Understanding pharmacokinetics in the clinical setting (Proceedings)
Clinical pharmacokinetics is concerned with the rational, safe, and effective use of drugs. It studies the factors that determine the time course of the plasma concentration of a drug and its variability. The ideal goal is to tailor the drug and dosing regimen to the unique characteristics of each patient1. Pharmacokinetic information contained in the drug package insert can be an important tool when there is a need to adapt the dosage regimen to particular clinical scenarios (e.g. renal impairment, change in bacterial susceptibility, etc). Pharmacokinetic information is most useful when the range of doses (or concentrations) in which the drug exhibits linear pharmacokinetics is known. Linear pharmacokinetics implies direct proportionality between dose and exposure. For example, under linear kinetics, a 20 mg/kg dose provides two-fold the exposure (but not necessarily the pharmacological effect) of a 10 mg/kg dose. Some drugs exhibit linear pharmacokinetics within a wide range of doses and concentrations, while others do not. Therefore, when examining the pharmacokinetic information in the drug insert we can start by determining the PK linearity and range. Under nonlinear pharmacokinetics, there is no proportionality between dose and exposure, and therefore dose adjustment becomes a much more difficult task. The principles discussed by the author are based on the assumption of linear PK (also called first-order PK), which is by far the most common scenario.
Clinical pharmacodynamics is concerned with the rational, safe and effective use of drugs. It studies the relationship between drug exposure and pharmacological or toxic effect. Pharmacodynamic studies often allow defining exposure targets that are optimally related to the desired level of pharmacological effect (e.g. a range of AUC values that optimizes the probability of bacterial eradication during an infection)2. Important therapeutic questions that may arise during the course of drug administration include:
What should be the dose interval? Is compliance likely to be a problem? Are there any potential interaction with the patient's other drugs? What if the "normal average" dosing regimen is not appropriate for this patient? Should liver or renal impairment be taken into account? How do I tailor the dose to the changing bacterial susceptibility in my patient? How should I interpret TDM findings? When both pharmacokinetic and pharmacodynamic information are available, clinicians are better equipped to provide rational answers to these and other questions as well as to calculate adjusted dosage regimens. One of the primary sources of PK and PD information is the package insert itself.Objectives Of The Presentation
1. To review the PK and PD information included in the drug label.
2. To discuss the practical application of PK and PD information contained on the label.
Relevant Pharmacokinetic Information In The Drug Package Insert
Fraction of Drug Unbound in Plasma (f u )
Free drug in plasma can diffuse to tissues and act on receptors to produce an effect. While drug displacement from plasma protein binding sites by a competing drug is almost always unimportant, protein binding may be significant in the interpretation of plasma concentrations of drugs (e.g. when interpreting the results of therapeutic drug monitoring for displaced drugs or drugs with nonlinear plasma protein binding). Protein binding is also important with antimicrobials. When adjusting the dosage regimen of antimicrobials based on PKPD indices of efficacy (e.g. AUC/MIC or T>MIC), the exposure parameters (Cp, or AUC) should be expressed in terms of unbound drug (e.g. Cpu = Cp × fu). Expressed in this way, PKPD indices of efficacy can be extrapolated across species (e.g. from mice to dogs).