**5. Early clinical studies with primary endpoints of safety**

Earlier this chapter described the primary objective of Phase I as determining safety in a small number of subjects before the introduction of the drug into patients. This remains true, but for the purposes of this chapter, Phase I studies will be described as studies whereby safety measurements are the primary endpoint (or finding) and where primary endpoints are PK-related.

to capture absorption rates, peak concentrations, distribution and elimination phases, and would minimally be 2–3 times the elimination half-life, preferably 4–5 times the elimination half-life. Sometimes at lower dose levels this is difficult due to the limitation of the bioana-

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When PK information is needed for dose escalation a common practice is to perform interim PK analyses as the study progresses, where the PK is examined in one group before proceeding to the next higher dose level group. This is a time sensitive process where careful planning with logistics between the clinic conducting the study, sample shipment, the laboratory analyzing the samples, the scientist performing the PK calculations, and sometimes a data safety monitoring board (DSMB) who will review the data and make a determination along with the sponsor and principal investigator in charge of clinic conduct. Once at least two dose levels have been administered, the scientist will use the data obtained to date in order to determine if the increase in exposure is proportional to the increase in dose (dose proportionality) and if so to predict what exposures might be at the next dose level, given that dose proportionality continues to the next dose. If dose proportionality is not seen (the PK may be described as 'nonlinear') [31], and the increase is higher than proportional to the increase in dose, escalation to higher dose levels should proceed with caution, as saturation of a metabolic or elimination pathway could lead to sharp increases in PK concentrations with only a small increase in dose. If PK concentrations are less than proportional to the increase in dose, indicating a saturation in the absorption process, then the dose escalation schedule may need to be revis-

PK information gained in the single-ascending dose assessment of a drug development program is used further in the design of the next clinical study, which for most drugs is the multiple-ascending dose study. Because most drugs need to be given repeatedly over time, safety information for continuous use is needed. In this study, the drug is administered for the number of doses required (based on the single-dose PK) to reach steady-state levels, the highest exposure a given drug regimen will achieve, where the given drug exhibits first-order elimination (**Figure 5**). Again, the main purpose of the study is to determine safety at maximum exposures, but PK at these exposures is applicable to the design of the next study in the drug development program. Steady-state levels depend upon the half-life, the dose, and how often the drug is given (also called the frequency of administration). If PK properties after a single dose are known, then the number of repeated doses given at equal intervals for a duration of approximately 5 times the half-life will reach predictable steady-state levels. Confirmation of steady-state in this type of study is usually assessed by determining if trough (predose) concentrations for the last few doses are approaching a constant value; [32] this also helps confirm that the half-life observed after single doses was based upon the elimination phase, that the PK is indeed first order, and is or is not 'linear' over time. Linear or nonlinear, the single- and multiple-dose studies in Phase I not only determine safety at a certain exposure, but the relationship of dose to exposure, leading to predictability to adequately achieve

lytical method used to measure drug concentrations.

ited in order to achieve target exposures.

**5.3. Multiple-ascending-dose studies (MAD)**

target exposures further along in Phases II and III.
