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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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  • 2
    Electronic Resource
    Electronic Resource
    Truncated Area Under the Curve as a Measure of Relative Extent of Bioavailability: Evaluation Using Experimental Data and Monte Carlo Simulations (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1621-1629 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; partial AUCs ; truncated AUCs ; long half-life ; Monte Carlo simulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The use of truncated areas under the curve (AUCs) could be a significant advantage for bioequivalence studies of drugs with long half-lives. The purpose of this study was to evaluate the performance of truncated AUCs as measures of relative extent of bioavailability using a large database of experimental data and Monte Carlo simulations. Methods. The experimental data consisted of 123 single-dose, 2-treatment, crossover studies with at least 18 subjects/study. Monte Carlo techniques were also used to simulate studies that reflected a wide variety of experimental conditions. AUCs were calculated over different time intervals and the standard two one-sided t tests procedure was used to assess bioequivalence. Results. The experimental data showed that conclusions concerning bioequivalence were identical between AUCs truncated at four times the time of peak concentration (Tmax) and AUCs extrapolated to infinity (AUCinf) in 120/123 or 97.6% of studies. There was little change in the intra-subject CVs for AUCs truncated at 3*Tmax or later. The results of Monte Carlo simulations were generally consistent with the experimental data and showed that AUCs truncated at 72 hours (AUC0−72) performed well compared to AUCinf as measures of bioequivalence for drugs with long half-lives. Conclusions. Based on both the experimental and simulated data, AUCs truncated after the absorption phase perform well as measures of relative extent of bioavailability. Truncated AUCs offer a particular advantage for drugs with long half-lives and these results indicate that it would be reasonable to limit the sample collection period to 72 hours in bioequivalence studies of oral formulations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011971620661
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  • 3
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetics of Terfenadine (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 832-838 
    Details
    ISSN: 1573-904X
    Keywords: terfenadine ; carboxylic acid terfenadine ; population pharmacokinetics ; nonlinear mixed effects modeling ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. After oral administration of terfenadine, plasma concentrations of the parent drug are usually below the limits of quantitation of conventional analytical methods because of extensive first-pass metabolism. Data are usually reported on the carboxylic acid metabolite (Ml) but there are no published reports of pharmacokinetic parameters for terfenadine itself. The present study was undertaken to evaluate the population pharmacokinetics of terfenadine. Methods. Data from 132 healthy male subjects who participated in several different studies were included in this analysis. After an overnight fast, each subject received a single 120 mg oral dose of terfenadine; blood samples were collected for 72 hours. Terfenadine plasma concentrations were measured using HPLC with mass spectrometry detection and Ml plasma concentrations were measured using HPLC with fluorescence detection. A 2-compartment model was fitted to the terfenadine data using NONMEM; terfenadine and Ml data were also analyzed by noncompartmental methods. Results. Population mean Ka was 2.80 hr−1, Tlag was 0.33 hr, Cl/F was 4.42 × 103 1/hr, VC/F was 89.8 ×1031, Q/F was 1.85 ×103 1/hr and Vp/F was 29.1 × 1031. Intersubject CV ranged from 66 to 244% and the residual intrasubject CV was 21%. Based on noncompartmental methods, mean terfenadine Cmax was 1.54 ng/ml, Tmax was 1.3 hr, t1/2 λZ was 15.1 hr, Cl/F was 5.48 × 103 1/hr and Vλz/F was 119.2 × 1031. Ml concentrations exceeded terfenadine concentrations by more than 100 fold and showed less intersubject variability. Conclusions. Terfenadine disposition was characterized by a 2-compartment model with large intersubject variability, consistent with its significant first-pass effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016036624935
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    Paper (German National Licenses)
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