Pharmacokinetic Pharmacodynamic and Dose Response Considerations

Evaluation of the pharmacokinetics and pharmacodynamics, and their comparability, in the three major racial groups most relevant to the ICH regions (Asian, Black, and Caucasian) is critical to the registration of medicines in the ICH regions. Basic pharmacokinetic evaluation should characterize absorption, distribution, metabolism, excretion (ADME), and where appropriate, food-drug and drug-drug interactions. Adequate pharmacokinetic comparison between populations of different regions allows rational consideration of what kinds of further pharmacodynamic and clinical studies (bridging studies) are needed for the new region. In contrast to the pharmacokinetics of a medication, where differences between populations may be attributed primarily to intrinsic ethnic factors and are readily identified, the pharmacodynamic response (clinical effectiveness, safety, and dose-response) may be influenced by both intrinsic and extrinsic ethnic factors and this may be difficult to identify except by conducting clinical studies in the new region.

In general, dose-response (or concentration-response) should be evaluated for both pharmacologic effect (where one is considered pertinent) and clinical endpoints in a new foreign region. The pharmacologic effect, including dose-response, may also be evaluated in the foreign region in a population representative of the new region.

Depending on the situation, data on clinical efficacy and doseresponse in the new region may or may not be needed, e.g., if the drug class is familiar and the pharmacologic effect is closely linked to clinical effectiveness and dose-response, the foreign pharmacodynamic data may be a sufficient basis for approval and clinical endpoint and dose-response data may not be needed in the new region. The pharmacodynamic evaluation, and possible clinical evaluation (including dose-response), is important because of the possibility that the response curve may be shifted in a new population.

Examples of this are well documented, e.g., the decreased response in blood pressure of blacks to angiotensin-converting enzyme inhibitors.

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