scholarly journals Application of effect-compartment model to bumetanide-indomethacin interaction in dogs

1983 ◽  
Vol 11 (4) ◽  
pp. 355-368 ◽  
Author(s):  
David E. Smith ◽  
Henry S. H. Lau ◽  
Jeffrey L. Fox
Keyword(s):  
Compartment Model ◽  
Effect Compartment ◽  
Effect Compartment Model

scholarly journals Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

2001 ◽  
Vol 45 (6) ◽  
pp. 1682-1687 ◽  
Author(s):  
Antoine Dupuis ◽  
William Couet ◽  
Joël Paquereau ◽  
Stanley Debarre ◽  
Agnès Portron ◽  
...  
Keyword(s):  
Spline Function ◽  
Elimination Rate ◽  
Compartment Model ◽  
Central Compartment ◽  
Pharmacodynamic Modeling ◽  
Effect Compartment ◽  
Partial Seizures ◽  
Effect Compartment Model ◽  
The Relationship ◽  
Electroencephalogram Eeg

ABSTRACT A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min−1 for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.

Mechanism-based Pharmacokinetic–Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine in Healthy Volunteers

2006 ◽  
Vol 104 (6) ◽  
pp. 1232-1242 ◽  
Author(s):  
Ashraf Yassen ◽  
Erik Olofsen ◽  
Raymonda Romberg ◽  
Elise Sarton ◽  
Meindert Danhof ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Healthy Volunteers ◽  
Rate Constant ◽  
Time Course ◽  
Antinociceptive Effect ◽  
Receptor Occupancy ◽  
Compartment Model ◽  
Effect Compartment ◽  
Effect Compartment Model ◽  
Dissociation Model

Background The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. Methods Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. Results A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). Conclusion This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

scholarly journals Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Norfloxacin in Rats

2003 ◽  
Vol 47 (6) ◽  
pp. 1952-1957 ◽  
Author(s):  
Marylore Chenel ◽  
Agnès Barbot ◽  
Antoine Dupuis ◽  
Olivier Mimoz ◽  
Joël Paquereau ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Body Weight ◽  
Spline Function ◽  
Compartment Model ◽  
Pharmacodynamic Modeling ◽  
Effect Compartment ◽  
Blood Samples ◽  
Effect Compartment Model ◽  
The Relationship ◽  
Electroencephalogram Eeg

ABSTRACT A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight−1 min−1 over 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E. Fuseau and L. B. Sheiner, Clin. Pharmacol. Ther. 35:733-741, 1984).

Population Pharmacokinetics of Piritramide in Surgical Patients 

1999 ◽  
Vol 90 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Thomas Bouillon ◽  
Daniela Kietzmann ◽  
Rudiger Port ◽  
Ingolf Meineke ◽  
Andreas Hoeft
Keyword(s):  
Population Pharmacokinetics ◽  
Venous Blood ◽  
Compartment Model ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Bolus Administration ◽  
Time Data ◽  
Intermittent Bolus ◽  
Patient Consent

Background Piritramide is a synthetic opioid used for postoperative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery. Methods After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data. Results The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 x (1 + 9.32 x 10(-3) x (age - 47 yr)) [l], V3 = 212 x (1 + 6.37 x 10(-3) x (age - 47 yr)) [l], Cl1 = 0.56 x (1 - 6.14 x 10(-3) x (age - 47 yr)) [l/min], Cl2 = 8.25 x (1 + 2.02 x 10(-2) x (Wt - 74 kg)) [l/min], Cl3 = 0.80 [l/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient. Conclusions Piritramide is distributed extensively and eliminated slowly. The pharmacokinetic profile of the drug allows for intermittent bolus administration even when constant effect compartment concentrations are desirable, e.g., for PLA.

Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil

2002 ◽  
Vol 97 (6) ◽  
pp. 1350-1362 ◽  
Author(s):  
Thomas Bouillon ◽  
Joergen Bruhn ◽  
Lucian Radu-Radulescu ◽  
Edward Bertaccini ◽  
Sang Park ◽  
...  
Keyword(s):  
Pharmacokinetic Interaction ◽  
Compartment Model ◽  
Significant Degree ◽  
Volume Of Distribution ◽  
Gas Chromatography Mass Spectrometry ◽  
Effect Compartment ◽  
Drug Concentrations ◽  
Time Courses ◽  
Elimination Clearance ◽  
The Individual

Background The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. Methods Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. Results The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. Conclusions Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.

scholarly journals Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

2008 ◽  
Vol 53 (3) ◽  
pp. 1067-1073 ◽  
Author(s):  
Déborah Hirt ◽  
Saik Urien ◽  
Elisabeth Rey ◽  
Elise Arrivé ◽  
Didier K. Ekouévi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cord Blood ◽  
Pregnant Women ◽  
High Performance ◽  
Placental Transfer ◽  
Compartment Model ◽  
Effect Compartment ◽  
Maternal Circulation ◽  
Time Curve ◽  
Immunodeficiency Virus

ABSTRACT The objectives of this study were to evaluate emtricitabine (FTC) pharmacokinetics in pregnant women and their neonates and to determine the optimal prophylactic dose for neonates after birth to prevent mother-to-child transmission of human immunodeficiency virus (HIV). A total of 38 HIV-infected pregnant women were administered tenofovir disoproxyl fumarate (300 mg)-FTC (200 mg) tablets—two tablets at the initiation of labor and one daily for 7 days postpartum. By pair, 11 maternal, one cord blood, and two neonatal FTC concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry validated method and analyzed by a population approach. Model and mean estimates (interpatient variability) were a two-compartment model for mothers, with an absorption rate constant of 0.54 h−1 (61%), apparent elimination and intercompartmental clearances of 23.2 (17%) and 6.04 liters·h−1, and apparent central and peripheral volumes of 127 and 237 liters, respectively; an effect compartment linked to maternal circulation for cord blood and a neonatal compartment disconnected, after delivery, with a 10.6-h half-life (30%). After the 400-mg FTC administration, the median population area under the concentration-time curve and the minimal and maximal plasma FTC concentrations in pregnant women were 14.3 mg·liter−1·h and 1.68 and 0.076 mg/liter, respectively. At delivery, median (range) predicted maternal and cord blood FTC concentrations were, respectively, 1.16 (0.14 to 1.99) and 0.72 (0.05 to 1.19) mg·liter−1. We concluded that the 400-mg FTC administration in pregnant women produces higher exposition than does the 200-mg administration in other adults, at steady state. FTC was shown to have good placental transfer (80%). Administering 1 mg FTC/kg as soon as possible after birth or 2 mg/kg 12 h after birth should produce neonatal concentrations comparable to the concentrations observed in adults.

scholarly journals Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis

2020 ◽  
Author(s):  
Salvador Fudio ◽  
Josep Tabernero ◽  
Vivek Subbiah ◽  
Sant P. Chawla ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Compartment Model ◽  
Least Square ◽  
Cardiac Conduction ◽  
Response Analysis ◽  
Effect Compartment ◽  
Qtc Interval ◽  
Advanced Solid Tumors ◽  
Relevant Effect ◽  
Ich E14

Abstract Purpose This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors. Methods Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis. Results A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. Conclusions ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

scholarly journals Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

2015 ◽  
Vol 59 (11) ◽  
pp. 6800-6806 ◽  
Author(s):  
Elodie Valade ◽  
Jean-Marc Tréluyer ◽  
Silvia M. Illamola ◽  
Naïm Bouazza ◽  
Frantz Foissac ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Seminal Plasma ◽  
Genital Tract ◽  
Compartment Model ◽  
Effect Compartment ◽  
Population Pharmacokinetic ◽  
Male Genital Tract ◽  
Time Curve ◽  
The Impact ◽  
Male Genital

ABSTRACTWe aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 38.04 and 12.95 mg · liter−1· h, respectively). The median (range) SP-to-BP AUC0–24ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0–24ratios were lower than 1. The impact of FTC SP AUC0–24or FTC SP-to-BP AUC0–24ratio on spVL detection was not significant (P= 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

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