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  • 1
    Electronic Resource
    Electronic Resource
    Comparison of Single and Multiple Dose Pharmacokinetics Using Clinical Bioequivalence Data and Monte Carlo Simulations (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1330-1336 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; absorption rate ; steady-state bioavailability ; Monte Carlo simulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination. Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens. Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing. On the other hand, drugs with higher AI appeared to have smaller CI at steady-state. For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing. A Monte Carlo simulation study of SD and MD bioequivalence trials was performed. The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation. All the possible combinations of these factors were tested with SD and MD study designs. All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials). Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI, high variability and a large difference in absorption constants (ka) between test and reference formulations. The mean AUC and CMAX CI ranges for this situation decreased from 15 to 6 and from 16 to 10, respectively, in going from SD to MD design. Thus, there was concordance between simulated and experimental data. The probability of failing the bioequivalence test is shown to dramatically decrease upon multiple dosing due to the changes (range and shift) in the confidence interval.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018906931100
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  • 2
    Electronic Resource
    Electronic Resource
    Evaluation of Bioequivalence of Highly Variable Drugs Using Monte Carlo Simulations. I. Estimation of Rate of Absorption for Single and Multiple Dose Trials Using Cmax (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1634-1641 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; highly variable drugs ; absorption rate ; Monte Carlo simulations ; single dose bioequivalence trials ; multiple dose bioequivalence trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A Monte Carlo simulation study was done to investigate the effects of high intrasubject variation in clearance (CL), and volume of distribution (V) on the calculation of the 90% confidence interval (CI) for Cmax for single dose and multiple dose studies. Methods. Simulations were done for both immediate release and sustained release scenarios. The simulated data were compared with clinical data from bioequivalence studies performed on indomethacin and verapamil. Results. Previous reviews and simulations have shown that the probability of failure for the Cmax for single dose studies was always greater than that for multiple dose studies. However, the results for the simulated scenarios currently investigated indicate that if intrasubject (period-to-period) variation in CL and V is high (% CV's above 25%, and 12%, respectively), multiple dose studies can exhibit a higher probability of failure for Cmax than do single dose studies. Furthermore, Cmax values from studies performed with a sustained release scenario are more sensitive to changes in Ka, CL, and V than are results of studies on immediate release products. As an example, the probability of failure for immediate release products in simulated single dose studies is about 11% and 21% when the mean difference in Ka is 10% and 20%, respectively; while, the probability of failure for multiple dose studies is about 36% regardless of the difference in Ka. The corresponding values for the probability of failure for sustained release products were 25%, 53% for single dose studies and 39% for multiple dose studies. The simulations also indicate that changes in the fraction absorbed have a greater effect on the estimation of Cmax in multiple dose regimens than in single dose studies. Conclusions. The results from these investigations indicate that multiple dose studies do not necessarily always reduce variability in Cmax.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016288916410
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 141-168 
    Details
    ISSN: 1573-8744
    Keywords: theophylline kinetics ; population pharmacokinetics ; NONMEM ; age and kinetics ; gender and kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl);weight was inferior to age and did not statistically improve the model (p〉0.005when combined with age. Total Clincreased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Clvalues: for a given age, Clwas 34% higher for blacks than the reference population composed of the remaining patients, and Clfor males was 25% higher than that for females. The volume of distribution (Vdfor the population was estimated to be 0.62 L/kg. The interindividual variability in Cland Vdexpressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 μg/ml. The STCs that represented some degree of outpatient dosing were 21 % lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059025
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    Paper (German National Licenses)
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