Clinical Pharmacokinetics University of Nizwa College of Pharmacy and Nursing School of Pharmacy Clinical Pharmacokinetics PHCY 350 Lecture-16 Prediction and Refinement of Human Kinetics from In Vitro, Preclinical and Early Clinical Data Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outline Upon completion of this lecture the students will be able to describe the role of micro dosing in clinical studies, explain the integration between human specific data gained from in-vitro system, compare the data obtained with virtual patient populations.

Allometry is the study of relationship between the size of the body and its component parts and functions. Microdosing uses human model. Its demand is greatest for compounds that exhibit linearity over therapeutic dose range. Involves administration of a minute dose (microdose) intended not to produce any pharmacologic response, followed by linear scaling of the resultant pharmacokinetic data to pharmacologic doses.

Whole body Physiologic Models There is lack of integration between human specific data gained from in-vitro hepatocyte (metabolism) or intestinal (absorption) systems, into scaled animal plasma data to better predict human profiles. Whole body physiologic model comprising organs connected to each other via the recirculating vasculature (arteries and veins). Some organs like GI and liver are in series, whereas most tissues are in parallel with drug entering via arterial supply and leaving via vein.

Q= blood flow to a tissue Qca=Cardiac output Flows to organs denoted by first two letters of the organ, except ha and hv=flows in hepatic artery and hepatic vein

Moving to Virtual Patient Populations In clinical practice, factors like age, disease, genetics, gender, concomitant drugs, herbal preparations, diet, dosage form and smoking, produce limitless collection of pharmacokinetic summary so that no individuals are likely to have identical profile. In an individual, the pharmacokinetic profile of a drug constantly change from time to time.

Scenario A drug is under development for treatment of diabetes mellitus. Based on combination of in vitro data and observations in various early clinical studies in young adults, the drug is known to have good oral bioavailability and to be eliminated predominantly by CYP3A4 metabolism with some renal excretion. The kinetics of the drug appears to be linear with wide dose range. The two major metabolites are inactive.

Multiple dosing studies demonstrate that efficacy is best correlated with AUC(0-24hr) at plateau. The therapeutic window lies in the range of 1 to 5mg-hr/L. Based on this information, together with pharmacokinetics of the drug in typical patient population and knowing that CYP3A4 in any patient cannot be reliably predicted, the decision is to market three dose strengths, namely 5,10 and 20 mg. Also to recommend that patients be started with 5 mg and titrated upward based on response.