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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.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

T'jollyn H,Vermeulen A,Van Bocxlaer J,Colin P

doi

10.1007/s40262-017-0549-x

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

59-69

issue

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-017-0549-x

journal_volume

pub_type

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