Efficacy-time profile

However, there are other major factors in determining the dosing regimen, such as the nature of the concentration-response relationship for both efficacy and toxicity (therapeutic window) and commercial/ compliance factors. There are additional reasons why caution should be applied in assuming an efficacy-time profile from a given plasma concentration-time profile. Some reasons why the time course of drug concentration and effect may differ are given in Table 5.1. 

In this equation, FB is defined as the bioaccessibility coefficient, z. e., fraction of lipid released from the food matrix into juices of the gastrointestinal tract FT is defined as the transport coefficient, i.e., fraction of the released lipid component transported across the intestinal epithelium and Fm is the fraction of the lipid component that reaches the systemic circulation without being metabolized. It is usually important to measure the concentration of a bioactive component at a particular location to establish its efficacy. Thus, the concentration-time profile of a specific bioactive component at a particular site of action may be helpful in the... 

A pharmacodynamic (PD) model describing the relationship between the observed concentration/exposure measure (e.g. the area under the plasma concentration-time profile AUC) and the observed drug effects on biomarkers, efficacy or safety measurements (or endpoints). Time dependent changes (e.g. development of tolerance) and influence of intrinsic and extrinsic factors should also be reflected in the model. 

We had sought to address two questions (a) what is the elimination half-life of DS-96 in the murine model, and does the tV2 correspond to pharmacodynamic data shown in Fig. 12.19 (b) what is the therapeutic plasma concentration of DS-96 that corresponds to full protection against endotoxemic challenge in mice. DS-96 at a dose of 200 (xg/mouse (8 mg/kg) was administered to CF1 mice via i.p. and i.v. routes. Plasma concentrations of DS-96 were determined by LC-MS/MS using a deuterated DS-96 internal standard (Nguyen et al., 2008 Shrestha et al., 2008). The elimination tV2 in mice is about 400 min (Fig. 12.22), which is consistent with the observed pharmacodynamic (in vivo efficacy) data shown in Fig. 12.19. The observed concentration-versus-time profile of DS-96 in the mouse i.p. model suggests that a plasma concentration of 0.5-1.5 txg/mL corresponds to complete protection by a dose of 200 ng/animal of LPS in the D-galactosamine-primed model of endotoxin-induced lethality. 

Figure 1 Plasma concentration time profiles for a single 42-mg dose of a hypothetical drug with a half-life of 8 hours, Vj 42 liters, and oral bioavailability of 80%. Dashed curve intravenous bolus dose. Solid curve oral dose. Dotted horizontal lines represent plasma concentrations required for efficacy (green) and for the onset of adverse events (red).

By its nature, DMPK is a mathematical discipline that describes the concentration-time profile of a drug and links this to its efficacy response and safety profile. From its mathematical basis, DMPK has developed as a truly predictive quantitative discipline. A number of fundamental DMPK principles and mathematical equations have underpinned this transformation. 

As a general rule, in vivo assays are more challenging than in vitro assays because the matrices for the samples are more complex. The most common use for in vivo assays is to measure the concentration of NCE dosed into a laboratory animal by collecting multiple sample time points, one can use the analytical results to plot the PK profile of the NCE and also obtain various PK parameters that help determine a test compound s PK properties. Preclinical PK parameters of a test compound are then used to predict its human PK parameters. Another use of in vivo assays is combining the results with pharmacodynamic (PD) observations to perform PK/PD modeling.77 82 PK/PD modeling is an important aspect of new drug discovery because it can be used to predict the exposures and durations required to determine clinical efficacy of a NCE. 

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