Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor.
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.
Mohanty
Utkala
U
Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
Dixit
Narendra M
NM
D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000097:blood / Q000493:pharmacokinetics*; D023581:HIV Fusion Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008954:Models, Biological; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D013997:Time Factors
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide