properties. We hypothesized that it might be effective at attenuating the adverse impact observed on the coronary compartment and myocardium in the transition phase to heart failure in the UM-X7.1 cardiomyopathic (CM) hamster. METHODS: The effects of 4-month exposure to lercanidipine 3 and 10 mg/kg (daily oral administration) were evaluated in 150-day-old CM hamsters and in age-matched normal hamsters. Coronary reactivity (reactive hyperemia to 30-s coronary occlusion) and the response to the administration of acetylcholine (100 nmol/L) and sodium nitroprusside (1 micromol/L) were assessed monthly, using the isolated perfused heart model. The left ventricular chamber dilatation index and wall thickness, myocardial fibrosis and myocardial capillary density (papillary muscle) were estimated in selected subgroups at monthly intervals. RESULTS: High-dose lercanidipine had beneficial effects on coronary dysfunctions: at month 4 of the treatment period, reactive hyperemia to short duration ischemia was improved, as was the endothelium-dependent vasodilator response (acetylcholine=68 %+/-16 % vs 11 %+/-5 % in untreated CM hamsters, P<0.05) and endothelium-independent vasodilator response (sodium nitroprusside=36 %+/-5 % vs 22 %+/-12 % in untreated CM hamsters, P<0.05). Capillary density averaged 10,879+/-474 capillaries per mm2 in papillary muscle from normal hamsters; this value did not change over time in normal hamsters and was not affected during the transition phase to heart failure in CM hamsters. Lercanidipine preserved myocardial capillary density in these conditions. Chronic exposure to lercanidipine had no impact on myocardial remodeling observed in CM hamsters. CONCLUSION: Lercanidipine had a beneficial impact on the coronary compartment in the transition phase to heart failure in a model of dilated cardiomyopathy.

Effect of chronic treatment with bovine recombinant growth hormone on cardiac dysfunction and lesion progression in UM-X7.1 cardiomyopathic hamsters.

In view of the potentially beneficial effect of GH on ventricular function of humans suffering from idiopathic dilated cardiomyopathy, we undertook a study to evaluate the optimal time to initiate treatment with GH and its duration in UM-X7.1 cardiomyopathic hamsters (CMH). GH (1 mg/kg.d) therapy was initiated either in the early or late (30 and 160 d old, respectively) phases of the disease and continued until death at 240 d of age. Age- and sex-matched Golden Syrian hamsters (GSH) were used as controls. Basal IGF-1 levels in serum were reduced by nearly half in CMH compared with GSH but were increased within a physiological range in male hamsters. In contrast, female hamsters presented elevated basal serum IGF-1 levels that were not further elevated by GH administration, as reported in experimental models and humans. Accordingly, the present study will focus on the effects of GH therapy on cardiac performance in male hamsters. GH did not improve ventricular function when starting at a late stage of the disease compared with CMH controls. Maximum rate of left ventricular pressure development decreased by approximately 64% in CMH treated early with recombinant bovine GH. Ventricular dysfunction was associated with morphologic indices of hypertrophy, ventricular dilatation, and extensive fibrosis. Mortality was strikingly increased in GH-treated CMH for 210 d (four males and eight females), as opposed to four females (and no male) in the vehicle-treated group. These results suggest that chronic treatment with recombinant bovine GH in CMH, starting at an early stage of lesion development, is associated with a reduced cardiac performance at the terminal stage of the disease.

Role of nitric oxide synthase, cytochrome P-450, and cyclooxygenase in the inotropic and lusitropic cardiac response to increased coronary perfusion.

Although studies have reported that increase in coronary perfusion (CP) results in positive inotropic effects, the underlying mechanisms of these actions and possible alterations in myocardial diastolic function are not well defined. Hypothesis was that nitric oxide (NO) and derivatives of cytochrome (CYT) P-450 or cyclooxygenase (COX) might contribute to interplay between coronary and myocardial compartments in these conditions. Using isovolumically contracting, isolated perfused hamster heart model, coronary flow (CF) was increased mechanically, stepwise in the physiologic range (+2 to +10 ml/min), before and after inhibition of NO synthase by NG-nitro-l-arginine methyl ester (l-NAME) (30 microM), CYT P-450 by SKF525A (1 microM), or COX by indomethacin (10 microM). CP pressure, left ventricular systolic pressure (VSP) and ventricular diastolic pressure (VDP), and heart rate (HR) were monitored continuously during the experiments. Mechanical increases in CF resulted in gradual change in CP pressure (+20% to +100%), left VSP (+5% to +40%) and VDP (+2% to +25%), whereas HR was not affected. In presence of l-NAME, the positive inotropic response and negative lusitropic effect of CF changes were similar. Exposure to SKF525A did not modify cardiac response to mechanical increases in CF. In presence of COX inhibitor indomethacin, left VSP rose to a level similar to that observed in control conditions, whereas VDP deteriorated further. These results suggest that mediators originating from NO synthase, CYT P-450, or COX do not contribute to positive inotropic response elicited by increased CP. However, COX derivatives seem to attenuate impairment of myocardial relaxation observed in these conditions. Such findings may have implications in development of therapeutics for patients with myocardial diastolic dysfunction.