Pharmacokinetic Assessment in Patients Receiving Continuous RRT

Abstract

The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.

Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT

“…We showed that CRRT waste (effluent) can serve as a biomatrix for estimating plasma free drug concentrations in lieu of repeated phlebotomy and that interindividual variability in b-lactam pharmacokinetics (PK) undermines target attainment in critically ill patients receiving CRRT (11,12,14). Indeed, recent publications from the Kidney Disease Improving Global Outcomes and the Kidney Health Initiative groups highlight the knowledge gap and need for improved drug dosing in acute renal disease (15,16). It is now clear that one size fits all dosing using standard adjustments to account for renal failure and dialysis does not guarantee adequate plasma concentrations in all or even most patients.…”

Influence of kidney disease on drug disposition: An assessment of industry studies submitted to the FDA for new chemical entities 1999–2010

“…Limited studies declined in both NCE groups. Several recent reviews have focused on enrollment inclusion and exclusion criteria for CKD and dialysis patients, as well as the number of subjects who should comprise each renal function category …”

“…Indeed only 1 NCE, voriconazole oral, was evaluated to determine PK changes associated with the delivery of CRRT during the 12‐year observation period . The KDIGO consensus group and others have called on regulatory agencies to mandate PK evaluations in AKI patients including those receiving CRRT therapy …”

The future of critical care: renal support in 2027

“…The lack of reliable clinical data to guide antibiotic use and the associated risk of under-dosing during CRRT have been identified as major problems—dosing continues to be done largely on an empiric basis [45] (Table 1). Over the next decade, multiple clinical trials evaluating the antibiotics most commonly prescribed to CRRT patients will be performed.…”