PK-PD modeling

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. 

Mechanism-based PK/PD modeling and validation. This involves the four distinct steps of building PK model, building PD model, linking PK and PD models, and simulation of treatment regimens or trials for useful prediction. 

In the process of PK/PD modeling, it is important to describe, prospectively, the objectives of the modeling, the study design, and the available PK and PD data. The assumptions of the model can be related to dose-response, PK, PD, or one or more of the assumptions listed in Table 18.1. 

One should definitely examine them to appreciate how easy it has become to create and analyze PK and PD models. If you are interested in further information, a literature search on of electronic databases for material on PK/PD modeling should use both the spellings "modeling" and "modelling" because they are used interchangeably. 

Bioavailability of human insulin assessed from pharmacological data. After extravascu-lar administration only the time course governs the observed pharmacological effects. The pharmacological data was translated into theoretical plasma-concentration data using the PK/PD model. The results of the PK/PD analysis indicate that the doses administered can be accurately predicted from pharmacological data... 

Lorazepam The PK-PD modeling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers showed that the parameter values derived from PK/PD modeling, and especially the EC values, may provide sensitive indices that can be used, rather than the raw data derived from PD measurements, to compare CNS effects of benzodiazepines... 

Cetrizine The PK-PD modeling characterized the time course of cetirizine effect on histamine-induced skin reactions (wheal and flare). The histamine-induced flare was at least 80% inhibited at the start of the second administration. Thereafter, on successive administrations, the inhibition was even more pronounced and the response control was nearly total... 

FormoteroF Interactions of formoterol and theophylline were evaluated with the use of PK/PD modeling. The values for the eosinopenic effects were fixed at 0. Effects of both drugs combined were described with a noncompetitive interaction model... 

Piperacillin- tazobactam In vitro anti-infective effect of piperacillin-tazobactam (PIP-TZB) combinations on Escherichia coli showed through a PK/PD model that for these combinations, three-times-a-day administration is as effective as four times a day. Pharmacodynamic activity of the combinations can be prolonged by sufficiently high inhibitor concentrations... 

Population PK/PD models, which in addition to the characterization of PK and PD, involve relationships between covariates (for instance, patient characteristics such as age, body weight) and PK/PD parameters, allow us to assess and to quantify potential sources of variability in exposure and response in specific target population, even under erratic and limited sampling conditions. Often implications of significant covariate effects can be evaluated by computer simulations using the population PK/PD model. 

Luckow, V. and Della Paschoa, O., PK/PD modeling of high-dose diltiazem—absorption-rate dependency of the hysteresis loop, Int.. Clin. Pharmacol. Ther., 35, 418-425,1997. 

PK models (Section 13.2.4), PD models (Section 13.2.5), and PK/PD models (Section 13.2.6) can be used in two different ways, that is, in simulations (Section 13.2.7) and in data analysis (Section 13.2.8). Simulations can be performed if the model structure and its underlying parameter values are known. In fact, for any arbitrary dose or dosing schedule the drug concentration profile in each part of the model can be calculated. The quantitative measures of the effectiveness of drug targeting (Section 13.4) can also be evaluated. If actual measurements have been performed in in-vivo experiments in laboratory animals or man, the relevant model structure and its parameter values can be assessed by analysis of plasma disappearance curves, excretion rate profiles, tissue concentration data, and so forth (Section 13.2.8). 

PK/PD models are obtained by combining a PK model (Section 13.2.4) and a PD model (Section 13.2.5), allowing the quantification of the relationship between drug administration and drug action. The principles of PK/PD modelling will be dealt with briefly. For a more detailed treatise, some excellent reviews can be found in the literature [21]. 

If an appropriate model is selected and the model parameters are known, the time course of the drug concentration in each compartment (PK models) and the drug effect (PK/PD models) can be calculated for any dosing regimen. In addition, the relevant measures of the effectiveness of drug targeting can be calculated (see Section 13.4). 

Evaluation of Effectiveness of Drug Targeting Using PK and PK/PD Modelling... 

Despite the promising applications of PK and PK/PD modelling in many fields of drug research [3,49] and drug utilization [29], awareness of their limitations is necessary. Among others, the following aspects may interfere with successful PK and PK/PD modelling and analy-... 

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