**5.2. Single-ascending-dose studies (SAD)**

Typically, the FIH study is the single-ascending dose study, where small numbers of subjects are dosed carefully with either the drug or placebo, and safety is monitored by recording adverse events, clinical laboratory measurements, vital signs, electrocardiograms, and additional tests depending on concerns raised in the animal studies or from the known pharmacology. Once a small dose is administered and considered to be safe, then a higher dose (typically 2–3 times higher than the starting dose) is administered to a new group of subjects which is then considered before a higher yet dose is given. The escalation schedule for ascending doses needs to be considered carefully, using smaller increments of increase with higher risk drugs, the predicted therapeutic range for the drug, and the levels of exposure where toxicity was seen in animals [30]. Study protocols for drugs considered to be high risk or of narrow therapeutic range may have stopping criteria based on PK as well as safety. Some study protocols will set an upper limit on PK parameters of exposure that are not to be exceeded in the study. The escalation schedule or planned doses may be revised depending upon the outcome of the previously dosed groups. Unexpected toxicity may require lowering the dose and subsequent doses; lower than expected exposure (if assessed before the study finishes) might require increasing the planned doses or accelerating the dose escalation.

The design of the FIH study will incorporate animal data or interspecies scaling predictions to determine when and how long blood (usually plasma or serum) should be sampled for PK measurements. Ideally, to characterize a PK profile, sampling would be optimized 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 bioanalytical method used to measure drug concentrations.

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 revisited in order to achieve target exposures.

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

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

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

**5.1. First in human studies**

**5.2. Single-ascending-dose studies (SAD)**

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.

The main purpose of the first in human clinical study (FIH) for a drug is to test that it is safe, meaning that subjects are monitored for signs of toxicity, especially those indicating risk of mortality or morbidity. Tolerability, the ability of a patient to use the drug for its intended indication, without unacceptable, non-life-threatening adverse events that would require discontinuation of treatment, is also an important consideration. Risk-to-benefit ratios are considered when determining the required tolerability and risks of toxicity; a drug for a life-saving, unmet clinical need, such as cancer, would be considered for approval even if it carries more risk than a drug for a self-limiting or non-life-threatening disease, such as the common cold. From the animal data discussed above, researchers have a good idea of the types of toxicity and at what exposures they may occur for a given drug, yet the first human study is critical in confirming the drug's potential for toxicity in a human. PK in a FIH is therefore very informative, telling us not just if toxicity occurs, but at what exposure that toxicity correlates with.

Typically, the FIH study is the single-ascending dose study, where small numbers of subjects are dosed carefully with either the drug or placebo, and safety is monitored by recording adverse events, clinical laboratory measurements, vital signs, electrocardiograms, and additional tests depending on concerns raised in the animal studies or from the known pharmacology. Once a small dose is administered and considered to be safe, then a higher dose (typically 2–3 times higher than the starting dose) is administered to a new group of subjects which is then considered before a higher yet dose is given. The escalation schedule for ascending doses needs to be considered carefully, using smaller increments of increase with higher risk drugs, the predicted therapeutic range for the drug, and the levels of exposure where toxicity was seen in animals [30]. Study protocols for drugs considered to be high risk or of narrow therapeutic range may have stopping criteria based on PK as well as safety. Some study protocols will set an upper limit on PK parameters of exposure that are not to be exceeded in the study. The escalation schedule or planned doses may be revised depending upon the outcome of the previously dosed groups. Unexpected toxicity may require lowering the dose and subsequent doses; lower than expected exposure (if assessed before the study finishes)

might require increasing the planned doses or accelerating the dose escalation.

The design of the FIH study will incorporate animal data or interspecies scaling predictions to determine when and how long blood (usually plasma or serum) should be sampled for PK measurements. Ideally, to characterize a PK profile, sampling would be optimized 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 target exposures further along in Phases II and III.

**6.1. Food effect studies**

One of the most important PK studies for an orally administered (and sometimes with inhaled drugs where some drug is swallowed) is the food-effect study. An experienced clinical pharmacokineticist will say that the absence of a food effect on the rate or extent of a drug's absorption is rare, and looking at many drugs, most have some difference in absorption between fed and fasted states. Food-effect information is typically not clear from nonclinical studies in most programs, as animals are usually fed ad libitum or on a regular schedule in toxicology studies. A food effect can be somewhat predicted for a specific drug, with knowledge of its solubility, its lipophilicity, and pH dependence on ionization and partitioning, but a human study is required to confirm the extent of the food-effect [34]. Since food in the stomach can affect gastric pH and potentially bind to a drug, and food and/or its fat content can affect gastric emptying time, the probability of some effect on absorption is high. A food effects range from very subtle changes in just Tmax or Cmax, to several-fold increases or decreases in overall exposure, to ultimately where a lipophilic drug might be totally unabsorbed without a minimum of dietary fat. PK parameters, especially Cmax, Tmax, and AUC, can characterize this difference with only a single dose of drug, in a crossover study design, where each subject is administered the drug with and without food. Many drug development programs strive to get this information as early as possible to determine the optimal dosing conditions, and is often part of the SAD, MAD, or SAD/MAD study protocol.

Application of Pharmacokinetics in Early Drug Development

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The purpose of the food-effect PK study is to determine if a difference occurs, and if this difference is clinically significant. If found to be clinically significant, that is that food decreases absorption enough to make it less effective, or that it increases absorption enough to cause toxicity. If the PK shows a clinically significant food effect, adjustment of the therapeutic dose and/or instructions on how the drug should be administered will be included in the approved drug labeling. The type of drug is also important in this decision, as commonly food may delay Tmax and decrease Cmax, but if only the extent of exposure (AUC) is important for the

Once the pharmacokinetic behavior of a drug and its initial safety is confirmed in normal healthy volunteers in the early Phase 1 studies, additional Phase 1 studies are performed to determine if PK differs in various special populations [35]. A simple special population study can be used to bridge the entire drug development program of a drug for one population to apply to another population. An example would be a drug developed in Japanese populations that is then intended to also be marketed in the US. Most small molecule drugs are investigated in subjects with hepatic or renal impairment [36, 37], and depending on the drug's intended use, additional studies in elderly, obese, certain racial/ethnic groups, or others are performed. While safety is monitored in these studies, the PK endpoints allow inference of safety and efficacy that has been determined in previous studies. In other words, if age does not appear to affect the PK of a drug, it is well accepted that the previous safety findings will also likely apply, in general, if the drug is used without regard to age. In hepatic and renal impairment, plasma proteins, such as albumin, can be lower than in healthy subjects, so free drug

drug's efficacy, then the food effect might not be clinically relevant.

**6.2. PK studies in special populations**

**Figure 5.** Single dose and steady-state pharmacokinetics.

It should be noted that the single- and multiple-dose studies are not always run in two separate studies. Depending upon the sponsor, type of drug, its PK qualities, and how much dose-limiting toxicity is expected, these assessments may all be performed under a single study protocol [33]. These studies are termed SAD/MAD studies, and may be designed in two parts, a single-dose and a multiple-dose part to follow when the first is completed or partially completed. Sometimes the study is designed for the sequential groups to get a single dose followed by a washout period where they are monitored, and then the same group will be started on multiple doses at the same level as the first dose for a period of time expected to reach steady state. Safety and or PK is examined for that group, and if deemed safe, then the dose is escalated in the next group.
