**7. Summary**

concentrations are often examined to determine if any PK differences are related to the differences in binding, or if increased free drug concentrations might result in any drug effect differences [38]. These studies are often single-dose PK studies in the special group and in healthy volunteers of similar demographics. PK parameters of exposure are key in the between-group

As mentioned previously, nonclinical studies are key in screening a drug for potential drug– drug interactions (DDIs). Once the cytochrome P450 enzymes and transporters for which a new drug is a substrate, an inhibitor, or can induce expression, are identified, clinical studies are performed to confirm, quantitate, and determine clinical significance of any DDI. It would be tedious and cost prohibitive to test every possible DDI, so appropriate probes [39] (other drugs which are known CYP or transporter substrates, inhibitors, or inducers) are chosen to be co-administered and PK measured to determine if a clinically relevant DDI through a specific metabolism or transporter pathway exists [40]. Without PK measurements in this type study, it would take large numbers of subjects to study a drug–drug interaction with safety endpoints only, however with PK, a small number of subjects' exposures to one or both drugs can determine if there is a safety risk by examining previous PK measurements and correlated safety findings. These study designs may differ depending upon the potential interaction, but usually the drug under development is dosed to steady-state at a therapeutic dose. Often these studies are conducted with 12–24 healthy subjects confined to a research clinic, and consist of a fixed treatment sequence for all subjects. An example of a common design would be where the probe drug is administered alone, followed by a washout period, then the multiple doses of the investigational drug are given until steady-state levels are reached, then the probe drug is co-administered. PK of the probe drug is measured to determine if the PK is affected. The sequence could be reversed if the investigational drug is hypothesized to be affected by the probe drug. Two-way DDI designs are also used to determine the two drugs affect each other. The primary PK endpoints are generally Cmax and AUCs to determine if peak or overall exposure differ due to a DDI, but Tmax and elimination rates are helpful in determining if the mechanism is due to decreased metabolism or a change in absorption.

Interpretation of the PK data for these studies is often straightforward; if a DDI increases exposure of a drug, depending upon its safety profile, to a degree that toxicity could develop, or decreases exposure enough that efficacy would be lost, then warnings will be issued in the approved labeling. Occasionally unexpected results in these studies are seen such that relating the results to specific enzymes or transporters becomes difficult, especially when multiple enzymes or unknown transporters are involved. In such instances, the characterization of DDIs helps in the design of Phase 2 and 3 studies where a study protocol excludes patients

A concern for a small molecule drug in development is the question of whether the drug is readily removed from the body completely, and how that complete elimination occurs. Less

taking certain medications, and allow the safe investigation in patient populations.

comparisons; however, elimination rates and absorption rates are also important.

70 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

**6.3. Drug-Drug interaction studies**

**6.4. Radiolabeled drug studies**

The above overview has shown that pharmacokinetics is an integral part of drug development, and a critical part of early drug development. At the beginning of Phase 1 in the development program only animal data is available; hence, what is known through pharmacokinetic measurements in those animal studies is applied in designing Phase 1 human studies. This chapter outlined the importance of pharmacokinetic data in drug development overall and in specific types of early clinical studies. The PK measurements in the FIH study provide confirmation of safety at the measured exposures from the tested dose levels. Even if exposures from a given dose change due to food-effects, drug–drug interaction, drug-disease interactions, or use in a special population, safety can be associated and risks assessed by bridging these results to the initial safety or efficacy exposures. Throughout the drug development program, pharmacokinetics is a tool used to link exposure to efficacy and safety, and it assists in the determination of dosages of marketed drugs; for this reason, PK data are an important part of the information provided to clinicians.
