Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

2006 ◽  
Vol 104 (3) ◽  
pp. 466-474 ◽  
Author(s):  
Mariska Y. M. Peeters ◽  
Sandra A. Prins ◽  
Catherijne A. J. Knibbe ◽  
Joost DeJongh ◽  
Ron H. N. van Schaik ◽  
...  
Keyword(s):  
Bispectral Index ◽  
Coefficient Of Variation ◽  
Craniofacial Surgery ◽  
Dose Titration ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Healthy Children ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Emax Model ◽  
Behavior Scale

Background To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. Methods After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. Conclusions Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.

Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery

2006 ◽  
Vol 105 (6) ◽  
pp. 1135-1146 ◽  
Author(s):  
Mariska Y. M. Peeters ◽  
Sandra A. Prins ◽  
Catherijne A. J. Knibbe ◽  
Joost DeJongh ◽  
Ron A. A. Mathôt ◽  
...  
Keyword(s):  
Bispectral Index ◽  
Interindividual Variability ◽  
Initial Dosage ◽  
Optimal Dose ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Major Surgery ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Emax Model

Background Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group. Methods Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 mum with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized. Conclusion In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.

Perioperative Pharmacodynamics of Acetaminophen Analgesia in Children 

1999 ◽  
Vol 90 (2) ◽  
pp. 411-421 ◽  
Author(s):  
Brian J. Anderson ◽  
Nicholas H. G. Holford ◽  
Gerald A. Woollard ◽  
Suchitra Kanagasundaram ◽  
Murali Mahadevan
Keyword(s):  
Coefficient Of Variation ◽  
Half Life ◽  
Lag Time ◽  
Hill Coefficient ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Emax Model

Background There are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia. Methods Children undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100). No other analgesic agents were administered. Individual concentrations of acetaminophen in serum and pain scores (0-10) measured over a 4-h postoperative period were analyzed using a nonlinear mixed-effects model (NONMEM). Results Mean (% CV) estimates of population pharmacokinetic parameters with percent coefficient of variation, standardized to a 70-kg person, for a one-compartment model with first-order input, lag time, and first order-elimination were a volume of distribution of 60 (21) 1 and a clearance of 13.5 (46) 1/h. Rectally administered acetaminophen had an absorption half-life of 35 (63) min with a lag time of 40 min. The absorption half-life for the oral preparation was 4.5 (63) min without a detectable lag time. The relative bioavailability of the rectal compared with the oral formulation was 0.54. The equilibration half-time of an effect compartment was 1.6 (131) h. Pharmacodynamic population parameter estimates (percent coefficient of variation) for a fractional sigmoidal Emax model, in which the greatest possible pain relief equates to an Emax of 1, were Emax = 1, EC50 (the concentration producing 50% of Emax) = 3.4 (94) mg/l, and Hill coefficient = 0.54 (42). Conclusions The pharmacodynamics of acetaminophen can be described using a sigmoidal Emax model with a low Hill coefficient. To achieve a mean posttonsillectomy pain score of 3.6 of 10, an effect compartment concentration of 10 mg/l is necessary.

A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery

2012 ◽  
Vol 107 (04) ◽  
pp. 775-785 ◽  
Author(s):  
Thorsten Lehr ◽  
Karl-Heinz Liesenfeld ◽  
Sebastian Haertter ◽  
Alexander Staab ◽  
Chantaratsamon Dansirikul
Keyword(s):  
Atrial Fibrillation ◽  
Healthy Volunteers ◽  
Orthopaedic Surgery ◽  
Dabigatran Etexilate ◽  
Plasma Concentrations ◽  
Thrombin Inhibitor ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Emax Model ◽  
Orally Bioavailable

SummaryDabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabig-atran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

scholarly journals Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model

2007 ◽  
Vol 51 (12) ◽  
pp. 4351-4355 ◽  
Author(s):  
Paul G. Ambrose ◽  
Alan Forrest ◽  
William A. Craig ◽  
Chistopher M. Rubino ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Survival Data ◽  
Sensitivity Analyses ◽  
Maximum Effect ◽  
Infection Model ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Adults And Children

ABSTRACT We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC of the drug for the organism (AUC0-24/MIC ratio) was the PK-PD measure most predictive of survival (R 2 = 0.96). The 50% effective dose (ED50) and the ED90 and ED99 corresponded to AUC0-24/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED99). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation 

1999 ◽  
Vol 90 (2) ◽  
pp. 451-457 ◽  
Author(s):  
Toong C. Lee ◽  
Bruce G. Charles ◽  
Glen J. Harte ◽  
Peter H. Gray ◽  
Peter A. Steer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Population Pharmacokinetics ◽  
Premature Infants ◽  
Coefficient Of Variation ◽  
Population Analysis ◽  
Volume Of Distribution ◽  
Continuous Treatment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Very Premature Infants

Background Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. Methods Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. Results Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. Conclusions Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

1998 ◽  
Vol 16 (8) ◽  
pp. 2770-2779 ◽  
Author(s):  
M A Villalona-Calero ◽  
S D Baker ◽  
L Hammond ◽  
C Aylesworth ◽  
S G Eckhardt ◽  
...  
Keyword(s):  
Cardiovascular Effects ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Maximum Effect ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Emax Model ◽  
Solid Malignancies

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

scholarly journals Comparison between cerebral state index and bispectral index as measures of electroencephalographic effects of sevoflurane using combined sigmoidal Emax model

2011 ◽  
Vol 32 (10) ◽  
pp. 1208-1214 ◽  
Author(s):  
Dong Woo Han ◽  
Olinto-Jose Linares-Perdomo ◽  
Jong Seok Lee ◽  
Jun Ho Kim ◽  
Steven E Kern
Keyword(s):  
Bispectral Index ◽  
Emax Model ◽  
State Index

The Dynamic Relationship between End-tidal Sevoflurane and Isoflurane Concentrations and Bispectral Index and Spectral Edge Frequency of the Electroencephalogram 

1999 ◽  
Vol 90 (5) ◽  
pp. 1345-1353 ◽  
Author(s):  
Erik Olofsen ◽  
Albert Dahan
Keyword(s):  
Bispectral Index ◽  
Effect Compartment ◽  
Spectral Edge Frequency ◽  
Spectral Edge ◽  
Emax Model ◽  
Dynamic Relationship ◽  
Ic50 Values ◽  
American Society ◽  
End Tidal ◽  
Speed Of Onset

Background Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0)). Methods Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD. Results The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05). Conclusions The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

2015 ◽  
Vol 60 (1) ◽  
pp. 522-531 ◽  
Author(s):  
Kristen Nichols ◽  
Eun Kyoung Chung ◽  
Chad A. Knoderer ◽  
Lauren E. Buenger ◽  
Daniel P. Healy ◽  
...  
Keyword(s):  
Steady State ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Study Objective ◽  
Population Pharmacokinetics And Pharmacodynamics ◽  
Extended Infusion

ABSTRACTThe study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

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