Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Area of Science:

• Pharmacology
• Nephrology
• Drug Development

Background:

• Patient-specific renal function is key for drug dosing, but direct measurement is often impractical.
• Estimates of renal function, historically Cockcroft-Gault, are increasingly shifting to the MDRD equation for GFR.
• Inconsistent regulatory guidance leads to heterogeneous drug dosing recommendations, impacting healthcare.

Purpose of the Study:

• To review current regulatory guidance for renal impairment pharmacokinetic studies.
• To examine the implications of this guidance on drug development and clinical practice.
• To propose a standardized approach for assessing renal function in drug development.

Main Methods:

• Review of current regulatory guidelines from FDA and EMA.
• Analysis of dosing recommendations in new drug labels.
• Case study analysis of three recently approved antibiotics (ceftazidime/avibactam, delafloxacin, meropenem/vaborbactam).

Main Results:

• The use of MDRD-estimated GFR in drug labels has significantly increased but shows variability.
• Disharmonious recommendations from regulatory bodies contribute to heterogeneity in renal function assessment.
• Current practices create challenges for industry, health systems, and clinicians.

Conclusions:

• Measuring GFR in Phase 1 studies is recommended.
• Employing the CKD-EPI equation can help standardize CKD staging and population pharmacokinetic analyses.
• Harmonizing renal function assessment will improve drug development and clinical dosing.