How do drugs move through the animal (Proceedings)

Concepts

In most cases, we administer drugs at a different site than we want to drug to act. Understanding how drugs get to their site of action and how long they stay there is essential to making therapeutic decisions about which drug, what route, how much, how often, and for how long.

We most commonly measure the concentrations of drug in the plasma or serum, even though many of our target cells for drug activity are outside the plasma. This is based on the assumption that plasma concentrations correlate with tissue concentrations, so conclusions about tissue concentration can be made from plasma concentrations. This may not be true for all drugs, but it holds true for enough important compounds that it is a reasonable assumption until demonstrated to be untrue for a particular compound.

Simulated graphs are presented below to demonstrate the effects of changes that impact drug movement. These simulations were performed at the website of David Bourne, http://www.boomer.org/c/php/pk1701.php.

Absorption

Absorption is sometimes defined as the proportion of drug moving from the administered drug product into the bloodstream. Drugs administered IV are assumed to be 100% absorbed by definition. For drugs administered PO, major losses of drug occur at enterocyte membranes in the GI tract, via metabolism in the gut wall (e.g., peptidases), and via metabolism in the liver (since drug absorbed from the GI tract enters portal circulation first and can therefore bring drug into contact with enzymes in hepatocytes before it enters peripheral circulation). Absorption rate can be indicated by the half-life of absorption, sometimes designated as t½.

A simulation of serum concentrations is presented in the graph below, in which the only difference between the two lines is a doubling of the absorption rate. This results in a higher Cmax, as well as a shorter time above any given concentration (once absorption is mostly completed).

Distribution

Distribution refers to the movement of drug from the bloodstream into the interstitial fluid and other tissues. The mathematical parameter usually used to describe distribution is the volume of distribution (V or Vd or VDss). The volume of distribution can be defined as the apparent volume of fluid needed to contain the total amount of a drug in the body at the same concentration as it is in the plasma. It is an indication of whether drug tends to remain in the vascular system, in total body water, or in tissues.

A simulation of serum concentration is shown below, in which the only difference between the two lines is a doubling of the volume of distribution. In this case, a higher volume of distribution results in a lower peak concentration and lower concentrations throughout the time course.

Metabolism

Metabolism may change pro-drug to active drug, active drug to active metabolite, or active drug to inactive metabolite. A basic understanding of how a drug is metabolized (or if a drug is metabolized) will aid in clinical decision-making in cases in which mechanisms of metabolism are compromised because of disease. Active metabolites should also be considered when examining drug concentration data, since graphs of concentration data may be misleading if they do not contain parent drug and active metabolite.

Elimination

Elimination generally refers to elimination from plasma or serum, and the rate of elimination is designated as ka. Elimination half-life is the time taken for the serum concentration to drop by half, and is often designated as t½ . For the most part, it is assumed that the drugs we use regularly for therapeutic purposes follow first order elimination. This means that a constant proportion of drug is removed from the body per unit time. There are some exceptions, in which a constant amount of drug is removed from the body per unit time, designated zero order. Zero order elimination generally occurs when clearance mechanisms have become saturated, so zero order kinetics are more often seen with toxic doses of drug.

A simulation of serum concentrations in which the elimination rate is doubled is presented below. When elimination rate is increased, overall concentrations are lower as is the peak concentration.

A simulation of serum concentrations is presented below, in which the only difference between the lines is a doubling of the dose administered. Careful examination of the graph reveals that the peak concentration in the curve representing the doubled dose is twice that of the lower dose, and the time that concentrations remain above a particular level are moved over one

half-life (in this case half-life was set at 1.7 hours).

Mathematical Descriptions

To be complete, we should briefly discuss how pharmacokineticists generate mathematical descriptions of drug movement to allow for predictions and to explain drug behavior and clinical effects. The major methods of mathematical modeling of drug concentration data include compartmental and non-compartment modeling. Compartmental modeling is used to mathematically describe drug movement under particular assumptions about how drugs act; the compartments assumed are not anatomical compartments but rather are artificial methods to describe rates of drug movement. Non-compartmental modeling is based on statistical moment theory, which makes no assumption about how drugs move but rather assumes the drug concentrations at a given time point are independent and can therefore be modeled in a stochastic manner. Regardless of how modeling and mathematically descriptions are performed, the goal is to explain why drug is moving in a particular way and to make predictions about drug movement.

Clinical Importance of Concepts

Mathematical descriptions of drug movement may be interesting to pharmacologists and pharmacokineticists, but may not seem useful at the clinical level. What is useful is to understand the implications of those mathematical descriptions in terms of drug selection and dosage and regimen design.

Withdrawal Time Determination

Withdrawal time determination refers to establishing the amount of time after treatment that an animal or its products must be kept from entering the food supply. There are several different ways of establishing a withdrawal time: the regulatory agency determination for a drug approval, the methods the Food Animal Drug Avoidance Databank uses to estimate a withdrawal time for a drug used in an extralabel manner, and the method a practitioner might use to estimate withdrawal time for a drug used in an extralabel manner when information from FARAD is not available.

How FDA Does it

The guidelines for industry to use in establishing withdrawal times are contained in Guidance For Industry #3 from the FDA Center for Veterinary Medicine (http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052180.pdf). This guidance outlines the studies required for determining the NOEL or "no observed effect level" of a drug (a measure of toxicity), which is the amount of drug expected to cause no harm if ingested. This number is then divided by a safety factor to determine the acceptable daily intake (ADI) of a drug. A safe concentration of drug in edible tissues is then determined by multiplying ADI by the average weight of an adult, and dividing by the FDA's estimate of grams of edible product consumed per day by the average adult. The ADI may be partitioned among milk and meat for product approved for lactating animals, so that usually ½ the daily intake is allowed in milk and ½ in meat. Current assumptions are that an adult consume 300 g muscle, 100 g liver, 50 g kidney, 50 g fat, 1.5 L milk, and 100 g eggs.

Once a safe concentration is established, studies are performed to evaluate tissue concentrations of drug in animals over time. The typical study would include 20 animals, with 5 animals being slaughtered at 4 different time points. A straight line is then fitted to the resulting concentration-time curve, and the time point at which the tissue concentration will be below the safe concentration for 99% of animals with 95% confidence is calculated.

How FARAD Does it

The Food Animal Residue Avoidance Databank uses published data and proprietary industry data to calculate estimated withdrawal times for products use in an extralabel manner in several ways. If a drug is approved in another country for the required indication and at the required dose, these withdrawal times can be adjusted to reflect safe concentrations allowed by the US. Data can be analyzed to estimate withdrawal times based on expected elimination half-lives from multiple sources by meta-analysis (statistically validated methods of combining data from multiple sources), based on allometric scaling from one species to another,

FARAD has periodically published FARAD Digests in the Journal of the Veterinary Medical Association, and practitioners are advised to get copies of these articles for their resources (see table below for citations). These Digests represent FARAD's best estimates of withdrawal times for commonly used drugs in food animal practice.

How a Practitioner Can Do it

Practitioners are advised to estimate withdrawal times on their own only if there are no other sources of information. A pharmacokinetic rule of thumb is that 99.9% of drug will be eliminated after 10 half-lives. If the half-life is calculated from serum concentration data, then 99.9% of drug will be eliminated from the serum after 10 serum half-lives. This is an important point, since tissue residues at slaughter are determined in muscle, liver, fat, kidney or other tissues, whereas elimination half-lives are often based on plasma data. If the elimination half-life is different in tissues than it is in plasma, then the 10 half-life rule may not be valid. In addition, even if 99.9% of drug is eliminated, there may still be enough drug to cause a violation, particularly if the drug is not approved in the food animal species being treated. And finally, pharmacokinetic parameters are often measured in healthy animals and in animals that may be different physiologically than the animals being treated. Therefore, the elimination half-life use for the calculation may not reflect the actual elimination rate in the particular animal being treated.

References

Brunton, LL, Lazo, JS, and Parker, KL, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th edition, McGraw-Hill, 2006

Riviere JE, Webb AI, Craigmill AL. Primer on estimating withdrawal times after extralabel drug use., J Am Vet Med Assoc. 1998 Oct 1;213(7):966-8.