Pharmacokinetics study design

Pharmacokinetic studies are designed to measure quantitatively the rate of uptake and metaboHsm of a material and determine the absorbed dose to determine the distribution of absorbed material and its metaboHtes among body fluids and tissues, and their rate of accumulation and efflux from the tissues and body fluids to determine the routes and relative rates of excretion of test material and metaboHtes and to determine the potential for binding to macromolecular and ceUular stmctures. 

Pharmacokinetic studies should allow an assessment of the relationship between the environmental-exposure conditions and the absorbed dose, and how these influence the doses of test material and metaboHtes received by various body tissues and fluids, and the potential for storage. Numerous texts are available on the design and conduct of metaboHsm and pharmacokinetic studies (117—119). 

Gieschke R, Reigner BG, Steimer JL. Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling. Int J Clin Pharmacol Ther 1997 35 469-74. 

In a study designed to gather pharmacokinetic data, two healthy human volunteers were exposed to HFC-134a at 4,000 ppm delivered via a mouthpiece (Vinegar et al. 1997). The exposures were scheduled to last for 30 min. Blood samples were collected throughout the exposures. The exposures were abruptly terminated following an unexpected and uncontrollable rise in pulse rate in one subject and a drop in pulse rate and blood pressure and loss of consciousness in the second. This vasovagal response is sometimes observed... 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

Use of Data from Metabolism and Pharmacokinetic Studies. Information from metabolism and pharmacokinetic studies can be used in the design and analysis of data from other toxicity studies. Some examples are described below. 

It should be noted that in both guidances BCS-based biowaivers do not apply to food effect BA studies or pharmacokinetic studies other than those designed to test for BE. 

The design of pharmacokinetic studies that need to be conducted for product approval is a function of how much is known about the active drug moiety, its clinical pharmacokinetics, and the biopharmaceutical properties of the dosage form, and regulatory requirements. As a minimum,... 

Costs are approximate (as of 2(X)2) and assume oral (gavage) administration and include costs of assay to confirm dose concentration and bioassay of pharmacokinetic samples. Significant variations for the same study design will be found between different contractors ( 20%), different study designs ( 25%) and different routes of administration (intravenous 25%, inhalation by snout only + 50-100%). 

Q takes into account, where appropriate, fhe inclusion in the study design of sufficient animals to study recovery and pharmacokinetics, the projected mean body weight of the animals over the study and a 20% contingency for unexpected losses, etc. 

A comprehensive knowledge of all the preclin-ical information about a compound is an essential requirement for the safe conduct of the first study in man. Toxicology, metabolism, pharmacokinetics and pharmacodynamics are all important despite their limited predictive power for man. As explained above, the study design must take the findings into account. 

FDA Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function Study Design, Data Analysis and Impact on Dosing and Labelling. Rockville, MD FDA, 1999. 

The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug s safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects. 

For the majority of these multicomponent mixtures, the active constituents are often unknown. In other words, a substance that is detectable in body fluids is not necessarily the active compound of an extract. Further, the different compounds will have a different bioavailability, thereby complicating the design of pharmacokinetic studies with HMPs. Natural compounds are often prodrugs that are metabolized in the digestive tract. Moreover, HMPs can contain large polar molecules that might be expected to have poor and unpredictable bioavailability (7). 

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