T'jollyn Huybrecht, Colin Pieter, Van Bocxlaer Jan, Vermeulen An
Ghent University
Objectives: : In drug therapy, the drug effect is assumed to be correlated with the unbound drug concentration circulating in the blood. In scientific literature, there’s an ongoing discussion whether alterations in plasma protein levels affect a drug’s unbound PK to a clinically significant effect and hence influence treatment efficacy (1, 2). In order to determine the effect of alterations in plasma albumin levels on the total and unbound PK of a drug, a simulation study in Simcyp was set up.
Methods: A virtual hypoalbuminaemic population was created in which half of the available plasma albumin was redistributed from plasma to the extracellular water surrounding the tissue cells (albumin leakage from intravascular to extravascular water) (1). A set of 4 compound files was created within Simcyp (high and low volume of distribution (Vd) and liver CLint). The change in total and unbound plasma and tissue concentrations of these compounds was assessed.
Results: Based on this simulation scenario, the effect of albumin leakage on the total and unbound PK of low/high clearance drugs was independent from their distributional behavior. For low clearance drugs, Vtot, and CLtot increased in proportion to the change in fup (about two-fold) in hypoalbuminaemia, whereas AUC is decreased two-fold. AUCu, CLu, and unbound plasma concentration profiles are unchanged. For high clearance drugs, Vtot also increased proportionally with fup, whereas AUCtot and CLtot remained unchanged. CLu is decreased and AUCu is increased by a factor of 2, which is in line with the elevated unbound plasma concentration profiles.
Although the fup for low and high clearance drugs is doubled, the effective liver elimination is not increased. For low clearance drugs, the liver is provided with the same unbound drug input as in the normal situation, so unbound exposure is unaffected. However, since the total plasma concentration of high clearance drugs is lower in hypoalbuminaemia, non-restrictive elimination is much slower, increasing the unbound exposure to the drug.
Conclusions: In the case of 50% albumin redistribution to the extravascular space, dose reduction should only be considered for high clearance drugs for reasons of potential toxic side effects.
References:
[1] Roberts JA, Pea F, Lipman J. The clinical relevance of plasma protein binding changes. Clinical pharmacokinetics. 2013;52(1):1-8.
[2] Heuberger J, Schmidt S, Derendorf H. When is protein binding important? Journal of pharmaceutical sciences. 2013;102(9):3458-67.
Reference: PAGE 24 (2015) Abstr 3603 [www.page-meeting.org/?abstract=3603]
Poster: Drug/Disease modeling - Absorption & PBPK