Important PK Parameters

Pharmacokinetic studies in drug discovery research deal with the measurement of the drug eoneentration in plasma with respeet to time and the key parameters involved are volume of distribution (Fd), bioavailability (F), exposure (measured as the area under the curve or AUC), maximum plasma concentration attained (Cmax), time of maximum drug concentration (T ax). clearance (Cl) and half-life ( 1/2). These parameters and their role in drug discovery have been diseussed in detail in most text books related to drug metabolism and pharmaeokineties (DMPK), and have been discussed only briefly here. Eaeh of the above are defined as follows  

It is an indicator of the amount of drug in the bloodstream after passing through the different barriers in the body e.g. enzymatic or pH-induced degradation of the molecule, first-pass metabolism etc.) and is directly related to its physicochemical properties. 

Clearance Cl) is defined as the efficiency of extraction of the drug in its unaltered form from the systemic circulation in irreversible elimination from the body. Since multiple organs facilitate this elimination, the total body clearance is the sum of all the different clearance processes (such as renal, hepatic) and is expressed as mL min kg It is calculated as shown in equation (7.4)  

Bioequivalence (BE) is defined as the similarity in the rate and extent of therapeutic and toxic effects observed by the administration of equivalent doses of the pharmaceutical formulations or pharmaceutical alternatives, under similar conditions. It is estimated by comparing the analytical and the above-mentioned pharmacokinetic parameters at different doses for the pharmaceutical preparation under study. 

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Chapter 2 systematically defines some of the important PK parameters and guides the reader through the types of quantitative LC-MS experiments performed to elucidate the PK parameters necessary to move a drag through discovery, preclinical development, and clinical stages. Chapters 3, 4, and 5 respectively introduce the readers to quadmpole mass filters and liner ion traps, time-of-flight mass... 

Absolute bioavailability is one of the important PK parameters that can provide knowledge about the uptake mechanism, extent of first pass effect, and potential to enhance bioavailability by formulation optimization. However, absolute bioavailability is not routinely measured in the clinical study, since by conventional means it requires... 

If CLint is determined in vitro and if / is known, the important PK parameters (CLh, F, and h) ean be directly estimated using Eq. 13.14-13.16, assuming that Qh is constant, that is, 1.5 L/min, or approximately 21 mL/min/ kg for humans (Davies and Morris, 1993). Moreover, if nonspecific protein binding in the in vitro assay systems is factored into the equations, / should be replaced by //u, where/ is the unbound fraction in the in vitro metabolic systems, whieh can be determined using equilibrium dialysis (Soars et al., 2002). Therefore, Eq. 13.14 can be expressed as... 

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. 

In spite of the limitations/ interspecies scaling can be used to relate dosages across species in toxicology studies/ to predict human PK parameter estimates for macromoleculeS/ and/ as discussed in Chapters 30 and 31/ to guide dose selection in Phase I clinical trials. An understanding of the characteristics of the macromolecule is important for the interpretation and application of these results. 

A second class of PM models are used for predictive purposes. Predictive models are intended to have some impact or application to patients or subjects from whom data has not been obtained. Although these models contain descriptive components, they are used to answer what if questions about the effects of changes in the covariates of the model. For a predictive model, if one is interested in evaluating the effect of several dosing strategies on outcomes for a pivotal Phase 3 study via simulation, then the distribution of the PK parameters becomes very important. Another example would be the effect of subpopulation differences on a dosage strategy proposal. 

There are also other BE-type assessments. Interaction studies assess the influence on bioavailability by other individual factors, such as food, alcohol, or other drugs. Such studies are usually single-sequence crossover, but the assessment method remains the same—whether confidence intervals of AUC and Cmax ratios fall within (0.80, 1.25). The same can be said of PK similarity assessments between subject populations, for example, healthy volunteers versus patients. The assessment method is the same as that used for BE, but important differences remain. In typical BE studies, subjects are densely sampled so that individual PK parameters, AUC and Cmax, can be determined with precision. PK similarity assessments are concerned with the differences in different populations, instead of formulations. The assessments are usually based on multiple (parallel) studies, as crossover studies are not possible, and sequence and period effects are not considered. Assessments involve obtaining estimates of average PK parameters in the populations and the 90% confidence intervals for the ratios of the average PK parameters. 

We present a pediatric population PK (PPK) model development example to illustrate the impact that the model development approach to scaling parameters by size can have on pediatric PPK analyses a typical pediatric study is included. It is intuitive that patient size will affect PK parameters such as clearance, apparent volume, and intercompartmental clearance and that the range of patient size in most pediatric PPK data sets is large. Thus, it is expected that in most pediatric PPK studies subject size will affect multiple PK parameters. However, because there are complex interactions between covariates and parameters in pediatric populations, there are also intrinsic pitfalls of stepwise forward covariate inclusion. Selection of significant covariates via backward elimination has appeal in nonlinear model building however, it requires knowledge of the relationship between the covariate and model parameters (linear vs. nonlinear impact) and can encounter numerical difficulties with complex models and limited volume of data often available from pediatric studies. Thus, there is a need for PK analysis of pediatric data to treat size as a special covariate. Specifically, it is important to incorporate it into the model, in a mechanistically appropriate manner, prior to evaluations of other covariates. 

PK parameters can be characterized as descriptive or mechanistic parameters. The descriptive parameters are those used to describe exposure, while the mechanistic ones are the intrinsic properties of compounds controlling the extent and duration of exposure. Understanding the true meaning and relationship between these two categories is important for improving the chemical and physicochemical properties of drug candidates. 

Another guideline from the EMEA, Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins [13], has a section on immunogenicity, which stresses the importance of correlating antibody responses to drug exposure or relevant PK parameters. 

The prediction of human PK from precUnical in vitro and in vivo data remains an important goal in the drug discovery and development process to obtain an early estimate of efficacious human dose, dosing regimen, and safety window prior to first-in-human trials. From a clinical study perspective, under-prediction of human exposure would lead to safety concerns because actual exposures would be greater than expected, and inversely. The primary focus in the literature has been on the estimation of basic PK parameters such... 

Bioanalysis is a field of research dedicated to the quantitation of drugs and their metabolites in biological matrices, such as plasma, blood, urine, and tissue. In collaboration with various research functions, bioanalysis departments support many types of in vivo studies to provide concentration data for drugs and their metabolites, which plays an important role in the evaluation of PK parameters, formulation optimization, safety assessment, and interpretation of efficacy and toxicological observations. 

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