Two Main Mechanism Classes for Delayed Effects

There are two qualitatively different mechanisms linking plasma concentration time course to subsequent actions, effects, and responses. First, the drug molecule must be distributed to the site of action, e.g., at the cell surface in the extracellular fluid adjacent to a receptor. Second, a chain of events involving turnover of physiological mediators such as cyclic AMP, gene transcription factors, and proteins is required before the action is translated into an effect or clinical response. In...

Introduction to the Emax Model

The Emax model is a nonlinear model frequently used in dose-response analyses. The model is shown in Eq. (9.1) Ri The value of the response for patient i Di The level of the drug for patient i, the concentration may also be used in many settings E0 The basal effect, corresponding to the response when the dose of the drug is zero Emax The maximum effect attributable to the drug ED50 The dose, which produces half of Emax N The slope factor (Hill factor), measures sensitivity of the response to...

Dose Escalation

It is not always necessary to escalate to doses as high as the MTD in the FIH studies. The highest single dose tested can also be defined as the pharmacologically active dose (PAD) giving the maximal effect in the absence of toxicity (Figure 3.3). However, the estimation of the PAD from preclinical pharmacology studies may not be possible if animal models of the disease are not available or the understanding of the fundamental biochemical or physiological aspects of the mechanism of action of...

References

Patient specific dosing in a cancer Phase I clinical trial. Statistics in Medicine 20 2079-2090. Babb, J.S., Rogatko, A., and Zacks, S. 1998. Cancer Phase I clinical Trials efficient dose escalation with overdose control. Statistics in Medicine 17 1103-1120. Cheng, J., Langer, C., Aamdal, S., Robert, F., Engelhardt, L.R., Fernberg, O., Schiller, J. et al. (2004). Individualized patient dosing in Phase I clinical trials The role of EWOC in PNU-214936. Journal of...

Clinical Development Plan

In the early stage of drug development, as early as in the nonclinical stage, a clinical development plan (CDP) should be drafted. This plan should include clinical studies to be conducted in Phases I, II and III. The CDP should be guided by the draft drug label. The drug label provides detailed information on how the drug should be used. Hence, a draft label at the early stage of drug development lays out the target profile for the drug candidate. Clinical studies should be designed to help...

FDA Exposure Response Guidance

An important step was taken by the United States Food and Drug Administration FDA when it issued its Exposure Response Guidance Food and Drug Administration, 2003 . This document clearly distinguished the pharmacokinetic and pharmacodynamic sources of variability in response to a dose and offers practical advice for implementation of exposure response analysis. Unfortunately, it only hints at incorporation of the time course of response and focuses on the use of simple pharmacokinetic...

Hochbergs Stepup Procedure

This is also a sample-determined stepwise procedure, similar to that in Section 12.3.2. While Holm's step-down testing is a shortcut version of thepartition testing based on Bonferroni methods, Huang and Hsu 2005 show that Hochberg's step-up testing is also a special case, or shortcut version, of a partition testing based on Simes' test. Although more powerful than Bonferroni method Holm's procedure, Simes' test Hochberg's procedure control the Type I error rate familywise error rate at a only...

Traditional or 3 3 Design

The most widely used design in oncology is the traditional design also known as the standard or 3 3 design. According to the 3 3 design, subjects are assigned in groups of three starting with the lowest dose with the following provisions If only three patients have been assigned to the current dose so far, then If no toxicities are observed in a cohort of three, the next three patients are assigned to the next higher dose level If one toxicity is observed in a cohort of three, the next three...

Model Uncertainty and Model Selection

In the previous sections we have described a variety of commonly used dose-response models and given some possibilities of deriving initial parameter estimates for constructing model contrasts. We have not yet discussed the problem of selecting a model for the final analysis. This is a particularly important issue in the regulated environment of pharmaceutical drug development, since it is required to prespecify completely the statistical analysis and thus also the dose-response model used for...

Initial Parameter Values for the Oral Artesunate Dose Response Analysis Example

Smoothing Spline

As discussed in Section 9.5.2, starting values for the parameters are required for Proc NLIN. Figures 9.9 and 9.10 illustrate fitting a smoothing spline to the data to provide initial estimates of Emax model parameters. Figure 9.10. Estimation of starting value for N using a smoothing spline. Figure 9.10. Estimation of starting value for N using a smoothing spline. Figure 9.10 illustrates the use of Eq. 9.5 in estimating a starting value for the slope parameter N. Based on Figures 9.9. and...

Escalation with Overdose Control Design

The main attribute underlying EWOC is that it is designed to approach the MTD as fast as possible subject to the ethical constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. The design has many advantages over some competing schemes such as up-and-down designs and continual reassessment method see Babb et al. 1998 . In this section, we describe the methodology in details and give a real-life example illustrating this technique. Let Xmin...

Oral Artesunate Dose Response Analysis Example

Sigmoidal Hyperbolic

The following example is based on a study by Angus 2002 . The objective of the study was to characterize the dose-response of oral artesunate on falciparum malaria. Forty-seven adult patients were randomized to a single dose of oral artesunate varying from 0 to 250 mg together with a curative dose of oral mefloquine. A patient could receive a dose of either 0, 25, 50, 75, 100, 150, 200, or 250 mg. Figure 9.7 illustrates patients' parasite clearance time the time required for a patient to reach...