Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor

Abstract

We present a model of the pharmacokinetics of enfuvirtide, a potent inhibitor of the fusion of human immunodeficiency virus type 1 (HIV-1) with target cells. We assume that subcutaneously administered enfuvirtide accumulates in the injection region, diffuses locally, and gets absorbed into blood, where it reversibly associates with lipidic cell membranes and is eventually eliminated. We develop mathematical descriptions of each of these processes and predict the time-evolution of the concentration of enfuvirtide in plasma, C p . We find, interestingly, that diffusion of enfuvirtide in the subcutaneous region is decoupled from absorption, which enables deduction of analytical expressions for C p following single dose administration and ordinary differential equations following multiple dose administration and renders our model amenable to data analysis. Model predictions provide excellent fits to observed plasma concentration-time profiles of enfuvirtide following the intravenous and subcutaneous administration of a single dose and without any adjustable parameters capture quantitatively concentration-time profiles following the administration of multiple doses. Our model thus presents a robust description of the pharmacokinetics of enfuvirtide and may be applied in conjunction with models of viral dynamics to assess responses of HIV-1 patients to alternative enfuvirtide-based therapies. Further, our model reveals that key pharmacokinetic characteristics of enfuvirtide, viz., steady state values of peak and trough concentrations and area under the concentration-time curve, vary nearly linearly with dosage over a broad range of dosages and for different dosing regimens, which enables a priori estimation of enfuvirtide exposure levels for different treatment protocols and may serve to establish guidelines for therapy optimization.

In-host modeling

“…Under this hypothesis, a ‘pharamacodynamics (PD)’ model can be added to the ‘pharmacokinetic (PK)’ model (18), describing drug effectiveness over time to be: where is the drug concentration at time t , is the drug concentration in the blood where the drug is half-maximal, and n is a Hill coefficient ( Holford & Sheiner, 1981 ). Variations of such PK-PD models have been used in the investigation of drug efficacy in infections with hepatitis C ( Canini and Perelson, 2014 , Canini et al., 2015 , Dahari et al., 2010 , Shudo et al., 2008 , Talal et al., 2006 ), influenza ( Beauchemin et al., 2008 , Canini et al., 2014 ), and HIV ( Mohanty & Dixit, 2008 ).…”

Models of Viral Population Dynamics

“…More complex models that explicitly consider intracellular pharmacokinetics (Dixit and Perelson 2004) or additional compartments (Mohanty and Dixit 2008) have also been constructed. These models along with the model of viral dynamics have provided insights into the relationship between drug pharmacokinetics, adherence, and the emergence of resistance and treatment failure (Gilmore et al 2013;Rosenbloom et al 2013;Sedaghat et al 2008;Smith 2006;Wahl and Nowak 2000;Wu et al 2005).…”