Emerging areas of research in the assessment of pharmacokinetics in patients with chronic kidney disease.

Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development.