The clinical use of drugs is becoming increasingly more complex. An understanding of the relationship between the administered dose of a drug, the resulting concentration, and its biologic effect will facilitate the rational use of drug therapy. The study of pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) is the basis of pharmacotherapy (treating disease with medications). The purpose of this article is to provide a brief introduction to pharmacokinetics.

Defining Pharmacokinetics
Pharmacokinetics describes the time course of the drug concentration from a particular dosage regimen. It can tell us how much of a drug and how often it must be given to attain the desired drug concentration. Pharmacokinetics can be divided into four basic categories: Absorption, Distribution, Metabolism, and Excretion. This is commonly referred to as the ADME scheme. Absorption is the process by which a drug enters the body, and is often quantified by the pharmacokinetic parameter, bioavailability (F). Distribution refers to how the drug disperses throughout the body, and is usually expressed as the apparent volume of distribution (Vd). Metabolism is the biotransformation of drugs to forms that can be more readily excreted from the body. Excretion is the elimination of drug from the body, and can be described by the pharmacokinetic parameter, clearance. Table 1 describes some of the common pharmacokinetic parameters.


Oral bioavailability (F). The oral bioavailability is the fraction or percentage of the dose that reaches systemic circulation after oral administration. Factors that can alter the bioavailability include the dosage form (e.g., capsule, tablet), the chemical form of the drug (i.e., salt or ester form of the drug), the extent of metabolism before reaching systemic circulation (e.g., first pass effect, where drugs are metabolized in the gastrointestinal tract following absorption), and the absorption and dissolution characteristics of the drug itself.

Volume of distribution (Vd). The volume of distribution, also known as the “apparent volume of distribution,” quantifies how the drug disperses throughout the body. It can be expressed by the following equation:




A drug with a Vd greater than 3 liters (average adult plasma volume) indicates that the drug distributes to the tissues and outside the plasma compartment.

Half-life (t1/2). The half-life quantifies the amount of time that it takes for the plasma concentration or the amount in the body to decrease by one-half. The half-life provides information about the disposition of the drug. For example, it can be used to estimate the time it takes to achieve steady state, where the rate of drug administration equals the rate of drug elimination, and the drug concentration is constant. To achieve 90% of steady state, it takes approximately 3.3 half-lives.

Clearance. Clearance is the ability to remove drug from the plasma or the body. Clearance is usually expressed as volume per unit time (e.g., L/hr or mL/min). The kidneys play a major role in the elimination of many drugs from the body. As renal function declines, the dosage of medications may need to be adjusted to prevent accumulation and the potential for toxic effects (Garbardi & Abramson, 2005). Renal replacement modalities such as hemodialysis and continuous hemofiltration can also contribute to the clearance of drugs (Quan, & Aweeka, 2005). Factors that affect clearance can be found in Table 2.


Loading dose (LD). The loading dose is the initial dose required to achieve the desired plasma concentration (Cp). It can be expressed with the following equation:ꆱ


For example, what will be the plasma level following a 1000 mg loading dose of vancomycin in a 70 kg adult? The average Vd for vancomycin is 0.7 L/kg. Rearranging the above formula:


Maintenance Dose (MD). The maintenance dose is the dosage that is required to maintain a desired plasma concentration. The maintenance dose is determined by the clearance of the drug:


For example, what is the maintenance dose of a lidocaine infusion necessary to maintain a level of 3 mg/L in a 70 kg adult? Assume that the clearance of lidocaine is approximately 10 ml/kg/min.


Therapeutic Drug Monitoring
In a clinical setting, the plasma drug level can be measured to determine if a dosage regimen results in a drug concentration within a therapeutic range. The therapeutic range or window is a range of drug concentrations that achieves the desired result (efficacy), with minimal toxicity. Certain drugs such as the aminoglycoside antibiotics (e.g., gentamicin, tobramycin) have a narrow therapeutic range, that is the concentrations associated with efficacy are close to those associated with toxicity (Moore, Lietman, & Smith, 1987; Rybak et al., 1999). In order to interpret a plasma concentration, it is important to know when the sample was obtained relative to when the last dose was given. If a sample is obtained before the drug is completely distributed into the tissues, the plasma concentration may be falsely elevated. Conversely, if a sample is obtained before the drug is fully absorbed following oral administration, the plasma concentration may be lower than predicted. For many drugs, the “trough” level, drawn just before the next dose level is commonly utilized during routine therapeutic drug monitoring. Not only are trough concentrations convenient to obtain at a consistent time during the dosing interval, but they also minimize the influence from absorption or distribution on the level. Table 3 lists some of the common target drug concentrations (Winter, 2004).


Conclusions
The usage of medications should be adjusted to meet the individual needs of the patient. Application of pharmacokinetic principles will enable the clinician to design or optimize a pharmacotherapeutic regimen that maximizes efficacy and minimizes toxicity.



References
Garbardi, S., & Abramson, S. (2005). Drug dosing in chronic kidney disease. Medical Clinics of North America, 89, 649-687.

Moore, R.D., Lietman, P.S., & Smith, C.R. (1987). Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimal inhibitory concentration. Journal of Infectious Diseases, 155, 93-99.

Quan, D., & Aweeka, F. (2005). Dosing of drugs in renal failure. In M. Koda-Kimble (Ed.), Applied therapeutics: The clinical use of drugs (8th ed.) (pp.34-1–34-26). Baltimore, MD: Lippincott Williams & Wilkins.

Rybak, M.J., Abate, B.J., Kang, S.L., Ruffing, M.J., Learner, S.A., & Drusano, G.L. (1999). Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates observed nephrotoxicity and ototoxicity. Antimicrobial Agents Chemotherapy, 43(7), 1549-1555.

Winter, M.E. (2004). Basic clinical pharmacokinetics. Baltimore, MD: Lippincott Williams & Wilkins.