Clinical pharmacokinetics and pharmacodynamics
CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS
Overview of Clinical Pharmacokinetics
The application of Pharmacokinetics principals to patient care can aid the clinician in making rational drug. Use decision however, knowing the relationship between the time course of drug concentration and the pharmacological effect is critical to the application of Pharmacokinetics principals and the interpretation of plasma drug concentration in the patient care setting.
As a general rule traditional Pharmacokinetic research is an intensive study of a limited number of subjects resulting in very precise Pharmacokinetic and Pharacodynamic parameter estimates. Clinical Pharmacokinetics on the other hand is usually limited to very few and sometimes no plasma drug concentration requiring the clinicion to make an educated guess about key elements of drug disposition and the drug use process. In the research setting it is common to obtain ten our more samples for drug concentration measurement within a single dosing interval.
Therefore, understanding the usual manner in which drugs are absorbed, distributed and eliminated as well as the known factors that alter drug disposition and which of these elements is most likely to be altered in the individual patient is key to the clinicion ability to effectively use Pharmacokinetics.
Drugs with Narrow Versus Wide Therapeutic range
The therapeutic range is a concentration range that is likely to result in the desired clinical therapeutic response with an acceptable risk or livelihood of developing a toxic response. For every drug, there is a therapeutic range but it is those drugs in which the minimum concentration that is likely to result in the desired drug effect is relatively close to the higher drug concentration that is likely to result in a toxic response.
The therapeutic index is the ratio of the maximum desired concentration relative to the minimum desired concentration. The application of Pharmacokinetics principles may be limited in the use of some drugs. Drugs that have a wide therapeutic index may not require precise those adjustments when drug disposition is altered and a simple approximation may be satisfactory to limit the probability of toxicity and sure efficacy.
Drugs with a narrow therapeutic range however, tend to lend themselves to careful those adjustments and plasma drug concentration monitoring to help ensure optimal patient outcomes. For those drugs that are monitored with plasma drug concentration, there is usually a normal therapeutic range that attempts to define the concentration of drug where the benefit to drug is optimal. While the normal therapeutic range is important it is only a guide and it is the patient not the drug concentration that is therapeutic or toxic.
Plasma Protein Binding and Therapeutic Range
One potential factor that can change the normal therapeutic range is alteration in plasma protein binding. In most cases, clinical laboratories use assay procedures that measure and report the total plasma concentration. i.e. The drug concentration that is bound to plasma protein and the unbound plasma drug concentration. It is only the unbound drug in plasma that can cross the tissue where the receptors are located. Therefore, it is the unbound drug concentration that is proportional to the tissue and the receiptor drug concentration and the Pharmacodynamics response. Any change in plasma protein binding would be expected to alter the potential for any plasma drug concentration reported as both bound and unbound drug to result in a toxic therapeutic response. Many drugs have significant binding to plasma protein and the relationship between the unbound drug concentration and the total drug concentration is referred to as free fraction or fu.
Unbound drug concentration = (fu) (Total drug concentration)
Any factors that alter plasma protein binding will result in an altered free fraction. One approach is to calculate the normal plasma protein binding.
And then compare the normal plasma binding concentration to the normal therapeutic range to evaluate the drugs potential for either efficacy or toxicity. An alternative approach is to calculate an adjusted therapeutic range and compare this therapeutic range to the assayed drug concentration with altered plasma binding to evaluate the drugs potential for efficacy and toxicity.
In the face of growing drug resistance, the World Health Organization (WHO) has issued recommendations strongly encouraging the use of combination therapies to combat uncomplicated malaria. Amongst the most effective treatments are those combining an artemisinin derivative with a longer acting component such as amodiaquine, lumefantrine or piperaquine. Despite the widespread use of these treatments there is a lack of understanding regarding both pharmacokinetics and pharmacodynamics of the combinations, particularly in pediatric patients. The aim of this thesis was to describe how the dosing of antimalarials during combination therapy correlates with the outcome of treatment and to investigate factors that may influence this relationship.