**3. Pharmacokinetic analyses**

with hepatic or renal impairment. In these studies, pharmacokinetic endpoints are the primary goal, allowing relatively small studies (low numbers of subjects) to inform the future Phase 2 and 3 studies and marketing after approval. The results of these studies are reflected in the approved drug's labeling, where warnings about the use in certain disease-states or

In Phase 2 studies of clinical drug development, the objective is not only to determine that a drug continues to be safe but that it remains to be safe when used in patients with the disease it is intended for to treat. The information gathered in Phase 2 serves the dual purpose of studying safety and efficacy while providing proof to the sponsor that the drug is worthy of further development. The pivotal Phase 2 study for continuation of Phase 2 and/ or starting Phase 3 is often called 'Proof of Concept (POC).' The value of PK measurements in Phase 2 adds another layer of understanding how the body processes the drug; these studies determine differences in PK data between categories of patients, namely those with the targeted disease and normal healthy volunteers. Sometimes patients will have higher or lower exposures of a drug due to the difference in ability to absorb a drug, or the drug may be eliminated differently due to the disease state. In general, the more the patient is affected/ weakened by the disease, the more PK will differ from healthy subjects. Knowledge of the PK in the patient population forms a bridge to knowledge of safety and perhaps efficacy gathered in Phase 1. Phase 2 PK facilitates any need for dose adjustments to achieve safety or efficacy. PK correlations with efficacy can begin in earnest once patient data is available; this data along with the Phase 1 data is modeled and simulations using those models assist

Phase 3 in clinical drug development consists of several large studies in patient populations designed to collect further safety data, to observe possible adverse events which occur only rarely, to continue to evaluate efficacy and compare with current therapies for the indication, and to guide its use once approved and on the market. However, clinical research does not necessarily come to a halt at the end of Phase 3. After approval and marketing, additional studies may be run by the sponsor to establish marketing claims and to seek new indications. Adverse event data are continually collected to identify even rarer adverse events not uncovered in Phase 3. Phase 3 PK data is usually performed only as a few samples in many subjects or complete profiles in a subset of subjects; this data is for confirmatory purposes, used in correlation with efficacy or adverse events. This data is added to the ongoing modeling (discussed later in Section 3.1) to discern sources of variability in the PK data from the

The above descriptions of each phase of drug development may seem as though each phase precedes sequentially, one starting after the end of the other; however this may not always be the case. While typically the end of Phase 2 commences the beginning of Phase 3, the other phases may overlap in time. This is mainly to conserve research and development resources. For instance, the longer animal studies and reproductive toxicity studies may not run until the results are needed to support the Phase I and II studies for drugs that may require longer treatment durations or research in women of child-bearing potential (WOCBP), respectively

dosage adjustments are communicated.

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

in choosing the Phase 3 dose ranges.

patient population.

Pharmacokinetic analyses types can be broken into two general approaches: compartmental and non-compartmental. Non-compartmental analyses are a series of calculations that estimate the exposures and elimination properties of a drug with very few assumptions about the particular mechanisms involved. Non-compartmental exposure parameters (such as area under the concentration-time curve (AUC) and the maximum exposure (Cmax) can be calculated and are interpretable when no other PK information is available; these parameters indicate the amount of drug in the body and for how long it is there, and the peak concentration that is achieved.

Compartmental methods can be described as the determination of a mathematical expression, or model, which adequately describes the PK of a given drug. On the most basic level, these models consist of the mathematical description representing the body as one or a series of hypothetical volume compartments which drug distributes into and out of, or from which it is eliminated. These models not only describe the PK properties of a drug, but can be predictive of PK at different dose levels or administration conditions. Complex models aid in the elucidation of smaller processes which make up the PK in its entirety, such as the rate and capacity of the different metabolism pathways involved in a drug's elimination.
