Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.

@article{Jones2012UseOM,
  title={Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C.},
  author={Hannah M. Jones and Phylinda L. S. Chan and Piet H. van der Graaf and Rob Webster},
  journal={British journal of clinical pharmacology},
  year={2012},
  volume={73 1},
  pages={
          77-92
        }
}
AIM To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients. METHODS A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF-04878691 pharmacokinetics… 
PBPK models for the prediction of in vivo performance of oral dosage forms.
  • E. Kostewicz, L. Aarons, +13 authors J. Dressman
  • Medicine, Computer Science
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2014
TLDR
It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of P BPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.
Single Nucleotide Polymorphisms of Toll-Like Receptor 7 in Hepatitis C Virus Infection Patients from a High-Risk Chinese Population
TLDR
It is demonstrated that the carriage of rs179016 C allele had a negative effect on spontaneous clearance of HCV among males while rs1634323 G allele conferred a protective effect against persistent infection among female subjects.
Use of PD biomarkers to drive dose selection and early clinical decision making.
  • N. Robas
  • Chemistry, Medicine
    Bioanalysis
  • 2012
TLDR
This review will discuss the identification and validation of such 'fit-for-purpose' PD biomarkers, and case studies illustrating their use and value in dose selection and accelerating the clinical development of small-molecule drugs will be described.
Preclinical development of TLR ligands as drugs for the treatment of chronic viral infections
TLDR
This review provides an overview of the methodology for preclinical testing of TLR ligands for three major viral infections: hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV).
Hepatitis C viral kinetics: the past, present, and future.
TLDR
Recent modeling efforts in this direction of hepatitis C virus infection dynamics and in estimating crucial in vivo parameters characterizing the effectiveness of HCV therapy are reviewed.
Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases
TLDR
TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis and agonists of endosomal TLRs are very promising for treating chronic viral infections.
Advances in Antiviral Therapies Targeting Toll-like Receptors
TLDR
Toll-like receptors are a good choice for eradicating viral infections because they can fine-tune the immune response, but more focus should be placed on novel drugs that can induce significant and long-term immunity, while concomitantly alleviating side effects.
Novel drugs targeting Toll-like receptors for antiviral therapy.
TLDR
Recent advances in TLR biology are explored with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.
Chemical reagents modulate nucleic acid-activated toll-like receptors.
  • Xiao Li, Xinyuan Sun, Xuemin Guo, Xueren Li, Shouchun Peng, Xin Mu
  • Medicine
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
  • 2022
TLDR
This work summarized nucleic acid-sensing TLR-mediated IFN signaling pathways and the corresponding chemicals activating or deactivating their signaling.

References

SHOWING 1-10 OF 37 REFERENCES
Pharmacokinetic/Pharmacodynamic Model Analysis of Pegylated Interferon α-2a in Healthy Subjects
TLDR
The current PK/PD model well describes the enhanced PD effect, i.e. 2', 5'-OAS induction, as a consequence of the enhanced PK exposure of PEG-IFN, and confirms the value of applying the PK/ PD modeling approach to support the clinical development of potential products.
The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691)
TLDR
These doses of TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.
Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: The null responder
Our aim was to study the effect of ribavirin on viral kinetics and to study the early patterns of response to antiviral therapy of hepatitis C and their correlation with interferon pharmacokinetics
Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.
TLDR
Regimens involving pegylated interferon appear to be fairly well tolerated and the most favourable incremental discounted cost per QALY estimates were for patients infected with genotypes 2 and 3, and with low baseline viral load, in the range 2641-4194 pounds sterling.
IP‐10 predicts viral response and therapeutic outcome in difficult‐to‐treat patients with HCV genotype 1 infection
TLDR
Pretreatment IP‐10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load, and may prove helpful in decision‐making regarding pharmaceutical intervention.
Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma.
  • R. Motzer, A. Rakhit, +5 authors L. Hooftman
  • Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2001
TLDR
PEG-IFN is a modified form of IFNalpha2a with distinct pharmacokinetic advantages and immunomodulatory and antitumor activity for patients with advanced RCC and has potential for increased efficacy, less toxicity, or both.
Phase 1B, randomized, double‐blind, dose‐escalation trial of CPG 10101 in patients with chronic hepatitis C virus
TLDR
In this Phase 1 study, CPG 10101 was associated with dose‐dependent increases in markers of immune activation and decreases in HCV RNA levels, and the data support further clinical studies of C PG 10101 for treating chronic HCV infection.
First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer
TLDR
The systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer held promise for stimulating innate immune responses and significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables.
Side effects of therapy of hepatitis C and their management
TLDR
Current data suggest that maintaining adherence to a prescribed treatment regimen can enhance antiviral response and strategies to maximize adherence are being developed and, in the future, may include early identification of and therapy for depression and the selective use of hematopoietic growth factors to ameliorate hematologic abnormalities.
Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection
TLDR
Systemic administration of the selective TLR7 agonist isatoribine resulted in dose‐dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects.
...
1
2
3
4
...