Introduction

The role of metabolism and pharmacokinetics, under an industrial context, is to address the question of which compound should be selected for development among multiple candidates and how the compound should be dosed. As a discipline, pharmacokinetics (PK) is the study of what the body does to the drug, that is, the absorption, distribution, metabolism, and excretion (ADME) of the drug, whereas pharmacodynamics (PD) seeks to define what the drug does to the body, that is, the exposure and the response relationship. The integration of PK and PD in drug development from early to late stage can guide the decision-making process on lead generation, optimization, and product realization.

This chapter as outlined above first provides an overview about the value of PK/PD in drug development; second, it discusses the key PK/PD concepts; third, it presents the key PK/PD and metabolism studies in each developmental stage along with case studies; finally, it summarizes the regulatory expectations on PK/PD in drug development.

Pharmacokinetics is a discipline that characterizes the relationship between dose and concentration, whereas pharmaco-dynamics characterizes the relationship between the drug concentrations in either plasma or biophase and drug responses, including both beneficial and adverse effects.

Drug development is a sequential process involving iterative learn and confirm cycles. The strategy of the developmental value chain from discovery to preclinical through phase I to phase III and beyond is to develop and utilize new technologies, in vitro or animal models, that are less expensive and predictive of human pharmacokinetics in vivo and to maximize the information gained in humans to support the drug label. Figure 6.1 provides an overview of the phases of drug development and some of the key outcomes for metabolism and pharmacokinetics (MPK) in the four areas of target and compound selection, safety margin, proof of concept and dose ranging, and confirmation of safety and efficacy. The major responsibility of a drug metabolism and pharmacokinetics function within a pharmaceutical industry is to manage the exposure data generated along the developmental value chain in the four stages of research and development outlined on figure 6.1, each of which will be elucidated further in this chapter. The integration of PD information using biomarkers, surrogate markers, and clinical end points from early stage to late stage represents a more efficient and effective drug development paradigm (i.e., model-based drug development). PK/PD bridging becomes a common approach implemented in many stages or areas of drug development (e.g., bridging preclinical to clinical [allometric scaling], bridging old formulation to new formulation [in vitro-in vivo correlation, or IVIVC], bridging old region to new region, bridging old population [adults] to new population [pediatrics]).

Several abbreviations are presented in this figure and are described below:

Cp: Plasma concentration of a drug Ce: Drug concentration in the effect compartment eC50: Drug concentration that produces 50% of the maximal effect

IC50: Inhibitory drug concentration that produces 50% of the maximal effect MIC: Minimum inhibitory concentration NOAEL: No observed adverse effect level

Pharmacokinetics Pharmacodynamics

Pharmacokinetics Pharmacodynamics

In-vitro/animals Healthy subjects Patients r Target/compound selection c Predictive disease models o Biomarkers identification o Potency evaluation IC50 / EC50/ MIC o Exposure at NOAEL

r Safety margin r o Biomarkers evaIuation o Allometric scaling c PK guided dose increase o IVIVC o Bridging

Proof of concept & dose ranging o Surrogate / clinical endpoint evaluation c Dose selection o Patient variables o Bridging o M&S for trial design

Confirmation of efficacy & safety o Population

PK/PD c Special populations c Dose optimization c Bridging

In-vitro/animals Healthy subjects Patients r Target/compound selection c Predictive disease models o Biomarkers identification o Potency evaluation IC50 / EC50/ MIC o Exposure at NOAEL

r Safety margin r o Biomarkers evaIuation o Allometric scaling c PK guided dose increase o IVIVC o Bridging

Proof of concept & dose ranging o Surrogate / clinical endpoint evaluation c Dose selection o Patient variables o Bridging o M&S for trial design

Patients

Confirmation of efficacy & safety o Population

PK/PD c Special populations c Dose optimization c Bridging

Fig. 6.1. Introduction of PK/PD-Timeline/Roles

Absorption

Types of experiments

Physiological relevance

Solubility & permeability

Effect of transporters

BCS & in-vitro in-vivo correlation

Absolute / relative BA & BE

Food / beverage effect

> Can drug reach the blood circulation?

> Formulation screening

> Food /beverage interaction o Tissue penetration & kinetics

Distribution ° Tissue & plasma protein binding o QWBA in albino & pigmented rats o Comparing calculated Vd term to physiological Vol.

> Can drug reach the site of action?

> Protein binding displacement

> Site - specific toxicological concerns

Fig. 6.2. Absorption, Distribution, Metabolism & Elimination (ADME) -1

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