A Physiologically Based Pharmacokinetic Perspective on the Clinical Utility of Albumin-Based Dose Adjustments in Critically Ill Patients

Abstract

Introduction

In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration–time profile and associated pharmacokinetic parameters.

Methods

Four virtual compounds, representing a broad chemical space (low/high clearance/volume of distribution), were created and administered to a virtual population of normal patients and three types of hypo-albuminemic patients in Simcyp^®. The influence of decreased plasma protein binding in hypoalbuminemia on the pharmacokinetic parameters and profiles of these four compounds was investigated.

Results

Simulation results showed that while high-clearance compounds suffer from increased unbound exposure with decreased plasma protein binding, the unbound exposure of low-clearance compounds was unaffected. However, for the subset of low-clearance compounds with a small volume of distribution, it appeared that there were still alterations in their plasma concentration-time profiles. Since this may lead to different times above a minimum inhibitory concentration value, this might affect the bacterial killing for some anti-infective drugs. Overall, for any compound involved in the simulations, the unbound exposure did not decrease in plasma protein binding subjects relative to normal plasma protein binding subjects.

Discussion

This finding is in line with the few case-controlled studies in the literature. Hence, increasing the dose/dosing frequency seems futile and might reduce the benefit-risk ratio for narrow therapeutic index drugs. Moreover, these simulations indicate that when only total plasma concentrations and derived pharmacokinetic parameters are considered, incorrect conclusions will be drawn.

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