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

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.

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The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19

10.1101/2020.04.21.20073262 ◽

2020 ◽

Cited By ~ 1

Author(s):

Virginia D. Schmith ◽

Jie (Jessie) Zhou ◽

Lauren RL Lohmer

Keyword(s):

Plasma Concentration ◽

Oral Administration ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic ◽

Maximum Plasma ◽

Time Profiles ◽

Concentration Time ◽

Single Oral Administration ◽

The Ideal

AbstractIntroductionCaly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC50, 2 µM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted.MethodSimulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose.ResultsPlasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 µM).ConclusionsThe likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

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Population Pharmacokinetics of Levofloxacin, Gatifloxacin, and Moxifloxacin in Adults with Pulmonary Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01036-07 ◽

2007 ◽

Vol 52 (3) ◽

pp. 852-857 ◽

Cited By ~ 120

Author(s):

Charles A. Peloquin ◽

David Jamil Hadad ◽

Lucilia Pereira Dutra Molino ◽

Moises Palaci ◽

W. Henry Boom ◽

...

Keyword(s):

Plasma Concentrations ◽

University Hospital ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Maximum Plasma ◽

Population Parameter ◽

Time Data ◽

Time Curve ◽

Concentration Time

ABSTRACT The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 μg/ml; gatifloxacin, 4.75 μg/ml; moxifloxacin, 6.13 μg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.

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Plasma profile of cimicoxib in sheep after oral administration at two different rates

Polish Journal of Veterinary Sciences ◽

10.1515/pjvs-2017-0065 ◽

2017 ◽

Vol 20 (3) ◽

pp. 535-538

Author(s):

A. Di Salvo ◽

M. Giorgi ◽

H.K. Lee ◽

C. Vercelli ◽

F. Rueca ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Plasma Concentrations ◽

Individual Variability ◽

Maximum Plasma ◽

Dose Rates ◽

Single Oral Administration ◽

Concentration Peak ◽

Value Range ◽

Slow Absorption

Abstract Sheep are often subjected to painful procedures and thus they need to be treated with analgesics. Nevertheless, knowledges about pharmacokinetic features of these drugs in this species are poor. The aim of this study was to evaluate plasma behaviour of cimicoxib in sheep after a single oral administration at two different dose rates (4 and 6 mg/kg). Maximum plasma concentrations of cimicoxib were equal to 273.78 (median value; range 189.00-567.32) and 565.01 (range 308.27-822.59) ng/mL after treatment with 4 and 6 mg/kg, respectively. The time of maximum concentration (Tmax) was achieved between 4 and 10 hours following treatment at the lower dose, and between 6 and 10 hours after the administration of the higher dose, with one sheep achieving the concentration peak at 0.75 hours. The slow absorption and the great individual variability in plasma concentration, probably due to ruminal effects, suggest that cimicoxib is not suitable for oral treatment in sheep.

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Experimental determination of the pharmacokinetic properties of trimethoprim and sulfamethoxazole combination in the blood serum of broiler chickens

Veterinární Medicína ◽

10.17221/190/2020-vetmed ◽

2021 ◽

Author(s):

K Putecova ◽

K Nedbalcova ◽

I Bartejsova ◽

M Zouharova ◽

K Matiaskova ◽

...

Keyword(s):

Oral Administration ◽

Broiler Chickens ◽

Animal Health ◽

Pharmacokinetic Parameters ◽

Serum Samples ◽

Commercial Preparation ◽

Single Oral Administration ◽

Thermo Fisher Scientific ◽

Medicinal Substances

A rapid, simple and highly efficient analytical method for the targeted determination of trimethoprim and sulfamethoxazole in serum samples has been developed and used to measure the pharmacokinetic curve of these medicinal substances after administration to chicken broilers. The pharmacokinetics properties of trimethoprim and sulfamethoxazole were investigated in clinically healthy broiler chickens after the single oral administration of the commercial preparation Methoxasol (Eurovet Animal Health, B.V., The Netherlands) at a dose of 0.275 ml/kg b.w. After a single dose drug administration, the chickens were sacrificed by decapitation under general anaesthesia by Isoflurin 1 000 mg/g (Vetpharma AH, Spain) and the blood was collected at precisely defined intervals: 15, 30, 45, 60, 90, 120, 180, 360 and 720 min after the administration. The serum concentrations of amoxicillin were determined using Q Exactive tandem mass spectrometer (Thermo Fisher Scientific, USA) in conjunction with liquid chromatography. The detected pharmacokinetic parameters of trimethoprim after the oral administration were Cmax = 2.1 ± 1.0 µg/ml; Tmax = 1.5 h; t½ = 0.88 h; kel = 0.009 3 ± 0.001 1 1/h; AUCt = 2.901 ± 1.4 µg.h/ml; AUC∞ = 2.907 ± 1.5 µg.h/ml; Vd = 2.632 l/kg; Cl = 2.7 l/h. The pharmacokinetic parameters of sulfamethoxazole after the oral administration were Cmax = 47.1 ± 15.3 µg/ml; Tmax = 1 h; t½ = 1.92 h; kel = 0.004 6 ± 0.000 3 1/h; AUCt = 89.676 ± 26.9 µg.h/ml; AUC∞ = 94.612 ± 28.4 µg.h/ml; Vd = 0.584 l/kg; Cl = 0.21 l/h. To the best of our knowledge, this is the first pharmacokinetic study of the combination of sulfamethoxazole and trimethoprim in broiler chickens.

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Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

Natural Product Communications ◽

10.1177/1934578x1501000921 ◽

2015 ◽

Vol 10 (9) ◽

pp. 1934578X1501000 ◽

Cited By ~ 1

Author(s):

Rosario Russo ◽

Angelo Mancinelli ◽

Michele Ciccone ◽

Fabio Terruzzi ◽

Claudio Pisano ◽

...

Keyword(s):

Oral Administration ◽

Plasma Concentrations ◽

Compartmental Analysis ◽

Pharmacokinetic Profile ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Sprague Dawley ◽

Time Curve ◽

Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

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Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Hepatic Impairment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.5.1721-1726.2006 ◽

2006 ◽

Vol 50 (5) ◽

pp. 1721-1726 ◽

Cited By ~ 23

Author(s):

Xiao-Jian Zhou ◽

Thomas C. Marbury ◽

Harry W. Alcorn ◽

William B. Smith ◽

Gloria Dubuc Patrick ◽

...

Keyword(s):

Hepatitis B Virus ◽

Plasma Concentration ◽

Hepatitis B ◽

Hepatic Impairment ◽

Hepatic Function ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Concentration Time ◽

Chronic Hepatitis B Virus ◽

B Virus

ABSTRACT This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

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Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01098-13 ◽

2013 ◽

Vol 57 (12) ◽

pp. 6158-6164 ◽

Cited By ~ 5

Author(s):

Manoli Vourvahis ◽

Anna Plotka ◽

Laure Mendes da Costa ◽

Annie Fang ◽

Jayvant Heera

Keyword(s):

Healthy Subjects ◽

Geometric Mean ◽

Active Form ◽

Pharmacokinetic Interaction ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Open Label ◽

Fixed Sequence ◽

Dosing Interval ◽

Period 2

ABSTRACTThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ,Cmax, andCτwere increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ,Cmax, andCτdecreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

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Site-Specific Pharmacokinetics and Pharmacodynamics of Intramuscular Meperidine in Elderly Postoperative Patients

Annals of Pharmacotherapy ◽

10.1177/106002809703100102 ◽

1997 ◽

Vol 31 (1) ◽

pp. 23-28 ◽

Cited By ~ 12

Author(s):

Brian L Erstad ◽

Mimi L Meeks ◽

Hsiao-Hui Chow ◽

William D Rappaport ◽

Miriam L Levinson

Keyword(s):

Breakthrough Pain ◽

Tertiary Care ◽

Volume Of Distribution ◽

University Teaching ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Pharmacokinetics And Pharmacodynamics ◽

Pain Scores ◽

Concentration Time ◽

Pain Scales

OBJECTIVE: To examine and compare the pharmacokinetics and pharmacodynamics of meperidine when administered intramuscularly at gluteal and deltoid sites in elderly postoperative patients. DESIGN: Prospective, randomized investigation. SETTING: Tertiary care university teaching hospital. PATIENTS: Fourteen patients 60 years of age or older who were undergoing general surgery. INTERVENTION: A single dose of meperidine 0.75 mg/kg given intramuscularly at either a deltoid or gluteal site. MAIN OUTCOME MEASURES: Pharmacokinetic (based on concentration—time curves) and pharmacodynamic (i.e., pain scales, need for additional pain medication) comparisons were made, based on site of meperidine injection. RESULTS: No statistically significant differences were found in the maximum plasma concentration, volume of distribution, or clearance of meperidine by site of injection. Substantial interpatient variability in pharmacokinetic parameters was noted for both sites (range of maximum concentrations: 191–500 ng/mL gluteal, 166–374 ng/mL deltoid). Although pain scores were similar for the two groups, four of the patients in the group given gluteal injection required additional breakthrough pain management within 4 hours of meperidine injection compared with one patient in the group given deltoid injection. CONCLUSIONS: There is no obvious relationship between meperidine pharmacokinetic and pharmacodynamic parameters, regardless of intramuscular injection site. Breakthrough pain is common when patients are given intramuscular injections postoperatively, particularly when the gluteal route is used. When meperidine is used for analgesia in elderly postoperative patients, consideration should be given to more rapid and predictable routes (e.g., intravenous injection) of meperidine administration.

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A Chinese Traditional Medicine, Sho-Saiko-To (Xiao-Chaihu-Tang), Reduces the Bioavailability of Tolbutamide after Oral Administration in Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x99000409 ◽

1999 ◽

Vol 27 (03n04) ◽

pp. 355-363 ◽

Cited By ~ 8

Author(s):

Nobuhiro Nishimura ◽

Kohji Naora ◽

Hidenari Hirano ◽

Kikuo Iwamoto

Keyword(s):

Plasma Concentration ◽

Oral Administration ◽

Oral Bioavailability ◽

Absorption Rate ◽

Hepatic Metabolism ◽

Chinese Traditional Medicine ◽

Time Curve ◽

Concentration Time ◽

Single Oral Administration ◽

Plasma Concentration Time Curve

The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were investigated in rats. After intravenous administration of tolbutamide (5 mg/kg), no significant change in the pharma-cokinetics of tolbutamide was observed in both groups of single and multiple (7 days) pre-administration of Sho-saiko-to (50 mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co-administration of Sho-saiko-to tended to accelerate the initial absorption rate of tolbutamide. The area under the plasma concentration-time curve of tolbutamide after oral administration was significantly reduced by Sho-saiko-to. Subsequently, a significant decrease was observed in the oral bioavailability of this drug when Sho-saiko-to was given concomitantly. These findings suggest that Sho-saiko-to reduces the bioavailability of tolbutamide after oral dministration in rats, and that this change is not related to hepatic metabolism.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.2.820-823.2003 ◽

2003 ◽

Vol 47 (2) ◽

pp. 820-823 ◽

Cited By ~ 52

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.

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