Variability intersubject

Figure 9 shows the results of population analysis. It does not distinguish the intra- and intersubject variability. In our subsequent analysis [65], we defined intradose, intrasubject, and intersubject variances. The intradose variance charac-... 

FIGURE 6.16 Bar graph of (3-carotene and lycopene skin levels measured with selective RRS for seven subjects. White bars represent (3-carotene levels, black bars the lycopene levels. Note strong intersubject variability of (3-carotene to lycopene concentration ratios, indicated above the bar graphs. 

Intrasubject variability in pharmacod)mamics is generally much less than intersubject variability, allowing meaningful comparisons with placebo. 

Absorption - Atier ora administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10 mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax)- The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability the coefficient of variation, based on intersubject variability, was 35% to 60% for area under the curve (AUC) values. 

For the new compound as victim, in vitro data to predict L by the enzyme that is affected is what is critical to determine an accurate prediction. Bona fide values for fci, are hard to obtain, even for well established drugs. At best, values are estimates and intersubject variability in the term probably overwhelms any investment in attempts to gain highly precise values. However, it is important to note that the sensitivity of the prediction of DDI increases markedly as the value of the/cl exceeds 0.9 (Figure 8.4). 

Minto C, Li B, Tattam B, Brown K, Seale JP, Donnelly R. Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation—intersubject variability in systemic absorption from the lung. Br J Chn Pharmacol 2000 50(2) 116-24. 

Hellriegel et al. (1996) observed a signiLcant inverse linear relationship between the bioavailability of a drug and its coefLcient of variation. An insoluble drug with very low oral bioavailability usually has a very large intersubject variability in its absorption pharmacokinetic parameters, which may result in a worrisome safety proLle or unfavorable efLcacy. 

Intra- and intersubject variability Excessive sleepiness from untreated sleep apnea (OSA), and residual sleepiness in OSA patients treated with nCPAP... 

Secondly, this method fails to account for the majority of the intersubject variability in antipyrine disposition that exists among even those few subjects in whom the method has been applied. For example, when smoking and oral contraceptive use were considered alone (33), only 9% of the total variance in antipyrine kinetics among 207 normal volunteers was accounted for none of the other factors examined by multiple regression analysis could provide a clue as to what was responsible for the other 91 of the variance. 

The variability in the observations made during clinical trials can be attributed to differences between patients (intersubject variability), differences occurring within a patient from day to day (interoccasion variability) and residual variability, which can be attributed to assay variability or other unknown sources. The pharmacosta-tistical model characterizes these sources of variability and estimates the magnitude of the different sources of variability. 

The statistical model is incorporated as described in Section 17.4. The covariate model allows a description of relationships between covariates and model parameters, explaining parts of the intersubject variability and identifying sub-populations at risk for concentrations below or above the therapeutic range. 

In a double-blind, placebo-controlled, dose-ranging study in 35 antiretroviral-naive HIV-infected patients (Protocol 004), subjects were randomized to receive placebo or one of four raltegravir doses (100, 200, 400, or 600 mg) twice daily over 10 days. Although dose proportionality was not observed (possibly due to intersubject variability and the small number of patients), the pharmacokinetic data gathered in this study supported the selection of a 400-mg dose for raltegravir.27... 

Following a single oral dose of 250 mg to 15 subjects, mean peak plasma concentrations of 0.38 pg/ml of disulfiram, 0.77 pg/ml of diethyldithiocarbamic acid, 0.30 pg/ml of methyl diethyldithiocarbamate, and 1.7 pg/ml of diethylamine were attained in about 9 hours a mean peak plasma concentration of 22 pg/ml of carbon disulphide was reported at 6 hours there was considerable intersubject variability in the plasma concentrations (M. D. Faiman etai, Clin. Pharmac. Ther., 1984, 36, 520-526). 

Estimate the magnitude of intersubject variability Estimate the random residual variability... 

Population pharmacokinetic parameters quantify population mean kineticS/ between-subject variability (intersubject variability)/ and residual variability. Residual variability includes within-subject variability/ model misspecification/ and measurement error. This information is necessary to design a dosage regimen for a drug. If all patients were identical/ the same dose would be appropriate for all. However/ since... 

The rate and extent of drug absorption can also be affected by a wide variety of factors related to the characteristics of the subject/patient receiving the drug product. These factors are important to consider, because they can contribute to intrasubject and intersubject variability in the treatment of patients. Further, if not well controlled during the course of a bioavailability study, these factors can bias the study results and confound interpretation of the data. Examples include the following ... 

Epoxide hydrolase activity is present in most mammalian tissues and is high in the endoplasmic reticulum and cytosol of the liver. Humans appear to have considerable intersubject variability in the activity of epoxide hydrolase that may impact on individual susceptibility to the toxic action of certain epoxides This variability argues for the existence of several epoxide hydrolases. 

The limitations of enteric-coated dosage forms include the possibility of duodenal irritation from caustic drugs and an increase in intersubject variability... 

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