Effect of food on the pharmacokinetic characteristics of a single oral dose of LCB01-0371, a novel oxazolidinone antibiotic (original) (raw)
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Clinical Drug Investigation, 2005
To investigate the relative bioavailability and bioequivalence, in fasting and fed conditions, of repeated doses of two omeprazole enteric-coated formulations in healthy volunteers. Open label, single-centre study consisting of two consecutive randomised, two-way crossover trials (a fasting trial and a fed trial). Each trial consisted of two 7-day treatment periods in which subjects received one daily dose of the test (Ompranyt((R))) or reference (Mopral((R))) formulations. At day 7 and day 14 (fasting trial), products were administered in fasting conditions and blood samples were taken for omeprazole plasma assay over 12 hours. At day 21 and day 28 (fed trial), products were administered after a standard high-calorie and high-fat meal and 12-hour blood samples taken. Omeprazole plasma concentrations were quantified by a validated method using a reverse-phase high performance liquid chromatography with UV detection (HPLC-UV). Twenty-four subjects were enrolled and 23 completed the study. Under fasting conditions, the mean +/- SD maximum omeprazole plasma concentration (C(max)) was 797 +/- 471 mug/L for Ompranyt((R)) and 747 +/- 313 mug/L for Mopral((R)) with a point estimate (PE) of 1.01 and a 90% confidence interval (CI) of 0.88, 1.16. The mean +/- SD area under the plasma concentration curve from administration to last observed concentration (AUC(0-12)) was 1932 +/- 1611 mug . h/L and 1765 +/- 1327 mug . h/L for Ompranyt((R)) and Mopral((R)), respectively (PE = 1.09; 90% CI 0.95, 1.25). In the presence of food, the C(max) was 331 +/- 227 mug/L and 275 +/- 162 mug/L (PE = 1.21; 90% CI 0.92, 1.59) and AUC(0-12) was 1250 +/- 966 mug . h/L and 1087 +/- 861 mug . h/L (PE = 1.16; 90% CI 0.92, 1.47) for Ompranyt((R)) and Mopral((R)), respectively. Bioequivalence of the formulations in the fasting condition was demonstrated both for AUC(0-12) and for C(max) because the 90% CI lay within the acceptance range of 0.80-1.25. In contrast with the fasting condition, there were significant reductions in rate (C(max)) and extent (AUC(0-12)) of systemic exposure when test and reference formulations were administered with food. The food effect was more marked with Mopral((R)) than with Ompranyt((R)), and the bioequivalence criterion was not fulfilled because the 90% CI fell out of the acceptance range of 0.80, 1.25, for both C(max) and AUC(0-12). The two formulations were similarly well tolerated. Bioequivalence of Ompranyt((R)) (test formulation) and Mopral((R)) (reference) formulations was demonstrated after repeated dosing in the fasting condition. Following a high-calorie and high-fat meal, there was a significant reduction in rate and extent of systemic exposure for both products, with Ompranyt((R)) being less affected than Mopral((R)) by the presence of food.
Antimicrobial drug administration and food timings: clinico-pharmacological considerations
Exploratory Animal and Medical Research, 2021
Food may alter the extent or rate of absorption through various mechanisms, but not all pharmacokinetic effects are clinically relevant. Understanding the possible clinical implications of taking a drug with or without a meal is important for achieving its quality use. Although the effect of food is not clinically important for many drugs, there are food-drug interactions which may have adverse consequences. These interactions can be avoided by taking the medicines with consideration of the time of taking meals.
Effect of Food on the Bioavailability of Omadacycline in Healthy Subjects
The Journal of Clinical Pharmacology, 2016
Omadacycline is a first-in-class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, open-label, 4-period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ࣙ6-hour fast, (B) high-fat, nondairy meal 4 hours before dosing, (C) high-fat, nondairy meal 2 hours before dosing, and (D) high-fat meal containing dairy 2 hours before dosing. Participants received a single 300-mg oral dose of omadacycline during each treatment period; periods were separated by ࣙ5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least-squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty-one participants were included in the PK analysis. Fasted AUC 0-Ý , AUC 0-t , and AUC 0-24 were 10.2, 7.2, and 7.2 μg•h/mL, respectively, and C max was 0.6 μg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300-mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.
Pharmaceutics
This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90-91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.
Clinical pharmacology and therapeutics, 2017
Ribociclib (KISQALI®), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using (1) biorelevant media solubility, (2) physiologically based pharmacokinetic (PBPK) modeling, (3) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis. This multi-pronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH altering agents on the absorption of ribociclib, without a dedicated drug-drug interaction trial. The bioequivalence of ribociclib exposure with or without a high-fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may ...
Clinical Pharmacology in Drug Development, 2014
Drs. Devineni and Manitpisitkul were the clinical pharmacology leaders for the studies and involved in study design and data interpretation. Mr. Murphy was the pharmacology scientist for the studies, contributing to pharmacokinetic data analysis and interpretation. Drs. Di Prospero and Rothenberg were the safety physicians responsible for the safety data analysis and interpretation. Mr. Ariyawansa was the project statisticians involved in statistical data analyses and providing outputs for interpretation. Mr. Stieltjes was the bioanalytical scientist responsible for sample analyses. All authors contributed to the data interpretation of the results as well as manuscript preparation. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data and approved submission to this journal. All authors contributed to the data interpretation, development, and review of this manuscript, and confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.