Clinical Pharmacokinetics University of Nizwa College of Pharmacy and Nursing School of Pharmacy Clinical Pharmacokinetics PHCY 350 Lecture-13 PHARMACOKINETIC ALTERATIONS IN OBESITY 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 differentiate over weight and obesity and its effects in disposition of drugs, classify body size and weight descriptors, the pharmacokinetics in an obese patient and to estimate drug clearance in obese individuals.

WHO Definitions Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A crude population measure of obesity is the body mass index (BMI), a person’s weight (in kilograms) divided by the square of his or her height (in meters). A person with a BMI of 30 or more is generally considered obese. A person with a BMI equal to or more than 25 is considered overweight.

They are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases and cancer. Obesity alters the disposition of drugs in the body (pharmacokinetics), which should be considered when prescribing medications in this patient population. Failure to adjust doses in obesity may result either in therapeutic failure or increased toxicity.

Classifications of Body Size – Weight Descriptors Body Mass Index (BMI) Obesity is defined by the CDC as a BMI of >30 kg/m2, and morbid obesity is defined as a BMI of >40 kg/m2. Body Surface Area (BSA): BSA is also a classification of body size. Calculating Body Surface Area involves the use of body weight and height. Two formulas are commonly used to calculate body surface area: (1). DuBois equation (2). Mosteller equation

Ideal Body Weight (IBW): These equations are the most commonly used today for dosing of specific medications such as acyclovir, Gentamycin, Digoxin and Theophylline. Men: Ideal Body Weight (in kilograms) = 50 + 2.3 kg per inch over 5 feet. Women: Ideal Body Weight (in kilograms) = 45.5 + 2.3 kg per inch over 5 feet.

Lean Body Weight (LBW): Use of Lean Body Weight is also recommended for dosage calculation of some drugs. Men: Lean Body Weight = [1.10 x ABW (kg)] – [120 X ABW (kg) / Height (cm2)] Women: Lean Body Weight = [1.07 x ABW (kg)] – [148 X ABW (kg) / Height (cm2)] Some medications may incompletely distributed into adipose tissue and require an adjusted weight for more accurate dosing. Lean Body Mass refers to the weight of bones, muscles, tendons and organs minus body fat. An adjusted, or dosing weight, is calculated to account for obese patients exceeding >125% of their ideal body weight.

Dosing weight=DWCF × (ABW–IBW) + IBW When dosing certain medications such as aminoglycosides, a dosing weight correction factor (DWCF) is used to account for increased body weight. It appears that fat distribution of aminoglycosides is incomplete, and 40% of the drug is estimated to distribute into adipose tissue. This explains why a dosing weight correction factor of 0.4 generally is used for all aminoglycosides dosing in obesity. Dosing weight=DWCF × (ABW–IBW) + IBW ABW=actual body weight, IBW=ideal body weight.

Absorption Changes in absorption would be predicted in obesity due to increased body surface area and increased cardiac output. This can lead to increased gut perfusion. There is no difference when comparing drug absorption in obese versus non obese patients.

Distribution The volume of distribution (Vd) of drugs may be altered in obese patients. Obesity results in increased adipose tissue mass, which can influence medications with lipophilic properties. Increased organ mass, lean body mass, and blood volume in obesity also can affect hydrophilic medications. The result of these physiologic changes in obesity can influence the volume of distribution of medications, potentially leading to sub- or supra-therapeutic concentrations.

Aminoglycosides are hydrophilic antibiotics commonly used for compound extremity fractures, osteomyelitis, and severe soft-tissue infections. The need for dosing adjustment in obesity has been established in Gentamycin, Tobramycin, and Amikacin. Aminoglycosides distribute primarily into the intravascular space and only moderately into the interstitial space. Therefore, aminoglycosides typically display a slightly larger volume of distribution (in liters) in obese patients than in lean patients. To prevent overdosing of aminoglycosides in obesity, a dosing weight correction factor of 0.4 is used to account for the altered volume of distribution.

Metabolism Changes in hepatic clearance of various medications may be due to alterations in Phase I (oxidation, reduction, and hydrolysis) and Phase II (conjugation by sulfation or glucuronidation) reactions within the liver. Antibiotics including Clindamycin and Metronidazole are metabolized via Phase I reactions and may be affected by obesity. Obesity also has been shown to increase Phase II drug biotransformation. Medications including Lorazepam and Oxazepam are metabolized by conjugation. Increased metabolism of these medications may result in suboptimal serum concentrations in obesity, which may lead to inadequate sedation.

Elimination Glomerular filtration rate (GFR) can be estimated by calculating the creatinine clearance (ClCr) to predict drug elimination. The clearance of many renally eliminated drugs correlates with ClCr. The Salazar-Corcoran equation takes into account multiple factors to provide a better estimation of ClCr in obesity including serum creatinine, gender, actual weight, age, and height.