Pharmacokinetic-pharmacodynamic modeling of alpha interferon response induced by a Toll-like 7 receptor agonist in mice

Abstract

Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.

FIG. 1.

Schematic of the models used to describe the PK-PD for IFN-α. A two-compartment model describes the PK of BHMA. The plasma drug concentration then drives the synthesis of IFN-α as described by a sigmoid E_max function, and IFN-α is degraded at a constant rate. S_max is the maximum rate of synthesis of IFN-α (in international units per milliliter per hour), SC₅₀ is the concentration of the compound (in nanograms per milliliter) required for half-maximal synthesis of IFN-α, k_out is the elimination rate constant for IFN-α (expressed as a value per hour), and C_p is the predicted plasma drug concentration (in nanograms per milliliter).

FIG. 2.

PK parameters for plasma samples from mice after oral dosing with 0.1 to 10 mg/kg BHMA, sorted by dose group. Observed values (solid black circles) and values from fitting to a two-compartment PK model (solid gray triangles) are shown. Dose levels (amounts [AMT]) per group are given in micrograms per kilogram at the top of each panel. Time is expressed in hours.

FIG. 3.

(A) Observed plasma IFN-αconcentrations (solid black circles) and typical predicted values according to equation 1 (solid gray triangles) after oral dosage with 0.1 to 10 mg/kg BHMA. Data are sorted by dose group, with dose levels (AMT) per group given in micrograms per kilogram at the top of each panel. Time is expressed in hours. (B and C) Goodness-of-fit diagnostic plots showing the typical predicted values for populations (B) and the individual model-predicted values (abscissa) versus observed values (ordinate) derived from the mixed-effects fit. The solid lines are the lines of unity.