Factors Affecting the Pharmacokinetic Characteristics of Rapacuronium 

1999 ◽  
Vol 90 (4) ◽  
pp. 993-1000 ◽  
Author(s):  
Dennis M. Fisher ◽  
Raymond Kahwaji ◽  
David Bevan ◽  
George Bikhazi ◽  
Robert J. Fragen ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Bolus Dose ◽  
Plasma Concentrations ◽  
Rapid Onset ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Single Bolus ◽  
Age Related ◽  
Single Bolus Dose

Background Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics. Methods Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters. Results Rapacuronium's weight-normalized plasma clearance was 7.03 x (1 - 0.0507 x (HgB - 13)) ml x kg(-1) x min(-1), where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4+/-1.4 ml x kg(-1) x min(-1), mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration. Conclusions In this patient population, neither age nor gender influence elimination of rapacuronium. This finding contrasts to an age-related decrease in plasma clearance observed in a study of 10 healthy volunteers and in a pooled analysis of the pharmacokinetic data from 206 adults in multiple clinical studies. Even if ORG9488 has a potency similar to that of rapacuronium, its plasma concentrations after a single bolus dose of rapacuronium are sufficiently small to contribute minimally to neuromuscular blockade.

Effect of Renal Failure and Cirrhosis on the Pharmacokinetics and Neuromuscular Effects of Rapacuronium Administered by Bolus Followed by Infusion

2000 ◽  
Vol 93 (6) ◽  
pp. 1384-1391 ◽  
Author(s):  
Dennis M. Fisher ◽  
Gerald A. Dempsey ◽  
D. Paul L. Atherton ◽  
Ronald Brown ◽  
Antonio Abengochea ◽  
...  
Keyword(s):  
Renal Failure ◽  
Plasma Clearance ◽  
Time Course ◽  
Bolus Dose ◽  
Hepatic Function ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Isoflurane Anesthesia ◽  
Mixed Effects Modeling ◽  
Single Bolus Dose

Background Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion. Methods During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling. Results Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium. Conclusion Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.

scholarly journals The Statistical Analysis of Pharmacokinetic Parameters in the Context of Bioequivalence Testing of Two Anthelmintic Formulas Based on Ivermectine and Triclabendazole in Sheep

2019 ◽  
Vol 65 (2) ◽  
pp. 60-65
Author(s):  
Lenard Farczadi ◽  
Laurian Vlase ◽  
Orsolya Melles ◽  
Ramona Tolomeiu ◽  
Octavia Tamas-Krumpe ◽  
...  
Keyword(s):  
High Performance ◽  
Reference Product ◽  
Plasma Concentrations ◽  
Pharmaceutical Formulations ◽  
Relative Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Test Product

AbstractConducting bioequivalence studies is an essential step during the market authorization process of generic pharmaceutical formulations, for both human or veterinary use. The aim of the present study was to evaluate the pharmacokinetics of triclabendazole sulphoxide, the main metabolite of triclabendazole, and ivermectin in order to evaluate the bioavailability and bioequivalence of a novel sheep anthelmintic formulation of oral suspension for sheep treatment containing triclabendazole 50 mg/mL and ivermectin 1 mg/mL compared to the reference product. In order to determine relative bioavailability of the test product with respect to the reference product the study was conducted on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. For the determination of triclabendazole sulphoxide and ivermectin sheep plasma concentrations, two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods were developed and validated. The measured plasma concentrations of triclabendazole sulphoxide and ivermectin were used for the pharmacokinetic analysis and the determination of bioequivalence between the test product with regards to the reference product. The noncompartmental analysis of the pharmacokinetic data for both triclabendazole sulphoxide and ivermectin showed similarities between first-order kinetics of the test and reference product. The relevant pharmacokinetic parameters (Cmax, AUClast, AUCtot) were determined and the bioequivalence between the test and reference product could be concluded.

Analysis of phase I pharmacokinetic studies with targeted molecules based on gender and age

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
S. Di Segni ◽  
I. Sperduti ◽  
A. Cinquina ◽  
M. Contestabile ◽  
B. Nuvoli ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Parameter ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Targeted Agents ◽  
Female Population ◽  
Male And Female ◽  
Age Related ◽  
The Impact

2521 Background: Pharmacokinetic parameters are usually not sufficiently correlated with patient characteristics, such as age, gender, or excretory organ function, and with outcome measures. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions and acting as a predictive/prognostic factor. Methods: We analyzed Phase I/II oncology trials of solid tumors with targeted agents enrolling Male and Female population (age>18yrs), reporting pharmacokinetic analysis, published between 2000 and 2007. We excluded trials involving Radiation therapy alone, Hematological malignancies, and trials of Gender related pathology (ovarian, prostate and breast cancer). Standard descriptive statistics was used. Results: 160 phase I and II trials involving 48 targeted agents has been selected. 44%, 37% and 19% of the population enrolled for PK analysis is respectively male, female or unknown gender. 65% of the trials have male preponderance. Authors did not specified number of male and female if only a group of patients enrolled in the trial was submitted to pharmacokinetic analysis. 95% of the trials enrolled patients > 65years, while 16% of the trials enrolled patients >80years. But only 3% of studies specified individual patient age and less than 6% of papers showed the number of male and female for each dose level, while about 10% of studies considered ethnicity as a characteristic. Conclusions: What emerged from our analysis is the irregularity and the lack of important informations when reported for publication. Knowing the impact of important prognostic/predictive factor of such clinical parameter (age, gender) we believe that more informations should be reported in the trials in order to evaluate if Toxicity and Efficacy could be gender or age related. Definitive data will be presented at the meeting. No significant financial relationships to disclose.

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report

2021 ◽  
Vol 8 ◽  
Author(s):  
Joe S. Smith ◽  
Jonathan P. Mochel ◽  
Windy M. Soto-Gonzalez ◽  
Rebecca R. Rahn ◽  
Bryanna N. Fayne ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Half Life ◽  
Plasma Clearance ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Study Objective ◽  
Elimination Half Life ◽  
Elimination Half

Background: Ruminant species are at risk of developing abomasal ulceration, but there is a lack of pharmacokinetic data for anti-ulcer therapies, such as the proton pump inhibitor pantoprazole, in goats.Objective: The primary study objective was to estimate the plasma pharmacokinetic parameters for pantoprazole in adult goats after intravenous administration. A secondary objective was to describe the pharmacokinetic parameters for the metabolite, pantoprazole sulfone, in goats.Methods: Pantoprazole was administered intravenously to six adult goats at a dose of 1 mg/kg. Plasma samples were collected over 36h and analyzed via reverse phase high performance liquid chromatography for determination of pantoprazole and pantoprazole sulfone concentrations. Pharmacokinetic parameters were determined by non-compartmental analysis.Results: Plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 0.345 mL/kg/min, 0.7 h, and 0.9 L/kg, respectively following IV administration. The maximum concentration, elimination half-life and area under the curve of pantoprazole sulfone were estimated at 0.1 μg/mL, 0.8 h, and 0.2 hr*μg/mL, respectively. The global extraction ratio was estimated 0.00795 ± 0.00138. All animals had normal physical examinations after conclusion of the study.Conclusion: The reported plasma clearance for pantoprazole is lower than reported for foals, calves, and alpacas. The elimination half-life appears to be < that reported for foals and calves. Future pharmacodynamic studies are necessary for determination of the efficacy of pantoprazole on acid suppression in goats.

scholarly journals Comprehensive assessment of the pharmacokinetic properties of a single bolus dose of colecalciferol in terms of efficacy and safety

2019 ◽  
Vol 22 (1) ◽  
pp. 4-9
Author(s):  
Liudmila A. Suplotova ◽  
Valeria A. Avdeeva ◽  
Ekaterina A. Pigarova ◽  
Liudmila Y. Rozhinskaya
Keyword(s):  
Vitamin D ◽  
Clinical Practice ◽  
Adverse Events ◽  
Vitamin D Deficiency ◽  
Calcium Metabolism ◽  
Bolus Dose ◽  
Efficacy And Safety ◽  
Single Bolus ◽  
Pharmacokinetic Properties ◽  
Single Bolus Dose

Background: The lack of a unified approach to the treatment of deficiency and vitamin D deficiency stimulated a detailed study of the dynamics of indicators of phosphorus-calcium metabolism, parathyroid hormone, 25(OH)D (calcidiol). Aim: To evaluate the pharmacokinetic properties of colecalciferol at a dosage of 150 000 IU, from the standpoint of its efficacy and safety in clinical practice. Materials and methods: Observational, single-center, prospective, selective, uncontrolled study of a comprehensive assessment of the pharmacokinetic properties of a single saturating dose of 150 000 IU of colecalciferol. To assess the pharmacokinetic properties of colecalciferol at a dosage of 150 000 IU, we set efficacy and safety criteria. The criterion for the effectiveness of treatment was to achieve an adequate level of vitamin D (more than 30 ng / ml at the initial insufficient level and more than 20 ng / ml for patients with vitamin D deficiency). The safety criteria for the correction of vitamin D deficiency or deficiency were the absence of patient complaints, adverse events and / or serious adverse events, as well as the preservation of the main laboratory parameters of phosphorus-calcium metabolism within the reference values. Results: When studying the efficacy of a dose of 150 000 IU in patients with vitamin D deficiency and insufficiency, it was found that the level of calcidiol was significantly higher in the group after treatment with colecalciferol compared with the group before treatment (p 0.05). The peak of the maximum value for patients with deficiency was established on the 14 day from the moment of administration of colecalciferol and was 37.1 6.28 ng / ml, and for patients with initial vitamin D deficiency 40.1 3.71 ng / ml. In the study of the safety of colecalciferol in a bolus dose of 150 000 IU, there were no statistically significant differences in the laboratory parameters of calcium-phosphorus metabolism, both in the group before treatment and after correction of deficiency and vitamin D insufficiency in both groups. Conclusion: Colecalciferol in the form of a single bolus dose of 150 000 IU demonstrated its efficacy and safety in real clinical practice.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

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