scholarly journals Phenotypic differences in nebivolol metabolism and bioavailability in healthy volunteers

2015 ◽  
Vol 88 (2) ◽  
pp. 208-213 ◽  
Author(s):  
Corina Briciu ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
Anca Buzoianu ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Active Metabolite ◽  
Genetic Regulation ◽  
Standard Normal Distribution ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Phenotypic Differences ◽  
Standard Normal ◽  
Unique Distribution

Introduction: Nebivolol, a third-generation β-blocker, is subject to extensive first-pass metabolism and produces active β-blocking hydroxylated metabolites, like 4-OH-nebivolol. It is primarily a substrate of CYP2D6, a metabolic pathway that is under polymorphic genetic regulation. The objective of this study was to assess the metabolizer phenotype and to evaluate the interphenotype bioavailability and metabolism of nebivolol.Material and methods: Forty-three healthy volunteers were included in this open-label, non-randomized clinical trial and each volunteer received a single dose of 5 mg nebivolol. Non-compartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The phenotypic distribution was assessed based on the AUC (aria under the curve) metabolic ratio of nebivolol/4-OH-nebivolol and statistical analysis. An interphenotype comparison of nebivolol metabolism and bioavailability was performed based on the pharmacokinetic parameters of nebivolol and its active metabolite.Results: Nebivolol/4-OH-nebivolol AUC metabolic ratios were not characterized by a standard normal distribution. The unique distribution emphasized the existence of two groups and the 43 healthy volunteers were classified as follows: poor metabolizers (PMs)=3, extensive metabolizers (EMs)=40. The phenotype had a marked impact on nebivolol metabolism. The exposure to nebivolol was 15-fold greater for PMs in comparison to EMs.  Conclusion: 40 EMs and 3 PMs were differentiated by using the pharmacokinetic parameters of nebivolol and its active metabolite. The study highlighted the existence of interphenotype differences regarding nebivolol metabolism and bioavailability.

scholarly journals Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers

2017 ◽  
Vol 20 ◽  
pp. 68 ◽  
Author(s):  
Ana-Maria Gheldiu ◽  
Laurian Vlase ◽  
Adina Popa ◽  
Corina Briciu ◽  
Dana Muntean ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Single Dose ◽  
Healthy Volunteers ◽  
Active Metabolite ◽  
Pharmacokinetic Interaction ◽  
Compartmental Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Hydroxylated Metabolite

Purpose: To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics. Methods: This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods. Results: Fluvoxamine pretreatment increased Cmax and AUC0-∞  of nebivolol (Cmax: 1.67 ± 0.690  vs 2.20 ± 0.970  ng/mL; AUC0-∞: 12.1 ± 11.0  vs 19.3 ± 19.5  ng*h/mL ) and of its active metabolite (Cmax: 0.680  ± 0.220  vs 0.960 ± 0.290  ng/mL; AUC0-∞: 17.6 ±20.1  vs 25.5 ± 29.9  ng*h/mL). Apart from Cmax,AUC0-t and AUC0-∞, the other pharmacokinetic parameters (tmax, kel and t½) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake. Conclusions: Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction. 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.

Effects of Age and Gender on the Pharmacokinetics of Bromfenac in Healthy Volunteers

1997 ◽  
Vol 31 (4) ◽  
pp. 400-405 ◽  
Author(s):  
Joseph P Boni ◽  
Sheryl A Decleene ◽  
William H Cevallos ◽  
David R Hicks ◽  
Joan M Korth-Bradley
Keyword(s):  
Healthy Volunteers ◽  
Equilibrium Dialysis ◽  
The Elderly ◽  
Apparent Volume ◽  
Antiinflammatory Drug ◽  
Elderly Group ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label

Objective To compare the pharmacokinetic parameters of bromfenac, a nonsteroidal antiinflammatory drug under development, in healthy volunteers of various ages and either gender, after single and multiple doses. Design Open-label, single- and multiple-dose, nonrandomized, parallel study. Participants Twenty young (18–45 y), 12 young-elderly (65–74 y), and 12 elderly (75–85 y) subjects were studied. Half of the subjects in each group were women. Interventions Bromfenac was given as a single 50-mg dose and then as 50-mg doses every 12 hours for 3 additional days. Twelve blood samples were collected for 12 hours after the first and last doses. Main Outcome Measures Bromfenac concentrations were measured by using an HPLC procedure with ultraviolet detection. Unbound bromfenac concentrations were measured by equilibrium dialysis. Pharmacokinetic analysis was performed by noncompartmental techniques. Results No significant differences related to gender were detected. Significant differences were observed in half-life (t1/2), AUC, clearance, and apparent volume of distribution when the elderly group was compared with the young group and in t1/2 when the elderly group was compared with the young-elderly group, although substantial overlap among groups was observed. Conclusions Administration of bromfenac to young-elderly or elderly subjects of either gender does not require a dosage adjustment in acute settings. Consideration should be made to titrating dosages in patients over 75 years of age who require repeated doses.

scholarly journals Similar Results in Children with Asthma for Steady State Pharmacokinetic Parameters of Ciclesonide Inhaled with or without Spacer

2010 ◽  
Vol 4 ◽  
pp. CMPed.S4311 ◽  
Author(s):  
H. Boss ◽  
P. Minic ◽  
R. Nave
Keyword(s):  
Active Metabolite ◽  
Day Treatment ◽  
Systemic Exposure ◽  
Dose Inhaler ◽  
Pharmacokinetic Parameters ◽  
Metered Dose Inhaler ◽  
Inhaled Corticosteroid ◽  
Open Label ◽  
Metered Dose ◽  
Children With Asthma

Background Ciclesonide is an inhaled corticosteroid administered by a metered dose inhaler (MDI) to treat bronchial asthma. After inhalation, the inactive ciclesonide is converted by esterases in the airways to active metabolite desisobutyryl-ciclesonide (des-CIC). Aim To compare the pharmacokinetic (PK) parameters of des-CIC in children after administration of therapeutic dose of ciclesonide with and without spacer (AeroChamber Plus™). Methods Open-label, 3 period, cross over, repeated dose, PK study in 37 children with mild to moderate stable asthma (age: 6–11 y; body weight: 20–53 kg). During each 7-day treatment period, ciclesonide was inhaled once in the morning: A) 160 μg MDI with spacer, B) 80 μg MDI with spacer, and C) 160 μg MDI without spacer. Serum PK parameters of ciclesonide and des-CIC were determined on Day 7 of each period. The primary PK parameters were the AUCτ and Cmax for des-CIC. Results Inhaling ciclesonide with spacer led to a dose proportional systemic exposure (AUCτ) of des-CIC (0.316 μg*h/L for 80 μg and 0.663 μg*h/L for 160 μg). The dose-normalized systemic exposure for des-CIC (based on AUCτ) was 27% higher after inhalation of ciclesonide 80 μg or 160 μg with spacer than without spacer; the corresponding Cmax values for des-CIC were, respectively, 63% and 55% higher with spacer. No clinically relevant abnormalities or adverse drug reactions were observed. Conclusions Inhalation of therapeutic ciclesonide dose with spacer led to a slight increase in the systemic exposure of des-CIC, which does not warrant dose adjustment.

scholarly journals THE INFLUENCE OF PAROXETINE ON THE PHARMACOKINETICS OF ATOMOXETINE AND ITS MAIN METABOLITE

2015 ◽  
Vol 88 (4) ◽  
pp. 513-520 ◽  
Author(s):  
Ioana Todor ◽  
Adina Popa ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Active Metabolite ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Extensive Metabolizers ◽  
Open Label ◽  
Main Metabolite ◽  
Daily Dose ◽  
Metabolite Pharmacokinetics

Background and aims. To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers.Methods. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine  and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period.Results. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively.Conclusions. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

scholarly journals The Bioavailability and Pharmacokinetics of Silymarin SMEDDS Formulation Study in Healthy Thai Volunteers

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Chuleegone Sornsuvit ◽  
Darunee Hongwiset ◽  
Songwut Yotsawimonwat ◽  
Manatchaya Toonkum ◽  
Satawat Thongsawat ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Pharmacokinetic Study ◽  
Oral Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Blood Samples ◽  
Rapid Absorption ◽  
The Mean

The present study aimed to determine the pharmacokinetic parameters and bioavailability of silymarin 140 mg SMEDDS formulation. An open-label, single-dose pharmacokinetic study was conducted. Twelve healthy volunteers were included in the study. After the volunteers had fasted overnight for 10 h, a single-dose generic silymarin 140 mg SMEDDS soft capsule was administered. Then 10 ml blood samples were taken at 0.0, 0.25, 0.50, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, and 12.0 h. The plasma silybin concentrations were analyzed using validated LC-MS/MS. The pharmacokinetic parameters were analyzed and calculated. The pharmacokinetic parameters were calculated after silymarin had been administered as a single capsule. The mean (range) Cmax was 812.43 (259.47–1505.47) ng/ml at 0.80 (0.25–1.67) h (tmax). The mean (range) AUC0-t and AUC0-inf were 658.80 (268.29–1045.01) ng.h/ml and 676.98 (274.10–1050.96) ng.h/ml, respectively. The mean ke and t1/2 were 0.5386 h-1 and 1.91 h, respectively. The silymarin SMEDDS formulation soft capsule showed rapid absorption and high oral bioavailability.

scholarly journals Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Davis ◽  
Krishanu Sengupta ◽  
Venkata Krishnaraju Alluri ◽  
Trimurtulu Golakoti
Keyword(s):  
Plasma Concentrations ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Oral Ingestion ◽  
Post Dose ◽  
Geometric Means ◽  
Funding Sources ◽  
Healthy Humans

Abstract Objectives A randomized, open label, balanced, two-way crossover study compared the oral bioavailability and pharmacokinetic profiles of two Boswellia products standardized to 3-O-acetyl-11-Keto-β-boswellic acid (AKBA). Methods Twenty-two fasted male participants completed the study. They received a single oral-dose of water-soluble Boswellia extract 78% (LI51202F1) or the standard Boswellia extract 30% (5-Loxin) at 30 mg AKBA equivalent with 240 mL water on 2 separate occasions 12 days apart. Plasma AKBA and KBA were analyzed using a LC-MS/MS in pre- (0 hr) and post-dose (00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 04.00, 08.00, 12.00 and 24.00 hrs) blood samples. Pharmacokinetic analysis was performed using WinNonlin® version 7.0 (Pharsight corporation, USA). Results Comparative analysis of the pharmacokinetic parameters showed LI51202F1 had higher (111.11%) Cmax for AKBA vs. 5-Loxin. The bioavailability indicated by Geometric means of AUC0-t and AUC0-∞ were 25.49% and 16.13% higher in LI51202F1 than 5-Loxin. Conclusions The present study demonstrates that oral ingestion of water soluble and standard Boswellia extracts resulted in similar bioavailability. Interestingly, the water-soluble version exhibited higher Cmax and AUC values, which could be attributed to the improved solubility of LI51202F1. Funding Sources Laila Nutraceuticals.

scholarly journals Pharmacokinetics of Single-Dose and Multi-Dose of Lovastatin/Niacin ER Tablet in Healthy Volunteers

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-yan Jia ◽  
Song Ying ◽  
Chen-tao Lu ◽  
Jing Yang ◽  
Li-kun Ding ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Healthy Volunteers ◽  
Least Square ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mixed Dyslipidemia ◽  
Dose Oral ◽  
Dose Combination ◽  
Healthy Chinese

An extended-release (ER) niacin and lovastatin fixed-dose combination has been developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The purpose of the present study was to examine the drug interaction between niacin and lovastatin after multi-dose oral administration of lovastatin/niacin ER combination in healthy Chinese volunteers. A single-center, randomized, open-label, 5-period crossover study was conducted in thirty healthy volunteers aged 18 to 45 years with a washout period of 8 days. Subjects were randomized to receive multiple doses of treatment A (1 500 mg niacin ER tablet), B (1 20 mg lovastatin tablet), C (1 20 mg lovastatin and 500 mg niacin-ER tablet), D (2 10 mg lovastatin and 350 mg niacin-ER tablets) or E (2 10 mg lovastatin and 500 mg niacin-ER tablets) in 1 of 5 sequences (ABCDE, BCDEA, CDEAB, DEABC, EABCD) per period. Lovastatin, niacin and its metabolites (nicotinuric acid and nicotinamide) were determined in plasma by LC/MS method. Pharmacokinetic parameters were calculated, and least square mean ratios and 90% confidence intervals for Cmax⁡ and AUC (0–24) were determined for lovastatin/niacin ER versus niacin ER or lovastatin. It revealed that the formulation had no potential drug interaction in healthy Chinese volunteers when the dosage was increased from 500 mg to 1000 mg.

scholarly journals Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
S. Nardi-Hiebl ◽  
J. W. Ndieyira ◽  
Y. Al Enzi ◽  
W. Al Akkad ◽  
T. Koch ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Intravenous Administration ◽  
Intranasal Administration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Open Label ◽  
Single Dose Study ◽  
Transmucosal Administration

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h  ∗  pg/ml, CV% = 32.86), followed by intravenous (672 h  ∗  pg/ml, CV% = 32.18) and intranasal administration (515 h  ∗  pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted relative bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

scholarly journals Pharmacokinetic Study of Amoxicillin Capsule in Healthy Bangladeshi Subjects using Urinary Excretion Data

1970 ◽  
Vol 8 (1) ◽  
pp. 53-59 ◽  
Author(s):  
Md Ashik Ullah ◽  
Mohammad Abul Kalam Azad ◽  
Rebeka Sultana ◽  
Eva Rahman Kabir ◽  
AHM Mahbub Latif ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Drug Disposition ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Ethnic Variation ◽  
Open Label ◽  
Time Intervals ◽  
Significant Difference ◽  
The Us ◽  
The Mean

The aim of the study was to compare the urinary excretion data and bioavailability of two 500 mgamoxicillin capsules formulations in healthy Bangladeshi subjects under fasting condition and evaluate the ethnicvariations in drug disposition. Twenty-four subjects were enrolled into this single-dose, randomized, open-label, twowaycross over study. A washout period of one week was allowed between two treatments. Following oraladministration, urine samples were collected at different time intervals and were analyzed using a validated HPLCmethod with UV detection. The pharmacokinetic parameters for two formulations were calculated by noncompartmentalmethod using the software Kinetica and statistical analysis was done for the evaluation ofbioequivalence. The pharmacokinetic analysis indicated that the kinetic disposition of two formulations was similar.This was evident when the mean (± standard deviation) values of the various pharmacokinetic parameters werecompared. No significant difference between two formulations was found when analyzed by paired t-test andANOVA. Therefore it can be concluded that the test product (SK-mox®) is bioequivalent to the reference product(Amoxil-Bencard®) based on the US FDA's regulatory definition. Moreover, an ethnic variation was observedfollowing 64.34% cumulative urinary recovery of amoxicillin over 12 hours when compared with other studies.Key words: Amoxicillin; pharmacokinetics; Bangladeshi subjects.DOI: 10.3329/dujps.v8i1.5336Dhaka Univ. J. Pharm. Sci. 8(1): 53-59, 2009 (June)

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