Dasatinib Can Be Administered Orally with or without a Meal.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4569-4569 ◽  
Author(s):  
Sanjeev Kaul ◽  
Chiyuan Wu ◽  
Shelley Mayfield ◽  
James Manning ◽  
Anne Blackwood-Chirchir
Keyword(s):  
Adverse Events ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Mass Spectrometric Method ◽  
High Fat ◽  
Low Fat ◽  
Fasted State ◽  
Tandem Mass Spectrometric ◽  
Fat Meal

Abstract Background: Food can change the bioavailability of a drug, which can have clinically significant consequences. This study was conducted to investigate the effect of food on the oral bioavailability of dasatinib (SPRYCEL®) in healthy adult subjects. Methods: Fifty-four healthy adult subjects received a single dose of dasatinib 100 mg dose, as 2 x 50 mg film-coated tablets after an overnight fast and within 10 minutes after the ingestion of a low-fat meal (315 kcal [20% fat, 68% carbohydrates, and 12% protein]) and a high-fat meal (985 kcal [52% fat, 34% carbohydrates, and 14% protein]) in a randomly assigned sequence. Individual treatments were separated by at least a 7-day washout period. Serial blood samples were collected for 24 hours after each treatment to determine dasatinib plasma concentrations using a validated liquid chromatography/tandem mass spectrometric method. Dasatinib pharmacokinetic (PK) parameters were determined using a non-compartmental method. Safety was monitored throughout the study. Results: Of the 54 healthy adult subjects (85% male, 61% Caucasian, mean age 32 y, and weight 80 kg), 48 completed the study. There were no serious adverse events. Adverse events and laboratory abnormalities were, in general, typical of those seen with dasatinib administration. PK results are summarized in the table below. Conclusions: Compared to the fasted state, a low-fat meal decreased Cmax and AUC of dasatinib by 21%; a high-fat meal decreased Cmax by 24% and increased AUC by 14%. These results are not expected to be of clinical relevance and, therefore, dasatinib may be taken without regard to meals. The drug was generally safe and well-tolerated when administered in the fed or fasted state. Statistical Analysis of PK Parameters for Dasatinib Treatment PK Parameter Geometric Mean Ratios (95% Confidence Intervals) Fed versus Fasted Low-Fat Meal Cmax 1.216 (1.047, 1.413) AUC 1.212 (1.100, 1.336) High-Fat Meal Cmax 0.758 (0.651, 0.882) AUC 1.140 (1.034, 1.257)

scholarly journals Effect of a High-Calorie, High-Fat Meal on the Bioavailability and Pharmacokinetics of PA-824 in Healthy Adult Subjects

2013 ◽  
Vol 57 (11) ◽  
pp. 5516-5520 ◽  
Author(s):  
Helen Winter ◽  
Ann Ginsberg ◽  
Erica Egizi ◽  
Ngozi Erondu ◽  
Karl Whitney ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Geometric Mean ◽  
Crossover Design ◽  
High Fat ◽  
Serious Adverse Events ◽  
Fed State ◽  
Fasted State ◽  
Dose Levels ◽  
Fat Meal ◽  
High Calorie

ABSTRACTPA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios ofCmaxand AUC0–∞revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The medianTmaxin the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the medianTmaxwas 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered atClinicalTrials.govunder registration numbers NCT01828827 and NCT01830439.)

scholarly journals The Lidose Hard Capsule Formulation of Fenofibrate is Suprabioavailable Compared to the Nanoparticle Tablet Formulation Under High-fat Fed Conditions

2015 ◽  
Vol 18 (1) ◽  
pp. 61 ◽  
Author(s):  
Roger K Verbeeck ◽  
Sophie De Niet ◽  
Sonia Lebrun ◽  
Mickael Tremege ◽  
Tim W. Rennie ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Relative Bioavailability ◽  
Fenofibric Acid ◽  
High Fat ◽  
Case Scenario ◽  
Capsule Formulation ◽  
Worst Case ◽  
Randomized Crossover Study ◽  
Fat Meal

Purpose: The therapeutic equivalence of multiple registered fenofibrate formulations, several of which are suprabioavailable and therefore marketed at lower dosage strengths than their reference products, is based on the results of bioequivalence studies. Most of these formulations show a higher bioavailability when taken with a high-fat meal. The relative bioavailability of two of these formulations, the 200 mg Lidose hard capsules and the 145 mg nanoparticle tablets, was assessed when taken with a high-fat meal. Methods: In this single dose, 2-way, randomized, crossover study, 24 healthy subjects received a 200 mg fenofibrate Lidose hard capsule (Test) and a 145 mg nanoparticle tablet (Reference) under high-fat fed conditions. Plasma concentrations of fenofibric acid were measured up to 72 hours by using a validated LC-MS/MS method. Results: The geometric mean ratios (Test/Reference) and the 90% confidence intervals for AUC0-t and Cmax were 1.37 (131.58 – 142.88) and 1.38 (124.60 – 152.93), respectively. The median (range) Tmax­ values of fenofibric acid were 4.5 h (3.0 – 8.0 h) and 3.25 h (1.0 – 6.5 h) after administration of the Lidose hard capsule and the nanoparticle tablet, respectively. Conclusion: Under high-fat fed conditions the extent of fenofibrate absorption was 37% higher for the 200 mg Lidose hard capsule compared to the 145 mg nanoparticle tablet, which is exactly as expected based on a mg-to-mg weight basis. The results of the present study underline the importance of assessing bioequivalence of fenofibrate formulations under identical fed conditions, and preferentially after a high-fat meal as this condition represents the worst-case scenario. Furthermore, the results of this study demonstrate that the 145 mg nanoparticle tablet is not bioequivalent to the 200 mg Lidose hard capsule when administered under high-fat meal conditions.  This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Effects of high- and low-fat meals on the diurnal response of plasma lipid metabolite concentrations in healthy middle-aged volunteers

1997 ◽  
Vol 77 (3) ◽  
pp. 375-390 ◽  
Author(s):  
D. L. Frape ◽  
N. R. Williams ◽  
A. J. Scriven ◽  
C. R. Palmer ◽  
Kathryn O'sullivan ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Plasma Lipid ◽  
Hdl Cholesterol ◽  
Blood Lipid ◽  
Tolerance Test ◽  
Cholesterol Concentration ◽  
High Fat ◽  
Middle Aged ◽  
Low Fat ◽  
Fat Meal

Three experiments were conducted in healthy middle-aged volunteers (six males and six females in Expt 1, six males and two females in Expt 2 and twelve males in Expt 3) with a mean BMI of 27 kg/m2 to determine whether there is a difference between morning and afternoon dietary fat clearance and utilization, and to determine in what way the fat and starch contents of the meal influence postprandial blood lipid metabolites over 4·5 h. Over 4 days in Expt 1 each subject received isoenergetic, high-carbohydrate (L, 5·5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a high fat lunch (NM) in a randomized and balanced arrangement. Each evening a standard meal was given. The following effects were significant (P<0·05): plasma triacylglycerol (TAG) responses were greater following M meals; plasma TAG concentrations were greater in the afternoon than in the morning, following two meals of the same composition, although the postprandial incremental response was less following lunch than following breakfast and peak responses were reached much earlier than after breakfast; a low-fat breakfast, or fasting at breakfast time, delayed the peak TAG response to a M lunch. The plasma concentrations of non-esterified fatty acids (NEFA) and of free glycerol were higher in the afternoon following M meals at breakfast and lunch, especially in males. This response was reduced, by the L breakfast preceding the M lunch. Two M meals in succession lowered plasma HDL-cholesterol concentration. In Expt 2 each subject received a very low-fat (VL) breakfast, followed by a lunch of the same composition. Each of these meals was followed, 110 min from the start of eating, by an infusion of Intralipid 10% emulsion at the rate of 1 ml/kg body weight over 60 s. Clearance rates of Intralipid were faster in the afternoon than in the morning (P= 0·024). In Expt 3 twelve subjects were randomly allocated to either treatment MM or LM meal patterns, as given in Expt 1. These were given daily for a period of 17 d, during which the change in fasting plasma TAG concentration was similar in both treatments. On days 1, 16 and 17 responses were measured to the M lunch and to a glucose tolerance test (GTT), conducted 2 h 17 min after lunch. The post-lunch responses confirmed those found in Expt 1; but immediately following the glucose dose there was an abrupt increase in plasma TAG that was greater in treatment LM than in treatment MM (P= 0·025), whereas plasma NEFA concentration decreased rapidly in both treatments at that time (P = 0·00066)

scholarly journals Central and peripheral arterial stiffness responses to uninterrupted prolonged sitting combined with a high-fat meal: a randomized controlled crossover trial

2021 ◽  
Author(s):  
Simon Fryer ◽  
Keeron Stone ◽  
Craig Paterson ◽  
Meghan Brown ◽  
James Faulkner ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Cardiovascular Health ◽  
Pulse Wave ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
High Fat ◽  
Low Fat ◽  
Peripheral Arterial ◽  
Fat Meal ◽  
Over Time

AbstractIndependently, prolonged uninterrupted sitting and the consumption of a meal high in saturated fats acutely disrupt normal cardiovascular function. Currently, the acute effects of these behaviors performed in combination on arterial stiffness, a marker of cardiovascular health, are unknown. This study sought to determine the effect of consuming a high-fat meal (Δ = 51 g fat) in conjunction with prolonged uninterrupted sitting (180 min) on measures of central and peripheral arterial stiffness. Using a randomized crossover design, 13 young healthy males consumed a high-fat (61 g) or low-fat (10 g) meal before 180 min of uninterrupted sitting. Carotid-femoral (cf) and femoral-ankle (fa) pulse wave velocity (PWV), aortic-femoral stiffness gradient (af-SG), superficial femoral PWV beta (β), and oscillometric pulse wave analysis outcomes were assessed pre and post sitting. cfPWV increased significantly more following the high-fat (mean difference [MD] = 0.59 m·s−1) meal than following the low-fat (MD = 0.2 m·s−1) meal, with no change in faPWV in either condition. The af-SG significantly decreased (worsened) (ηp2 = 0.569) over time in the high- and low-fat conditions (ratio = 0.1 and 0.1, respectively). Superficial femoral PWVβ significantly increased over time in the high- and low-fat conditions (ηp2 = 0.321; 0.8 and 0.4 m·s−1, respectively). Triglycerides increased over time in the high-fat trial only (ηp2 = 0.761). There were no significant changes in blood pressure. Consuming a high-fat meal prior to 180 min of uninterrupted sitting augments markers of cardiovascular disease risk more than consuming a low-fat meal prior to sitting.

Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3097-3097
Author(s):  
Nigel Waters ◽  
Manish R. Patel ◽  
Alison M. Schram ◽  
Jordi Rodon Ahnert ◽  
Shekeab Jauhari ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Drug Exposure ◽  
Target Range ◽  
Dosing Regimen ◽  
High Fat ◽  
Clinical Pharmacokinetics ◽  
Median Tmax ◽  
Fasted State ◽  
Rapid Absorption ◽  
Fat Meal

3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465.

scholarly journals Identification of the principal transcriptional regulators for low-fat and high-fat meal responsive genes in small intestine

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Octave Mucunguzi ◽  
Aicha Melouane ◽  
Abdelaziz Ghanemi ◽  
Mayumi Yoshioka ◽  
André Boivin ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transcriptional Regulators ◽  
High Fat ◽  
Low Fat ◽  
Fat Meal

scholarly journals Effects of a High-Fat Meal on the Relative Oral Bioavailability of Piperaquine

2005 ◽  
Vol 49 (6) ◽  
pp. 2407-2411 ◽  
Author(s):  
Ing-Kye Sim ◽  
Timothy M. E. Davis ◽  
Kenneth F. Ilett
Keyword(s):  
Oral Bioavailability ◽  
Geometric Mean ◽  
Pharmacokinetic Analysis ◽  
Lipid Solubility ◽  
Fasting State ◽  
High Fat ◽  
Time Curve ◽  
Hematological Indices ◽  
Concentration Time ◽  
Fat Meal

ABSTRACT Piperaquine (PQ) is an antimalarial drug whose high lipid solubility suggests that its absorption can be increased by a high-fat meal. We examined the pharmacokinetics of PQ phosphate (500 mg given orally) in the fasting state and after a high-fat meal in eight healthy Caucasian volunteers (randomized crossover). Plasma PQ concentration-time profiles were analyzed by using noncompartmental pharmacokinetic analysis. In the fed state, the geometric mean C max increased by 213%, from 21.0 to 65.8 μg/liter (P < 0.001). The time of C max was not significantly different between the fasting and fed states. The geometric mean area under the concentration-time curve from zero onward (AUC0-∞) increased by 98%, from 3,724 to 7,362 μg h/liter (P = 0.006). The oral bioavailability of PQ relative to the fasting state was 121% greater after the high-fat meal (95% confidence interval, 26 to 216% increase; P = 0.020). The side effects, postural blood pressure changes, electrocardiographic corrected QT interval, serum glucose, and other biochemical and hematological indices were similar in the fasting and fed states over 28 days of follow-up.

scholarly journals Is the effect of prior exercise on postprandial lipaemia the same for a moderate-fat meal as it is for a high-fat meal?

2010 ◽  
Vol 105 (4) ◽  
pp. 506-516 ◽  
Author(s):  
Nicholas M. Hurren ◽  
Frank F. Eves ◽  
Andrew K. Blannin
Keyword(s):  
Test Meal ◽  
Venous Blood ◽  
Exercise Bout ◽  
Moderate Intensity ◽  
High Fat ◽  
Moderate Intensity Exercise ◽  
Postprandial Lipaemia ◽  
Fasted State ◽  
Prior Exercise ◽  
Fat Meal

Moderate-intensity exercise can lower the TAG response to a high-fat meal; however, the British diet is moderate in fat, and no study to date has compared the effect of such exercise on responses to high-fat and moderate-fat meals. The present work investigated the effect of brisk walking performed 13 h before intake of both high-fat and moderate-fat meals on postprandial plasma TAG concentrations. Eight inactive, overweight men completed four separate 2 d trials, i.e. rest (Con) or a 90-min treadmill walk (Ex) on the evening of day 1, followed by the ingestion of a moderate-fat (Mod) or high-fat (High) meal on the morning of day 2. High-fat meals contained 66 % of total energy as fat, while the percentage was 35 % for moderate-fat meals; both the meals were, however, isoenergetic. On day 2, venous blood was sampled in the fasted state, 30 and 60 min after ingesting the test meal and then hourly until 6 h post-meal. Exercise reduced plasma TAG concentrations significantly (P < 0·001), with no exercise × meal interaction (P = 0·459). Walking reduced the total TAG response to a high-fat meal by 29 % (relative to High Con); the same bout of exercise performed before ingesting a moderate-fat meal lowered total TAG by 26 % (compared with Mod Con). The ability of a single moderate-intensity aerobic exercise bout to lower postprandial TAG concentrations is just as great, in percentage terms, when the test meal ingested is of a moderate rather than a high fat content.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

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