DRUG DOSING IN CONDITIONS THAT ALTER PHARMACOKINETICS AND PHARMACODYNAMICS

To encourage research on the pharmacokinetics and pharmacodynamics of drugs in acute and chronic conditions; further,

To encourage drug product manufacturers and other stakeholders to conduct and publicly report pharmacokinetic and pharmacodynamic research in pediatric, adult, geriatric, and patients at the extremes of weight to facilitate safe and effective dosing of drugs in these patient populations; further,

To advocate healthcare provider education and training that facilitate optimal patient-specific dosing in populations of patients with altered pharmacokinetics and pharmacodynamics; further,

To support development and use of standardized models, laboratory assessment, genomic testing, utilization biomarkers, and electronic health record documentation of pharmacokinetic and pharmacodynamic changes in acute and chronic conditions.

Rationale

The pharmacokinetic and pharmacodynamic properties of drugs found in drug information monographs are based on the drug’s absorption, distribution, metabolism, and excretion in healthy, adult patients during Phase I of a drug’s clinical trials. Many patients receiving drug therapy do not fit this profile, and many have compromised organ function. The medical community has long recognized the need for a standardized approach to evaluating organ system dysfunction. Although there are methods to determine organ function (e.g., the Cockcroft-Gault equation for renal function or the Child-Turcotte-Pugh Classification for Severity of Cirrhosis), there is debate as to whether these methods are true indicators of organ function, as the components that comprise these equations may fluctuate based on severity and patient status. Traditional laboratory values used to evaluate organ dysfunction can be bidirectional and conflicting as well.

With the exception of adjustments for renal dysfunction, there is not much information regarding dosage adjustment for specific drugs. Many organ systems are involved in a drug’s absorption, distribution, metabolism, and excretion. Hepatic effects, for example, are a risk area, as those effects are slower to be seen and have not been the subject of much research, and the number of drugs affected are smaller in number than renally excreted drugs. Both acute and chronic aspects of patient conditions may require monitoring and adjustment, including sepsis, encephalopathies, pregnancy, heart failure exacerbations, and cystic fibrosis. Certain protocols, such as therapeutic hypothermia, can also have clinically significant impact on a drug’s pharmacokinetic and pharmacodynamic behavior. There is also need to promote research and utilization of biomarkers into practice, as these may reflect organ function and may provide pharmacists with a more complete clinical picture.

Pharmacists are also seeing an increase in the number of patients at both extremes of weight, and there is a lack of information regarding dosing medications for these populations. ASHP advocates that the Food and Drug Administration develop guidance for voluntary drug dosing studies in these populations, as the need for this guidance is supported by the complexity of drug dosing that can vary based on drug and patient characteristics. Drug product manufacturers should be encouraged to complete pharmacokinetic and pharmacodynamic dosing studies, and to publicly report the results, especially for drugs for which significant weight extremes may have a clinical impact.