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

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.

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Factors Affecting the Pharmacokinetic Characteristics of Rapacuronium

Anesthesiology ◽

10.1097/00000542-199904000-00011 ◽

1999 ◽

Vol 90 (4) ◽

pp. 993-1000 ◽

Cited By ~ 8

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.

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Influence of Renal Failure on the Pharmacokinetics and Neuromuscular Effects of a Single Dose of Rapacuronium Bromide

Anesthesiology ◽

10.1097/00000542-199901000-00006 ◽

1999 ◽

Vol 90 (1) ◽

pp. 24-35 ◽

Cited By ~ 22

Author(s):

Janos Szenohradszky ◽

James E. Caldwell ◽

Peter M. C. Wright ◽

Ronald Brown ◽

Marie Lau ◽

...

Keyword(s):

Renal Failure ◽

Single Dose ◽

Healthy Volunteers ◽

Pharmacokinetic Parameters ◽

Muscle Twitch ◽

Adductor Pollicis Muscle ◽

Mixed Effects Modeling ◽

Train Of Four ◽

Repeated Dosing ◽

The Times

Background Because renal function affects the elimination of muscle relaxants, each new muscle relaxant must be evaluated in patients with renal failure. Accordingly, the neuromuscular effects and pharmacokinetics of rapacuronium were identified in patients with renal failure. Methods Rapacuronium (1.5 mg/kg) was administered to 10 healthy volunteers and 10 patients with renal failure who were undergoing non-transplant surgery, were 18-45 yr old, and were anesthetized with propofol. The adductor pollicis muscle twitch tension was monitored. Plasma samples were obtained frequently for a period of 8 h to measure the concentrations of ORG9487 and its metabolite, ORG9488. Pharmacokinetic parameters were determined using mixed-effects modeling. Results One patient was excluded from analysis because he was taking phenytoin chronically. Twitch depression at 1 min was less in patients than in healthy volunteers (median values: 92% in patients, 99% in volunteers). The times to 90% and peak twitch depression; to 10%, 25%, and 75% twitch recovery; and to 70% and 80% train-of-four ratios were similar in volunteers and patients. Rapacuronium's clearance was 32% less in patients with renal failure; in both groups, clearance decreased 0.909% per year of age compared with the value in a 30 yr old. The steady state distribution volume was 14% less in women than in men and 16% less in patients than in volunteers. For ORG9488, clearance was 85% less in patients than in volunteers. Conclusions The neuromuscular effects of a single dose of rapacuronium are affected minimally by renal failure. However, the decreased clearance of rapacuronium and its potent metabolite in renal failure suggests that repeated dosing of rapacuronium may lead to prolonged effects in patients with renal failure.

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Tigecycline Does Not Prolong Corrected QT Intervals in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01576-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1895-1901 ◽

Cited By ~ 5

Author(s):

Joan M. Korth-Bradley ◽

Paul C. McGovern ◽

Joanne Salageanu ◽

Kyle Matschke ◽

Anna Plotka ◽

...

Keyword(s):

Healthy Subjects ◽

Volume Of Distribution ◽

Mixed Effects ◽

Pharmacokinetic Parameters ◽

Qtc Interval ◽

Open Label ◽

Time Curve ◽

Linear Mixed Effects ◽

Mixed Effects Modeling ◽

Qt Intervals

ABSTRACTWe evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (Cmax), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (Vss), 610 liters; and terminal half-life (t1/2), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P= 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

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Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01244-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6791-6799 ◽

Cited By ~ 16

Author(s):

Kok-Yong Seng ◽

Kim-Hor Hee ◽

Gaik-Hong Soon ◽

Nicholas Chew ◽

Saye H. Khoo ◽

...

Keyword(s):

Isonicotinic Acid ◽

Compartment Model ◽

Hepatic Function ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Mixed Effects Modeling ◽

Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

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The Magnitude and Time Course of Vecuronium Potentiation by Desflurane Versus Isoflurane

Anesthesiology ◽

10.1097/00000542-199502000-00011 ◽

1995 ◽

Vol 82 (2) ◽

pp. 404-411 ◽

Cited By ~ 30

Author(s):

Peter M.C. Wright ◽

Paul Hart ◽

Marie Lau ◽

Ronald Brown ◽

Manohar L. Sharma ◽

...

Keyword(s):

Time Course ◽

Bolus Dose ◽

Response Times ◽

Muscle Relaxants ◽

Dose Requirement ◽

Duration Of Action ◽

Isoflurane Anesthesia ◽

Course Of Action ◽

Anesthetic Concentration ◽

End Tidal

Background Preliminary studies suggest that desflurane and isoflurane potentiate the action of muscle relaxants equally. However, variability between subjects may confound these comparisons. A crossover study was performed in volunteers on the ability of desflurane and isoflurane to potentiate the neuromuscular effect of vecuronium, to influence its duration of action, and on the magnitude and time course of reversal of potentiation when anesthesia was withdrawn. Methods Adductor pollicis twitch tension was monitored in 16 volunteers given 1.25 MAC desflurane on one occasion, and 1.25 MAC isoflurane on another. In eight subjects, vecuronium bolus dose potency was determined using a two-dose dose-response technique; the vecuronium infusion dose requirement to achieve 85% twitch depression also was determined. Also in these subjects, the magnitude and time course of spontaneous neuromuscular recovery were determined when the anesthetic was withdrawn while maintaining a constant vecuronium infusion. In the other eight subjects, the time course of action of 100 micrograms/kg vecuronium was determined. Results Vecuronium's ED50 and infusion requirement to maintain 85% twitch depression were 20% less during desflurane, compared to isoflurane, anesthesia; vecuronium plasma clearance was similar during the two anesthetics. After 100 micrograms/kg vecuronium, onset was faster and recovery was longer during desflurane anesthesia. When the end-tidal anesthetic concentration was abruptly reduced from 1.25 to 0.75 MAC, twitch tension increased similarly (approximately 15% of control), and time for the twitch tension to reach 90% of the final change was similar (approximately 30 min) with both anesthetics. Decreasing anesthetic concentration from 0.75 to 0.25 MAC increased twitch tension by 46 +/- 10% and 25 +/- 7% of control (mean +/- SD, P < 0.001) with desflurane and isoflurane, respectively; 90% response times for these changes were 31 +/- 10 min and 18 +/- 7 min (P < 0.05), respectively. Conclusions Desflurane potentiates the effect of vecuronium approximately 20% more than does an equipotent dose of isoflurane.

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Extremism Leads to Ostracism

Social Psychology ◽

10.1027/1864-9335/a000406 ◽

2020 ◽

Vol 51 (3) ◽

pp. 149-156

Author(s):

Andrew H. Hales ◽

Kipling D. Williams

Keyword(s):

Mixed Effects ◽

Social Connection ◽

Mixed Effects Modeling ◽

Activist Groups

Abstract. Ostracism has been shown to increase openness to extreme ideologies and groups. We investigated the consequences of this openness-to-extremity from the perspective of potential ostracizers. Does openness-to-extremity increase one’s prospects of being ostracized by others who are not affiliated with the extreme group? Participants rated willingness to ostracize 40 targets who belong to activist groups that vary in the type of goals/cause they support (prosocial vs. antisocial), and the extremity of their actions (moderate vs. extreme). Mixed-effects modeling showed that people are more willing to ostracize targets whose group engages in extreme actions. This effect was unexpectedly stronger for groups pursuing prosocial causes. It appears openness-to-extremity entails interpersonal cost, and could increase reliance on the extreme group for social connection.

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Supplemental Material for Dialectical Behavior Therapy for Borderline Personality Disorder: A Meta-Analysis Using Mixed-Effects Modeling

Journal of Consulting and Clinical Psychology ◽

10.1037/a0021015.supp ◽

2010 ◽

Keyword(s):

Borderline Personality Disorder ◽

Personality Disorder ◽

Behavior Therapy ◽

Dialectical Behavior Therapy ◽

Meta Analysis ◽

Mixed Effects ◽

Borderline Personality ◽

Mixed Effects Modeling

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The Anticoagulant Effect of Heparinoid Org 10172 During Haemodialysis: An Objective Assessment

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661535 ◽

1986 ◽

Vol 55 (02) ◽

pp. 271-275 ◽

Cited By ~ 22

Author(s):

Helen Ireland ◽

D A Lane ◽

Angela Flynn ◽

E Anastassiades ◽

J R Curtis

Keyword(s):

Renal Failure ◽

Bolus Dose ◽

Bolus Injection ◽

Objective Assessment ◽

Factor Xa ◽

Fibrin Clot ◽

Natural Origin ◽

Fibrin Formation ◽

Single Bolus Injection

SummaryThe heparinoid of natural origin Org 10172 has anti-factor Xa activity but minimal anti-thrombin activity, and little effect upon broad spectrum assays such as the KCCT in vitro. Its anticoagulant effects have been compared to those of commercial heparin in 7 patients undergoing haemodialysis for chronic renal failure. Commercial heparin was administered in a dose (5,000 iu bolus + 1,500 iu/hour continuous iv infusion) previously shown to inhibit fibrin formation during haemodialysis. This produced mean anti-factor Xa levels in plasma between 0.7-1.0 iu/ml and largely suppressed fibrin formation for 5 h dialysis measured as mean FPA levels in plasma. Administration of Org 10172 as a bolus of 1,350 anti-factor Xa u or 2,000-2,400 anti-factor Xa u produced plasma anti-factor Xa levels of less than 0.5 u/ml and allowed fibrin clot and FPA generation during dialysis. Org 10172 administered as a bolus dose of 4,000-4,800 anti-factor Xa u produced mean anti-factor Xa levels of greater than 0.5 u/ml, allowed dialysis of 6 patients for 5 h and appreciably suppressed FPA generation during dialysis, with little effect on the KCCT.It is concluded that the anti-factor Xa activity of Org 10172 may reflect its ability to inhibit fibrin during dialysis and that single bolus injection of Org 10172 may be a useful alternative method of achieving anticoagulation.

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