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  • 1
    Electronic Resource
    Electronic Resource
    Comparison of Different Methods to Evaluate Population Dose–Response and Relative Potency: Importance of Interoccasion Variability (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 67-83 
    Details
    ISSN: 1573-8744
    Keywords: dose–response ; mixed-effects modeling ; relative potency ; interoccasion variability ; albuterol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Different mixed-effects models were compared to evaluate the population dose–response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax ) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose–response and relative potency, there are important differences in the assumptions made by each method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020682729226
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 569-582 
    Details
    ISSN: 1573-8744
    Keywords: propranolol ; pharmacodynamic modeling ; exercise heart rate ; unbound and total concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, E max ,and sigmoid E max models. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the E max model was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were E max 33.6±4.5% and EC50 18.2±15.6ng/ml for total P and E max 33.5±4.3% and EC50 1.66±1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50 values showed similar intersubject variability. The observed unbound EC50 values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50 could not be accounted for by variability in P protein binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01068413
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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