Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

Abstract

Recombinant alpha interferon (IFN-␣) is used in the treatment of hepatitis C virus (HCV)-infected patientsbut 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-␣ 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-␣ 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.An estimated 200 million people worldwide (39) are infected with hepatitis c virus (HCV). The virus replicates primarily in the liver, and 70% of those infected go on to develop chronic infection, with a further 20% progressing to serious liver disease (6). The current standard of care for HCV infection is treatment with pegylated alpha interferon (IFN-␣) combined with ribavirin; however, this treatment is effective for less than 50% of patients (26). Furthermore, significant side effects, including flu-like symptoms, depression, injection site reactions, and hemolytic anemia, are observed (10). The need to develop more available, better-tolerated, and more effective medicines is therefore clear. To this end, one of the areas of interest has been the targeting of IFN inducers (13, 18) and specifically Toll-like 7 receptor (TLR-7) agonists (9). The TLR family plays a critical role in the innate immune response via recognition of pathogen-associated molecular patterns (PAMPs). These are conserved and essential to viability. TLR-7 itself is thought to be endosomally located and to recognize and bind single-stranded RNA. This results in the induction of type I IFN production, including a robust IFN-␣ response, leading in turn to an antiviral effect. This response has been described previously as recognizing abnormal localization of nucleic acid rather than structures or motifs absent from the host (reference 7; for a review, see also reference 8).Although the hypothesis supporting the development of TLR-7 agonists as novel drugs appears to be sound, the behavior of a given drug in the in vivo system is often very hard to predict, leading to attrition due to lack of efficacy or safety concerns (20). As a means to address this issue quantitatively, biomarker and translational pharmacology approaches (25) and modeling-and simulation-based drug development (22, 37) are being explored as ways forward. To develop an improved understanding of translational pharmacology, biomarkers of efficacy that are present both in preclinical species and in humans would be highly valuable. A number of potential biomarkers of relevance for HCV have been reported previously (see, e.g., references 1, 16, and 38). Of these biomarkers, IFN-␣ is attractive as it is readily measurable in preclinical species and humans by commercia...

The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system

“…For instance, the total area under the curve (AUC 0-∞ ) for oral dosing of imiquimod while fasting was 673±615 ng*h/ml while the AUC 0-∞ for subcutaneous doing of imiquimod was 405±64 ng*h/ml, demonstrating higher intersubject variability in oral administration due to first-pass metabolism [75]. A mouse pharmacokinetic and pharmacodynamic model can be useful to estimate oral bioavailability, half-life and clearance as well as predict the agonist interaction with receptors [76]. By using the TLR-7 agonist 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA), Benson et al .…”

“…By using the TLR-7 agonist 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA), Benson et al . discovered that the pharmacokinetics of BHMA followed a two-compartment model with first-order uptake from the GI tract and linear elimination [76]. Immune activation measured by IFN-α production showed peak levels at 1–2 h, and they were able to calculate a degradation constant for IFN-α of 0.96 h −1 and a half-life of 0.7 h, and complete clearance from the plasma was estimated at 3–4 h [76].…”

“…discovered that the pharmacokinetics of BHMA followed a two-compartment model with first-order uptake from the GI tract and linear elimination [76]. Immune activation measured by IFN-α production showed peak levels at 1–2 h, and they were able to calculate a degradation constant for IFN-α of 0.96 h −1 and a half-life of 0.7 h, and complete clearance from the plasma was estimated at 3–4 h [76]. Knowing these parameters for human studies could help understand the doses and dosing schedules necessary to sustain the required immune responses for treatment success while minimizing toxicity.…”

Hepatitis C Viral Kinetics

“…56 In this example, an HCV viral kinetic model was used to predict the antiviral activity of a TLR7 agonist, based on the observed level of stimulation of the IFN system with various dosing regimens of PF-0487691 in animals. Translational pharmacokinetic-pharmacodynamic modeling facilitated the selection of the first human doses and the estimation of the likely human effective dose.…”

“…Translational pharmacokinetic-pharmacodynamic modeling facilitated the selection of the first human doses and the estimation of the likely human effective dose. 56 Once healthy volunteer data were available, the model was updated with human clinical data and used to support a go/no-go decision with regard to further clinical development. 57 …”