Era of Pharmacokinetic Studies

The modern era of drug development related to clinical pharmacology studies may be thought to have begun in the 1970s. A key component was the development of bioanalytical methods needed to accurately detect plasma concentrations of administered drugs. This aspect has continued to improve until it is now possible to measure plasma levels for nearly every drug under development. This is an important factor in the study of the relationships of dose, exposure, and effect.

An important regulatory milestone was the creation of the distinct Human Pharmacokinetics and Bioavailability Section of NDAs [24]. This established a section in each NDA in which are contained all clinical pharmacology and biopharmaceutics studies. Prior to what is called the NDA rewrite, NDAs were not very consistent in content, and information to be included was not very precisely defined or well organized. When this Format and Content Guideline was first introduced in 1987, the types of studies were identified as:

• Pilot or background studies carried out in a small number of subjects as a preliminary assessment of ADME.

• Pharmacokinetic studies.

• Other in vivo studies such as those using pharmacological or clinical endpoints in humans or animals.

• In vitro studies such as dissolution and protein binding studies.

While the original focus was on in vivo studies in healthy subjects, this has expanded to include plasma sampling in patients as part of population pharmacokinetic studies, exposure response studies and pharmacokinetic/ pharmacodynamic studies.

There are numerous types of clinical pharmacology studies conducted during the development of a new drug. These include both studies on healthy subjects without the disease intended for treatment (Phase I) and studies involving patients (Phase II and III).

Studies in healthy subjects primarily focus on safety aspects of the drug, in establishing dose-toxicity relationships. These studies also investigate the pharmacokinetics for the drug under development, dose proportionality, absolute bioavailability, mass balance, effect of food, different formulations, as well as special populations.

Studies conducted in patients primarily relate to establishing efficacy and dose/response. In addition, optimal dosing interval, effect of severity of disease, tolerance, and adverse reactions are determined.

One significant example from this era involved a once-a-day extended release theophylline product which was shown to have a significant change in bioavailability when administered with a high fat meal. This important safety information resulted in the following precaution being added to the product's labeling:

Drug/Food Interactions Taking (this product) less than one hour before a high-fat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20mcg/mL level, above which theophylline toxicity is more likely to occur.

A CDER Guidance [25] is available which describes current recommendations related to food effect studies and labeling based upon the results of such studies. Drug administration relative to meals is sometimes of great importance. The labeling for atovaqone serves to illustrate a situation where drug must be taken with food for optimal efficacy:

Failure to administer (atovaquone) with meals may result in lower plasma atovaquone concentrations and may limit response to therapy.

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