scholarly journals Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Ryan M. McAdams ◽  
Daniel Pak ◽  
Bojan Lalovic ◽  
Brian Phillips ◽  
Danny D. Shen
Keyword(s):  
Steady State ◽  
Residence Time ◽  
Mean Residence Time ◽  
Time Course ◽  
Plasma Concentrations ◽  
Distribution Volume ◽  
Hypoxic Ischemic Encephalopathy ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Ischemic Encephalopathy

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks’ gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.

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 Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir

2001 ◽  
Vol 45 (12) ◽  
pp. 3663-3668 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Joseph J. Eron ◽  
William Lang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Protease Inhibitors ◽  
Pharmacokinetic Study ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Immunodeficiency Virus

ABSTRACT In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUCss] and 37% for peak plasma concentration at steady state [C max,ss]) and increased by indinavir (33% for AUCss). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUCss orC max,ss. Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.

Compartmental vs. noncompartmental modeling for two accessible pools

1984 ◽  
Vol 247 (3) ◽  
pp. R488-R496
Author(s):  
C. Cobelli ◽  
G. Toffolo
Keyword(s):  
Steady State ◽  
Body Mass ◽  
Residence Time ◽  
Mean Residence Time ◽  
Distribution Volume ◽  
Whole Body ◽  
Compartmental Modeling

We examine the limitations of noncompartmental vs. compartmental modeling when two accessible pools are available in kinetic experiments. Focus is on the estimation of mean residence time, whole-body mass, and steady-state equivalent distribution volume. Examples illustrate these points.

The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model 

1999 ◽  
Vol 90 (2) ◽  
pp. 535-544 ◽  
Author(s):  
Eugene H. Cox ◽  
Mariska W. E. Langemeijer ◽  
Josy M. Gubbens-Stibbe ◽  
Keith T. Muir ◽  
Meindert Danhof
Keyword(s):  
Steady State ◽  
Time Course ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Pharmacodynamic Model ◽  
Pharmacokinetic Parameters ◽  
Maximal Effect ◽  
Total Blood ◽  
The Mean

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). Conclusions Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

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 Meropenem-RPX7009 Concentrations in Plasma, Epithelial Lining Fluid, and Alveolar Macrophages of Healthy Adult Subjects

2015 ◽  
Vol 59 (12) ◽  
pp. 7232-7239 ◽  
Author(s):  
Eric Wenzler ◽  
Mark H. Gotfried ◽  
Jeffrey S. Loutit ◽  
Stephanie Durso ◽  
David C. Griffith ◽  
...  
Keyword(s):  
Time Course ◽  
Fixed Combination ◽  
Limit Of Detection ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Epithelial Lining ◽  
Time Curve ◽  
Similar Time ◽  
Epithelial Lining Fluid ◽  
Tract Infections

ABSTRACTThe steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows:Cmax= 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml,Vss= 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, andt1/2= 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

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