Clinical Pharmacokinetics University of Nizwa College of Pharmacy and Nursing School of Pharmacy Clinical Pharmacokinetics PHCY 350 Lecture-10 Individualization of Drug Treatment Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Identify causes of individual variability in drug response, Describe the impact of genetics and inherited variations, age, weight and gender differences observed in pharmacokinetics of drugs

Variability Significant differences in response to drugs commonly exists among patients (interindividual variability). Eg. Diazepam used in management of some anxiety disorders is marketed as 2-,5-, and 10-mg tablets. Intraindividual variability in drug response within a patient from one occasion to another is generally smaller than interindividual variability (less need of adjustment). The characterization of pharmacokinetic variability within the population is called population pharmacokinetics. The variability in drug response is not only with therapeutic efficacy of the drug but also applies to adverse effects.

Why people differ? The reasons why people differ in drug response to a drug includes genetics, age, gender, body weight, disease, drugs given concomitantly and various behavioral and environmental factors. Gender linked differences in hormonal balance, body composition and activity of certain enzymes evident in both pharmacokinetics and responses. Disease can be added source of variation in drug response. Greater modifications in dose is needed in renal and hepatic disorders. Dose adjustments needed in patients with congestive cardiac failure, thyroid disorders, gastrointestinal disorders and other diseases.

Eg. To prevent excessive accumulation and so reduce the risk of toxicity, the dosage of gentamycin used to treat a pleural infection of a patient must be reduced if the patient is renally compromised (major route of elimination). Patients with hyperthyroidism requires higher than usual doses of digoxin, a drug used to decrease likelihood of atrial fibrillation.

Factors that contribute to Variability in Drug Response Lack of adherence to and persistence in taking a dosage regimen. Major problem in clinical practice that needs patient motivation. Route of Administration Speed of absorption and bioavailability is route dependent. Food and Diet High fat meal slows gastric emptying Severe protein restriction reduce rate of drug metabolism, increases urine pH, which will affect renal clearance of pH sensitive drugs. Constituents in grape fruit juice are inhibitors of intestinal CYP3A4.

Factors that contribute to Variability in Drug Response Herbs Constituents can enhance or antagonize effects of drugs or act as inhibitors or inducers of drug metabolizing enzymes. Pollutants Drug effects less in smokers and pesticide exposed workers due to enhanced metabolism by CYP1A2. Time of day and season High morning time risk of angina, MI and stroke

Tissue weight, composition, blood flow Tissue enzyme activity Disease Age Genetics Tissue weight, composition, blood flow Tissue enzyme activity Tissue transporter activity Renal and biliary function Gastrointestinal function Gender Formulation Co medication Environment Diet/Nutrition Smoking Pharmacokinetics

Genetics Pharmacogenetics is the study of inherited variations in drug response. Pharmacogenomics is the application of genomic information to the identification of recognized drug targets and to the causes of variability in drug response. Basic biological unit of heredity is the gene. Genotype is the fundamental group of genes of an individual, the blueprint. Phenotype is the outward characteristic expression of an individual, such as the color of one’s eyes. Human genome comprises over 1.5 million single-nucleotide polymorphisms (SNPs), locations along DNA where a difference exists among individuals in the nucleotide.

Single-Nucleotide Polymorphisms (SNPs), DNA molecule 1 differs from DNA molecule 2 at a single base-pair location (a C/T polymorphism).

Genetic Polymorphism is defined clinically as the condition in which frequency of the variant occurs in greater than 1% of the population. This categorizes separate groups within population termed poor metabolizers. Some are grouped as extensive metabolizers, some are ultrafast metabolizers, because they possess up to 13 copies of the normal gene (wildtype) within the population. Enzyme (Phase-1 Reactions) Frequency of Poor Metabolizer status Drug Substrates CYP2D6 5-10% Caucasians, 3.8% African Americans, 0.9% Asians, 1% Arabs Codeine, flecainide, encainide, metoprolol, nortriptyline, timolol CYP2C9 1-3% Caucasians Celecoxib, fluvastatin, glyburide, phenytoin, tolbutamide, S-ibuprofen CYP2C19 3-5% Caucasians 16% Asians Diazepam, lansoprazole, omeprazole

Age, Weight and Gender Aging, characterized by periods of growth, development is a source of variability in drug response. As a result the usual adult dosage regimen may need to be modified to achieve optimal therapy, particularly in young and the old. Age of typical patient vary with drug and the indication of its use. Some diseases like heart failure, HTN,diabtes,arthritis and cancer more common among elderly. Others like asthma, back problems, eplilepsy and migraine may occur at any age groups. Hay fever, cystic fibrosis occur in childhood or early adulthood. Gender specific diseases are benign prostatic hyperplasia, breast cancer, prostate cancer and testicular cancer.

Diseases Major Source of variability in drug response due to differences in pharmacokinetics. Concurrent diseases such as hepatic cirrhosis, congestive cardiac failure and renal function impairment can alter dosage requirements. Hemodialysis and related procedures in end-stage renal disease also removes drugs and may require adjustment of drug administration.