IMPACT OF RENAL IMPAIRMENT SEVERITY ON HUMAN RENAL CLEARANCE OF XENOBIOTICS: A COMPARATIVE PHARMACOKINETIC ANALYSIS

Abstract

Renal impairment may significantly affect the disposition of xenobiotics through a decrease in renal clearance and an increase in the systemic exposure. This work investigated renal clearance in humans in relation to the severity of renal impairment and the role of dose, route of administration and molecular properties in clearance variability. A secondary pharmacokinetic analysis of 1,706 curated observations of over 500 exogenous compounds was performed. The renal clearance was compared between healthy, mild, moderate and severe renal-impairment groups, and matched analysis was performed to control for differences in compound, study, route and dose. Median renal clearance showed a progressive decrease from healthy to mild, moderate and severe renal impairment (6.228, 2.768, 1.590 and 0.568 L/h respectively). In these categories, the reductions in the medians were 36.9%, 61.2% and 84.2% which were all statistically significant after adjustment in the matched comparisons. The between-compound variability was substantial, with compound identity accounting for a large proportion of clearance variation, but no consistent systematic effects were found for administered dose or route. There were weak inverse relationships between molecular weight, lipophilicity and renal clearance, and a weak positive relationship between hydrogen-bond donor count and renal clearance. But all the molecular descriptors together accounted for only a small fraction of the variability. These findings demonstrate a strong severity-dependent decline in renal clearance while highlighting considerable compound-specific heterogeneity. The combination of renal-function status and drug-specific pharmacokinetic properties could facilitate the adjustment of drug dose and personalized therapy.

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