The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery 

1999 ◽  
Vol 90 (4) ◽  
pp. 1012-1018 ◽  
Author(s):  
James M. Bailey ◽  
Bruce E. Miller ◽  
Wei Lu ◽  
Steven R. Tosone ◽  
Kirk R. Kanter ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Plasma Concentration ◽  
Cardiac Index ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Loading Dose

Background Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing. Methods Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM. Results The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively. Conclusions A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.

Pharmacokinetics of Rapacuronium in Infants and Children with Intravenous and Intramuscular Administration

2000 ◽  
Vol 92 (2) ◽  
pp. 376-376 ◽  
Author(s):  
Lynne M. Reynolds ◽  
Andrew Infosino ◽  
Ronald Brown ◽  
Jim Hsu ◽  
Dennis M. Fisher
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Pediatric Anesthesia ◽  
Infants And Children ◽  
Intramuscular Administration ◽  
Pharmacokinetic Analysis ◽  
Intravenous Route ◽  
Population Pharmacokinetic ◽  
In Infants And Children

Background A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability. Methods Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration. Results Plasma clearance was 4.77 ml x kg(-1) x min(-1) + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min(-1) (72.4% of absorbed drug) and 0.0110 min(-1) (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot. Conclusions In infants and children, rapacuronium's clearance and steady state distribution volume are less than in adults. After intramuscular administration, bioavailability is 56%, and plasma rapacuronium concentrations peak within 4 or 5 min.

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 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.

scholarly journals Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
A young J. Park ◽  
Joshua Wang ◽  
Jordanna Jayne ◽  
Lynn Fukushima ◽  
Adupa P. Rao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dosage Form ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Published Data ◽  
Total Clearance ◽  
Content Type ◽  
Complicated Skin

ABSTRACT Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs.

scholarly journals Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

2012 ◽  
Vol 56 (6) ◽  
pp. 3032-3042 ◽  
Author(s):  
Lena E. Friberg ◽  
Patanjali Ravva ◽  
Mats O. Karlsson ◽  
Ping Liu
Keyword(s):  
Pediatric Population ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Time Curve ◽  
Individual Parameter ◽  
Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

Trigeminal Neuralgia: Time Course of Pain in Relation to Carbamazepine Dosing

Cephalalgia ◽  
1981 ◽  
Vol 1 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Torbjörn Tomson ◽  
Karl Ekbom
Keyword(s):  
Plasma Concentration ◽  
Trigeminal Neuralgia ◽  
Time Course ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Significant Drop ◽  
Idiopathic Trigeminal Neuralgia ◽  
Full Effect ◽  
Pain Distribution

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

scholarly journals Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

2015 ◽  
Vol 59 (12) ◽  
pp. 7240-7248 ◽  
Author(s):  
Ilias Karaiskos ◽  
Lena E. Friberg ◽  
Konstantinos Pontikis ◽  
Konstantinos Ioannidis ◽  
Vasiliki Tsagkari ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Gram Negative ◽  
Link Type ◽  
Colistin Methanesulfonate

ABSTRACTColistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009,http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012,http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011,http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

scholarly journals Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline Infectious Peritonitis (FIP)

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1000
Author(s):  
Jane Yu ◽  
Benjamin Kimble ◽  
Jacqueline M. Norris ◽  
Merran Govendir
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Feline Calicivirus ◽  
Potential Treatment ◽  
Feline Infectious Peritonitis ◽  
Feline Coronavirus

The pharmacokinetic profile of mefloquine was investigated as a preliminary study towards a potential treatment for feline coronavirus infections (such as feline infectious peritonitis) or feline calicivirus infections. Mefloquine was administered at 62.5 mg orally to seven clinically healthy cats twice weekly for four doses and mefloquine plasma concentrations over 336 h were measured using high pressure liquid chromatography (HPLC). The peak plasma concentration (Cmax) after a single oral dose of mefloquine was 2.71 ug/mL and time to reach Cmax (Tmax) was 15 h. The elimination half-life was 224 h. The plasma concentration reached a higher level at 4.06 ug/mL when mefloquine was administered with food. Adverse effects of dosing included vomiting following administration without food in some cats. Mild increases in serum symmetric dimethylarginine (SDMA), but not creatinine, concentrations were observed. Mefloquine may provide a safe effective treatment for feline coronavirus and feline calicivirus infections in cats.

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Pharmacology ◽  
2017 ◽  
Vol 100 (5-6) ◽  
pp. 301-307
Author(s):  
Maria Bianca Abrudan ◽  
Dana Maria Muntean ◽  
Daniela Saveta Popa ◽  
Ana-Maria Gheldiu ◽  
Maria Adriana Neag ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Metabolic Rate ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Femoral Vein ◽  
Plasma Concentrations ◽  
Drug Drug Interaction

Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

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