Pharmacokinetic Approaches

The two basic approaches to the direct assessment of lung dose are pharmacokinetic techniques and imaging techniques. The former is divided into classical pharmacokinetic techniques and indirect measurements, such as the urinary or 

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Information that can be obtained from such studies includes 

Total lung dose Extrapulmonary delivery Distribution within the airways Total systemic exposure 

The influence of factors such as disease and inhalation technique on deposition throughout the respiratory tract Clearance of particles from the lungs Intra- and intersubject variability Relationship between lung dose and therapeutic effects 

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While these models simulate the transfer of lead between many of the same physiological compartments, they use different methodologies to quantify lead exposure as well as the kinetics of lead transfer among the compartments. As described earlier, in contrast to PBPK models, classical pharmacokinetic models are calibrated to experimental data using transfer coefficients that may not have any physiological correlates. Examples of lead models that use PBPK and classical pharmacokinetic approaches are discussed in the following section, with a focus on the basis for model parameters, including age-specific blood flow rates and volumes for multiple body compartments, kinetic rate constants, tissue dosimetry,... 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Thybaud, E. and Caquet, T. Uptake and elimination of lindane by Lymnaea palustris (mollusca Gastropoda) a pharmacokinetic approach, Ecotoxicol. Environ. Saf., 21(3) 365-376, 1991. 

Pharmacodynamic Studies. Pharmacodynamic studies are not recommended for orally administered drug products when the drug is absorbed into the systemic circulation and a pharmacokinetic approach can be used to assess systemic exposure and establish BE. However, in those instances where a pharmacokinetic approach is not possible, suitably validated pharmacodynamic methods can be used to demonstrate BE. 

Comparative Clinical Studies. Where there are no other means, well-controlled clinical trials in humans may be useful to provide supportive evidence of BA or BE. However, the use of comparative clinical trials as an approach to demonstrate BE is generally considered insensitive and should be avoided where possible (21 CFR 320.24). The use of BE studies with clinical trial end points may be appropriate to demonstrate BE for orally administered drug products when measurement of the active ingredients or active moieties in an accessible biological fluid (pharmacokinetic approach) or pharmacodynamic approach is infeasible. 

An alternate approach is the population pharmacokinetic approach, or study. This approach relies on infrequent (sparse) sampling of blood from a larger population than would be used in a standard pharmacokinetic study to determine pharmacokinetic measures and/or parameters. 

The inherent difficulties in antagonizing a blocker Hke cocaine have led to the development of a pharmacokinetic approach that aims at acting directly on the drug itself to alter its distribution or accelerate its clearance [7-14]. Pharmacokinetic antagonism of cocaine could be implemented by administration of a molecule, such as an anti-cocaine antibody, that binds tightly to cocaine so as to prevent it from crossing the blood-brain barrier [ 15-20]. 

Yoon Y, Chun H, Kim E, Shon J, Bae K, et al. 2002. Genetic and environmental factors influencing on the disposition of digoxin a population pharmacokinetic approach. Clin. Pharmacol. Ther. 71 P73 (Abstr.)... 

One such method was a physiologically based pharmacokinetic approach using the mean total mercury level of 6.8 ppm in maternal hair for the entire Seychellois study cohort. Using the same formula as in the previous MRL calculation,... 

Other, newly identified special populations result from pharmacovigilance signals, unexpected use of the product in an unanticipated population, requirements for regulatory filings in non-ICH nations, or even the spread of disease into new geographical areas. Traditional pharmacokinetic approaches are usually the first step in assessing whether these events will alter product efficacy or safety. 

For a long time classical pharmacokinetic approaches could not be used, because the available analytical techniques were not sensitive enough to measure the low plasma levels in the picogram/mL range often observed after inhalation. However, with the availability of HPLC/MS techniques and their high sensitivity, pharmacokinetic analysis can now be performed for most inhalation drugs. 

Table 3 Questions Relevant for Bioequivalence Studies and Potential for Pharmacokinetic Approaches...

It is possible that for such types of drugs, new pharmacokinetic approaches would have to be derived to correctly describe their behavior in the body, particularly if one is interested in evaluating the degree of tissue targeting. 

Depending on the patient population, intensive plasma sampling schemes like those used in Phase I may or may not be feasible. If intensive sampling is not possible, population pharmacokinetic approaches, which require only a few samples per patient, can be used. ... 

The mqor limitation to all pharmacokinetic approaches such as these relate to the large data requirements needed to solve model parameters. A full solution for a multicompartment model requires a series of repheated expmments using a single chranical applied at different doses and experiments tominated at various time points. As mmtioned, in vitro studies would be conducted to obtain specific biophysical parameter estimates. All data are simultaneously analyzed. For many compounds, specific components of the full model may not be required thus, in reality the actual model fitted is simpler. Statistical algorithms are presently und developmrait to select the optimum model for the specific compound studied and collapse the remainder of the model structure into a matrix from which individual rate parameters... 

Travis CC, White RK, Arms AD. 1989. A physiologically based pharmacokinetic approach for assessing the cancer risk of tetrachloroethylene. In Paustenbach DJ ed. The Risk Assessment of Environmental and Human Health Hazards A Textbook of Case Studies. John Wiley Sons, New York 769-796. 

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