Kidney function assessment and its role in drug development, review and utilization

Abstract

A key regulatory requirement pertaining to drug development is characterization of the role of kidney function in drug disposition and response, along with provision of corresponding renal dose adjustment recommendations. Traditionally, this information has been derived from Phase I pharmacokinetic studies in which regulatory guidance exists for pharmaceutical manufacturers on the design, conduct, analysis, and interpretation of data. Categorization and stratification of subjects into kidney function groups and dosing recommendations have historically been based on creatinine clearance estimates using the Cockcroft–Gault equation. As new estimating equations have emerged, the choice of equation for assessment of kidney function has become an area of debate. This review highlights these equations and provides recent examples of the use of quantitative models, incorporating efficacy and safety to make rational dose recommendations in subjects with impaired kidney function.

Keywords::

• chronic kidney disease
• creatinine clearance
• drug development
• estimated glomerular filtration rate
• kidney function
• pharmacodynamics
• pharmacokinetics

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• An assessment of the impact of kidney disease on the disposition of new molecular entity (NMEs) during drug development is critical for the safe and effective use of drugs in this special population.

• Accurate assessment of kidney function is needed to provide rational dosing recommendations of NMEs to healthcare providers.

• The estimating equation that provides the most accurate assessment of kidney function has been debated in the literature and as newer methods of estimating kidney function emerge and are properly validated, those equations should be considered for drug dosing.

• Dosing recommendations of NMEs in subjects with impaired kidney function should not be based only on the results of small dedicated PK studies, but on data across the full clinical development program and appropriate quantitative approaches that will allow for more informed dosing guidelines.