Pharmacokinetic Alterations Associated with Critical Illness

Abstract

Haemodynamic, metabolic, and biochemical derangements in critically ill patients affect drug pharmacokinetics and pharmacodynamics making dose optimisation particularly challenging. Appropriate therapeutic dosing depends on the knowledge of the physiologic changes caused by the patient’s comorbidities, underlying disease, resuscitation strategies, and polypharmacy. Critical illness will result in altered drug protein binding, ionisation, and volume of distribution; it will also decrease oral drug absorption, intestinal and hepatic metabolism, and renal clearance. In contrast, the resuscitation strategies and the use of vasoactive drugs may oppose these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion. Metabolism is the main mechanism for drug clearance and is one of the main pharmacokinetic processes affected; it is influenced by patient-specific factors, such as comorbidities and genetics; therapeutic-specific factors, including drug characteristics and interactions; and disease-specific factors, like organ dysfunction. Moreover, organ support such as mechanical ventilation, renal replacement therapy, and extracorporeal membrane oxygenation may contribute to both inter- and intra-patient variability of drug pharmacokinetics. The combination of these competing factors makes it difficult to predict drug response in critically ill patients. Pharmacotherapy targeted to therapeutic goals and therapeutic drug monitoring is currently the best option for the safe care of the critically ill. The aim of this paper is to review the alterations in drug pharmacokinetics associated with critical illness and to summarise the available evidence.

Pharmacokinetics and exposure–safety relationship of ciprofol for sedation in mechanically ventilated patients in the intensive care unit

“…The propofol glucuronidation by kidney microsomes is three to four times higher than that of liver microsomes, 42 demonstrating the role of renal metabolism for this type of structure. For renal cleared drugs, such as vancomycin or aminoglycosides, decreased exposure in the critically ill population have already been reported in various studies 43 . Ciprofol is metabolized in the liver and excreted primarily through the urine.…”

“…For renal cleared drugs, such as vancomycin or aminoglycosides, decreased exposure in the critically ill population have already been reported in various studies. 43 Ciprofol is metabolized in the liver and excreted primarily through the urine. Renal function measure (creatinine clearance) and hepatic function measures (aspartate aminotransferase, alanine aminotransferase, alkaline phosphate, total bilirubin, and total protein) were tested during PopPK covariate model development and were not identified as significant covariates for ciprofol CL.…”

Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis

“…We studied the pharmacokinetics of anakinra in a closed-loop CRRT circuit. Incorporating an ex vivo study design enabled an independent assessment of the drug-circuit interaction from many of the additional factors that may impact drug pharmacokinetics in critically ill individuals such as organ and circulatory dysfunction, drug interactions, and fluid shifts (39)(40)(41). Ex vivo CRRT analyses provide important information for the prediction of drug clearance.…”

The Significance of Bayesian Pharmacokinetics in Dosing for Critically Ill Patients: A Primer for Clinicians Using Vancomycin as an Example

“…These significant Vd changes primarily impact antibiotics that are dependent on high concentrations for efficacy as increases in Vd reduce peak concentrations. Therefore, dose optimization in critically ill patients is needed to overcome the changes in Vd [ 27 ].…”