scholarly journals Linear pharmacokinetics of doxazosin in healthy subjects

2020 ◽  
Vol 11 (1) ◽  
pp. 1031-1039
Author(s):  
Duaa J. Al-Tamimi ◽  
Mays E. Alani ◽  
Afaq M. Ammoo ◽  
Jaafar J. Ibraheem
Keyword(s):  
Compartmental Analysis ◽  
Pharmacokinetic Parameters ◽  
Linear Pharmacokinetics ◽  
Time Data ◽  
Open Label ◽  
Male Adult ◽  
Concentration Time ◽  
Doxazosin Mesylate ◽  
Zero Time ◽  
Dose Tablet

Doxazosin is used for treating symptoms of benign prostatic hyperplasia (BPH). Besides, it is also prescribed for patients with mild to moderate essential hypertension. The object of the current study was to assess the linearity in the pharmacokinetics of doxazosin after administration of doxazosin as a single dose tablet containing 2, 4 and 8 mg doxazosin mesylate. Thirty Iraqi healthy male adult subjects were given 2, 4 and 8 mg doxazosin mesylate tablet in a randomized, cross-over, open-label, fasting, three-period, three-sequence design separated by one week wash out the interval between dosing. Serial blood samples were obtained from each subject before drug intake (zero time) and then at 0.33, 0.67, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36, 48, 60, and eventually at 72 hours after dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax and Thalf were determined from plasma concentration-time data of the drug by non-compartmental analysis. Statistical analysis of doxazosin pharmacokinetic parameters obtained after administration of the investigated dose ranges 2-8 mg demonstrated linear pharmacokinetics.

scholarly journals Determination of Appropriate Weight-Based Cutoffs for Empiric Cefazolin Dosing Using Data from a Phase 1 Pharmacokinetics and Safety Study of Cefazolin Administered for Surgical Prophylaxis in Pediatric Patients Aged 10 to 12 Years

2015 ◽  
Vol 59 (7) ◽  
pp. 4173-4180 ◽  
Author(s):  
Michael L. Schmitz ◽  
Jeffrey L. Blumer ◽  
Wes Cetnarowski ◽  
Christopher M. Rubino
Keyword(s):  
Pediatric Patients ◽  
Phase 1 ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Time Data ◽  
Surgical Prophylaxis ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Few Data

ABSTRACTDespite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.)

Pharmacokinetics and bioequivalence of generic etoricoxib in healthy volunteers

2021 ◽  
Vol 10 (3) ◽  
pp. 113-118
Author(s):  
Nishalini Harikrishnan ◽  
Ka-Liong Tan ◽  
Kar Ming Yee ◽  
Alia Shaari Ahmad Shukri ◽  
Nalla Ramana Reddy ◽  
...  
Keyword(s):  
Compartmental Analysis ◽  
Bioequivalence Study ◽  
Active Pharmaceutical Ingredient ◽  
Pharmacokinetic Profile ◽  
Time Profile ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Reference Drug ◽  
Test Formulation ◽  
R Ratio

Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product. Methods: This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated bioequivalence study involving a washout period of ten days. A total of 26 healthy male volunteers were recruited. The pharmacokinetic profile of the test formulation was compared with the reference formulation. Results/Discussion: The pharmacokinetic parameters of ETO were calculated based on the plasma drug concentration-time profile using non-compartmental analysis to determine its safety profile and tolerability. The Test/Reference (T/R) ratio of ETO was 104.36% (90% confidence interval (CI): 98.30%–110.80%) for area under curve (AUC)0-72 while the T/R ratio of maximum concentration (Cmax) was 101.39% (92.15%–111.56%). The 90% CI of the Cmax and AUC0-72 of ETO were within acceptable bioequivalence limits of 80%–125%. All values were within the predetermined limits of the Association of Southeast Asian Nation (ASEAN) bioequivalence guidelines. Conclusion: The test formulation was found to be bioequivalent with respect to the reference drug, according to ASEAN bioequivalence guidelines.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

scholarly journals Pharmacokinetics of Florfenicol in Healthy Pigs and in Pigs Experimentally Infected with Actinobacillus pleuropneumoniae

2003 ◽  
Vol 47 (2) ◽  
pp. 820-823 ◽  
Author(s):  
Jianzhong Liu ◽  
Ki-Fai Fung ◽  
Zhangliu Chen ◽  
Zhenling Zeng ◽  
Jie Zhang
Keyword(s):  
Half Life ◽  
Clinical Signs ◽  
Actinobacillus Pleuropneumoniae ◽  
Pharmacokinetic Parameters ◽  
X Rays ◽  
Time Data ◽  
Time Curve ◽  
Chromatography Method ◽  
Concentration Time ◽  
Significant Difference

ABSTRACT A comparative in vivo pharmacokinetic study of florfenicol was conducted in 18 crossbred pigs infected with Actinobacillus pleuropneumoniae following intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration of a single dose of 20 mg/kg. The disease model was confirmed by clinical signs, X rays, pathohistologic examinations, and organism isolation. Florfenicol concentrations in plasma were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm. Pharmacokinetic parameters were calculated by using the MCPKP software (Research Institute of Traditional Chinese Veterinary Medicine, Lanzhou, China). The disposition of florfenicol after a single i.v. bolus was described by a two-compartment model with values for the half-life at α phase (t 1/2α), the half-life at β phase (t 1/2β), the area under the concentration-time curve (AUC0-∞), and the volume of distribution at steady state (V ss) of 0.37 h, 2.91 h, 64.86 μg · h/ml, and 1.2 liter/kg, respectively. The concentration-time data fitted the one-compartment (after i.m.) and two-compartment (after p.o.) models with first-order absorption. The values for the maximum concentration of drug in serum (C max), t 1/2α, t 1/2β, and bioavailability after i.m. and p.o. dosing were 4.00 and 8.11 μg/ml, 0.12 and 3.91 h, 13.88 and 16.53 h, and 122.7 and 112.9%, respectively, for the two models. The study showed that florfenicol was absorbed quickly and completely, distributed widely, and eliminated slowly in the infected pigs, and there was no statistically significant difference between the pharmacokinetic profiles for the infected and healthy pigs.

Drug Degradation during HPLC Analysis of Aztreonam: Effect on Pharmacokinetic Parameter Estimation

1994 ◽  
Vol 28 (4) ◽  
pp. 444-446
Author(s):  
Lawrence V. Friedrich ◽  
Roger L. White ◽  
Michael B. Kays ◽  
David S. Burgess
Keyword(s):  
Serum Concentration ◽  
Pharmacokinetic Parameter ◽  
Hplc Analysis ◽  
Statistical Significance ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Time Data ◽  
Drug Degradation ◽  
Concentration Time ◽  
The Impact

OBJECTIVE: To assess the impact of degradation of aztreonam, a beta-lactam antibiotic, during HPLC analysis on pharmacokinetic parameter estimates. METHODS: The baseline (B) serum concentration-time data from a published pharmacokinetic study of aztreonam were degraded using first-order equations and a degradation rate constant (0.014 h-1) determined from a preliminary degradation study. Samples were mathematically degraded for autosampler run times of 8–13 h (D1) to approximate a normal work day and for autosampler run times of 16–17 h (D2) and compared with B data. It was assumed that B data were nondegraded and that changes in chromatography were the result of degradation of azetreonam and not to any changes in chromatographic conditions. A two-compartment model was used to fit the data and pharmacokinetic parameters were calculated using standard equations. Statistical significance between all pharmacokinetic parameters for B and D1 and B and D2 was determined using the paired, two-tailed Student's t-test. RESULTS: Increased variability was noted for all pharmacokinetic parameters for D1 and D2 compared with B. Statistically significant differences were found for clearance (B <D1, p=0.0095 and B <D2, p=0.0194), steady-state volume of distribution (B <D2, p=0.0392), and area under the serum concentration-time curve (B >D1, p=0.0497). CONCLUSIONS: Aztreonam degradation resulted in increased variability in pharmacokinetic parameter estimates. Investigators should be cognizant of this and preliminary studies should be performed to characterize degradation for the length of the expected autosampler run.

scholarly journals The Influence of the Different Disposition Characteristics of Snake Toxins on the Pharmacokinetics of Snake Venom

Toxins ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 188 ◽  
Author(s):  
Suchaya Sanhajariya ◽  
Geoffrey K. Isbister ◽  
Stephen B. Duffull
Keyword(s):  
Molecular Weight ◽  
Snake Venom ◽  
Time Course ◽  
Total Concentration ◽  
Weight Fraction ◽  
Pharmacokinetic Parameters ◽  
Time Data ◽  
Molecular Weights ◽  
Concentration Time ◽  
Wide Range

Snake venom is comprised of a combination of different proteins and peptides with a wide range of molecular weights and different disposition processes inherent to each compound. This causes venom to have a complex exposure profile. Our study investigates 1) how each molecular weight fraction (toxin) of venom contributes to the overall time course of the snake venom, and 2) the ability to determine toxin profiles based on the profile of the overall venom only. We undertook an in silico simulation and modelling study. Sixteen variations of venom, comprising of two to nine toxins with different molecular weights were investigated. The pharmacokinetic parameters (i.e., clearance,  C L , and volume of distribution,  V ) of each toxin were generated based on a log-linear relationship with molecular weight. The concentration–time data of each toxin were simulated for 100 virtual patients using MATLAB and the total concentration–time data of each toxin were modelled using NONMEM. We found that the data of sixteen mixtures were best described by either two- or three-compartment models, despite the venom being made up of more than three different toxins. This suggests that it is generally not possible to determine individual toxin profiles based on measurements of total venom concentrations only.

scholarly journals Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution in Children and Adolescents

1999 ◽  
Vol 43 (3) ◽  
pp. 634-638 ◽  
Author(s):  
Gregory L. Kearns ◽  
Susan M. Abdel-Rahman ◽  
Laura P. James ◽  
Douglas L. Blowey ◽  
James D. Marshall ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Rate Constant ◽  
Pediatric Patients ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Time Data ◽  
Concentration Time ◽  
The Mean

ABSTRACT Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 ± 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Y calc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means ± standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (C max) was 1,272.5 ± 622.1 ng/ml. The time to C max was 4.1 ± 1.5 h, and the lag time was 0.75 ± 0.56 h. The apparent absorption rate constant was 0.75 ± 0.48 1/h, and the elimination rate constant was 0.16 ± 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 ± 3,411.82 ng · h/ml. The apparent total plasma clearance was 0.81 ± 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 ± 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 ± 148.2 ng/ml) and 24 h (137.9 ± 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit >90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.

scholarly journals Lack of effect of vancomycin and gentamicin on auditory function in guinea pigs.

1996 ◽  
Vol 40 (5) ◽  
pp. 1098-1103
Author(s):  
K Nishihara ◽  
T Shimizu ◽  
H Kotaki ◽  
Y Sawada ◽  
T Okuno ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Hearing Threshold ◽  
Plasma Drug Concentration ◽  
Pharmacokinetic Parameters ◽  
Plasma Drug ◽  
Auditory Function ◽  
Time Data ◽  
Concentration Time ◽  
Penetration Ratio ◽  
Combined Administration

The dispositions of vancomycin (VCM) and gentamicin (GM) in plasma and perilymph after single and multiple administrations and the effects of multiple administrations of VCM or GM alone and the combination of both drugs on auditory function were studied in male guinea pigs. The pharmacokinetic parameters of VCM and GM obtained from plasma drug concentration-time data after single and multiple (22 days) intramuscular administrations of VCM (200 mg/kg of body weight) alone and GM (50 mg/kg) alone were not significantly different from those after combined administration of VCM (200 mg/kg) and GM (50 mg/kg). There was no change in the penetration ratio of VCM and GM into perilymph between administration of VCM or GM alone and the combination of both drugs. Furthermore, the hearing threshold of guinea pigs was not affected by VCM or GM alone or the combination of both drugs within the range of therapeutic VCM and GM levels in plasma in humans.

scholarly journals Bioequivalence Study of Two Formulations of Tramadol Capsules in Healthy Myanmar Volunteers

2020 ◽  
Author(s):  
Ye Htut Linn ◽  
Myat Myat Soe ◽  
K Khine Thu ◽  
Thida Tun ◽  
Mi Kun Kaw San ◽  
...  
Keyword(s):  
Oral Administration ◽  
Generic Drugs ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Time Data ◽  
Fluorescence Detector ◽  
Fasting Condition ◽  
Concentration Time ◽  
Single Oral Administration

Background: Tramadol is one of the most commonly used analgesics, thanks to its efficacy and safety. It is widely used in Myanmar for postoperative and cancer pain control. The use of generic drugs has been steadily increasing worldwide, mostly in developing countries. Generic drugs should have efficacy and safety comparable to their innovators or other approved generic products. Objectives: This study aims to compare the bioequivalence of locally producing, Tramadol BPI® capsule (test product) with the Tramazac® capsule (reference product) in healthy Myanmar volunteers. Methods: The bioequivalence was determined in 16 healthy Myanmar volunteers after a single oral administration of 100 mg tramadol (under fasting condition) in a randomized, openlabel, two-period, and two-treatment crossover study with a two-week washout period. Blood samples were collected at specified times, and plasma tramadol concentrations were measured with a validated high-performance liquid chromatography method with a fluorescence detector. Pharmacokinetic parameters were determined using the plasma concentration-time data in a noncompartmental model. Results: The analysis of variance of the logarithmically transformed parameters (maximum plasma concentration (Cmax), Area Under the concentration-time Curve from the time of administration to the last measured concentration (AUC0-t), and to infinity (AUC0-∞) revealed no sequence, period, and formulation effects between the test and reference products. Significant differences were found between the subjects within the sequence for both AUC0-t, and AUC0-∞, indicating a substantial intersubject variation. The geometric mean ratio of test/reference and their 90% confidence intervals were within the ASEAN (Association of Southeast Asian Nations) bioequivalence acceptance interval of 80% to 125%. Conclusion: Tramadol BPI® and Tramazac® capsules, after a single oral administration of 100 mg, were bioequivalent in respect of their rate and extent of absorption under fasting condition.

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.

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