Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Alfentanil 

1999 ◽  
Vol 91 (1) ◽  
pp. 144-155 ◽  
Author(s):  
Thomas Bouillon ◽  
Christina Schmidt ◽  
Gudrun Garstka ◽  
Dirk Heimbach ◽  
Dieter Stafforst ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Pharmacodynamic Modeling ◽  
Model Parameters ◽  
Pharmacokinetic Data ◽  
Indirect Response Models ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response ◽  
Arterial Blood

Background Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. Methods After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. Results The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid. Conclusions The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.

Mixed-effects Modeling of the Intrinsic Ventilatory Depressant Potency of Propofol in the Non-steady State

2004 ◽  
Vol 100 (2) ◽  
pp. 240-250 ◽  
Author(s):  
Thomas Bouillon ◽  
Joergen Bruhn ◽  
Lucian Radu-Radulescu ◽  
Corina Andresen ◽  
Carol Cohane ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Time Course ◽  
Minute Ventilation ◽  
Carbon Dioxide Production ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response ◽  
Arterial Blood ◽  
Ventilatory Depression

Background Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol. Methods Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included. Results The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%. Conclusion Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

Population pharmacokinetic-pharmacodynamic model of oxfendazole in healthy adults in a multiple ascending dose and food effect study and target attainment analysis

2021 ◽  
Author(s):  
Thanh Bach ◽  
Gregory A. Deye ◽  
Ellen E. Codd ◽  
John Horton ◽  
Patricia Winokur ◽  
...  
Keyword(s):  
Safety Concern ◽  
Hemoglobin Concentration ◽  
Healthy Adults ◽  
Pharmacodynamic Modeling ◽  
Parasitic Infections ◽  
Population Pharmacokinetic ◽  
Phase I Clinical Trials ◽  
Target Attainment ◽  
Indirect Response Model ◽  
Indirect Response

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed Phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a lifespan indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Pharmacokinetic-Pharmacodynamic Modeling of the New Steroid Hypnotic Eltanolone in Healthy Volunteers

1996 ◽  
Vol 85 (6) ◽  
pp. 1290-1299. ◽  
Author(s):  
Werner J. Hering ◽  
Harald Ihmsen ◽  
Harald Langer ◽  
Christoph Uhrlau ◽  
Michael Dinkel ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Healthy Volunteers ◽  
Clinical Signs ◽  
Pharmacodynamic Modeling ◽  
Model Parameters ◽  
Median Frequency ◽  
Serum Concentrations ◽  
Hypnotic Effect ◽  
Arterial Blood ◽  
Hypnotic Agent

Background In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers. Methods Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model. Results The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening. Conclusions Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

scholarly journals Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5294-5299 ◽  
Author(s):  
Gautam Baheti ◽  
Jennifer J. Kiser ◽  
Peter L. Havens ◽  
Courtney V. Fletcher
Keyword(s):  
Rate Constant ◽  
Sequential Analysis ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Distribution Volume ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Influence of ammonia on respiration

1961 ◽  
Vol 16 (4) ◽  
pp. 703-708 ◽  
Author(s):  
Attilio D. Renzetti ◽  
Barton A. Harris ◽  
John F. Bowen
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Intravenous Administration ◽  
Respiratory Exchange Ratio ◽  
Ventilatory Response ◽  
Poor Correlation ◽  
Neutral Solution ◽  
Arterial Blood ◽  
Arterial Ph ◽  
Metabolic Stimulation

Elevations of the concentration of ammonia in arterial blood to 20 times that of control values, or more, were induced in nine patients by the intravenous administration of an approximately neutral solution of 2 m glycine. During the course of the infusion, increases were observed in uptake of oxygen, output of carbon dioxide, respiratory exchange ratio, ventilation, and arterial pCO2; small reductions in arterial pH accompanied these changes. The net effects observed during glycine administration were metabolic stimulation and relative respiratory depression. A poor correlation (γ = 0.23) was shown to exist between ventilation and the calculated arterial ammonia tension. In addition, in the two patients so studied, the ventilatory response to the inhalation of 5% carbon dioxide in air was decreased during a period in which the concentration of ammonia in the blood was elevated. It is concluded that elevating the concentration of ammonia in the blood to as high as 500 μg/100 ml does not stimulate respiration and may depress it perhaps by changing the pH within chemosensitive cells toward alkalinity. Submitted on February 28, 1961

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