Pharmacodynamics baselines

A mechanism-based PK/PD model for rHu-EPO was used to capture the physiological knowledge of the biological system. An open, two-compartment disposition model with parallel linear and nonlinear clearance, and endogenous EPO at baseline, was used to describe recombinant human erythropoietin (rHu-EPO) disposition after intravenous administration [35]. The pharmacodynamic effect of rHu-... 

The Phase I study was designed as a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the pharmacokinetics and pharmacodynamics of the new ERA. Cohorts of nine subjects with baseline hemoglobin levels less than 14.5 g/dl were randomized to receive ERA treatment (N= 6) or matched placebo (N= 3) at each dose level. The various dose levels considered in this study were lx, 3x, lOx, 30x, lOOx, and 300x. The objective of the study was to identify the pharmacological effective dose (PED), defined as the dose level where four or more treated subjects achieved more than 1 g/dl increase from baseline in hemoglobin within 28 days. 

These findings may be of general importance since baseline parameters are crucial in determining pharmacodynamic responses [478], while feedback mechanisms are frequently involved in physiological processes, e.g., the secretion of hormones and the recurrent inhibitory pathway for q-aminobutyric acid (GABA) in the hippocampus, which has been described in almost every type of neural tissue ranging from the lowest invertebrates through humans [479], and the production of biotech products in humans [480]. 

The pharmacokinetics and pharmacodynamics of zaleplon (10 or 20 mg) and zolpidem (10 or 20 mg) have been investigated in a randomized, double-blind, crossover, placebo-controlled study in 10 healthy volunteers with no history of sleep disorder (15). The half-life of zaleplon was significantly shorter than that of zolpidem. Zaleplon produced less sedation than zolpidem at the two doses studied, and the sedation scores in the zaleplon groups returned to baseline sooner than in the zolpidem groups. Zaleplon had no effect on recent or remote recall, whereas zolpidem had a significant effect on both measures. 

Twenty-four subjects completed an 8-period balanced crossover study. For each subject, pharmacodynamic responses are taken at the test baseline, test 1 puff, test 4 puffs, reference baseline, reference 1 puff, and reference 4 puffs. A population model fit (Section 16.6.1.2) was conducted to describe the data. Responses at baseline were similar for both formulations, although they appeared to differ somewhat at 1 puff and 4 puffs. Overall, the profiles of the two formulations were judged as similar. 

W. Krzyzanski, A. Chakraborty, and W. J. Jusko, Algorithm for apphcation of Fourier analysis for biorhythmic baselines of pharmacodynamic indirect response models. Chro-nobiol Int 17 77-93 (2000). 

At times, the effect measured during a pharmacodynamic study has a value before the drug is administered to the patient. In these cases, the drug changes the patient s baseline value. Examples of these types of measurements are heart rate and blood pressure. In addition, a given drug may increase or decrease the baseline value. Two basic techniques are used to incorporate baseline values into pharmacodynamic data. One way incorporates the baseline value into the pharmacodynamic model the other way transforms the effect data to take baseline values into account. 

Incorporation of the baseline value into the pharmacodynamic model involves the addition of a new term to the previous equations. Eq is the symbol used to denote the baseline value of the effect that will be measured. The form that these equations takes depends on whether the drug increases or decreases the pharmacodynamic effect. When the drug increases the baseline value, Eq is added to the equations ... 

If the drug decreases the baseline value, the drug effect is subtracted from Eq in the pharmacodynamic models ... 

Whether to model a pharmacodynamic model parameter using an arithmetic or exponential scale is largely up to the analyst. Ideally, theory would help guide the choice, but there are certainly cases when an arithmetic scale is more appropriate than an exponential scale, such as when the baseline pharmacodynamic parameter has no constraint on individual values. However, more often than not the choice is left to the analyst and is somewhat arbitrarily made. In a data rich situation where each subject could be fit individually, one could examine the distribution of the fitted parameter estimates and see whether a histogram of the model parameter follows an approximate normal or log-normal distribution. If the distribution is approximately normal then an arithmetic scale seems more appropriate, whereas if the distribution is approximately log-normal then an exponential scale seems more appropriate. In the sparse data situation, one may fit both an arithmetic and exponential scale model and examine the objective function values. The model with the smallest objective function value is the scale that is used. 

The peak-serum level is attainable within 3-12 hour after injeetion. The elimination half-life ranges between 2-3 hours, and serum levels are undetectable after 16 hours. It is found that the hepatitis C replieation rates are in the trillions a day, having viral half-life of nearly 5 hours. Therefore, there exists a predominant inherent mismatch between pharmacokinetic and pharmacodynamic characteristic features which ultimately ends up in enhancing the prevailing replication rate of the virus above the baseline. 

Krzydanski, W., Chakraborty, A., and Jusko, W. J., Algorithm for application of Fourier analysis for biorhythmic baseline of pharmacodynamic indirect models, Chro-nobiol. Int., 17(l) 77-93, 2000. 

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