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Proposal 1159

Title of the Proposed Research

Validation of Pharmacokinetic/Viral Dynamic Modeling and Simulation using the Dolutegravir Phase IIa Dataset

Lead Researcher

Edward P. Acosta, Pharm.D.

Affiliation

University of Alabama at Birmingham

Funding Source

None

Potential Conflicts of Interest

Consulted for GSK/ViiV in the past and part of an NIH funded (IMPAACT) protocol for DTG pediatric development. There is no "perceived" conflict of interest.

Data Sharing Agreement Date

11 August 2015

Lay Summary

Lay Summary My laboratory performs a variety of antiviral pharmacokinetic modeling techniques. We have developed one such technique that combines pharmacokinetic data (drug concentration-time data) and viral dynamics (change in the amount of virus in the blood over time caused by the drug). Briefly, a pharmacokinetic model is created using drug concentrations from patients with a viral infection (HIV, influenza, etc.). The change in the amount of virus in the patients is also modeled sequentially; so for HIV infection we’d measure the viral load over the course of treatment and apply a model to describe how the amount of virus changes over time. This is called viral dynamics. After model validation, we then use the combined pharmacokinetic and viral dynamic models to conduct dose-ranging simulation studies in silico to determine the optimal amount of drug needed to maximally suppress viral replication (e.g., determine the concentration of drug required to reduce viral amounts by 95%, or EC95). This procedure could be used in early phase drug development to identify the optimum dose much sooner or it could be used to assess the ideal dose for drugs that are already approved but lack sufficient early phase dose-ranging data. As part of the company’s development process, they conducted a Phase IIa dose-ranging trial which has been published. This study showed an excellent concentration-response (pharmacodynamic) relationship between dolutegravir concentrations and change in viral load over a 10 day course of treatment. My goal is to obtain these raw data from ViiV in order to validate our pharmacokinetic/viral dynamic model described above. Since the optimal dose (and concentration) of dolutegravir is already known, we wish to determine if our model can generate a similar result or not. The information we need are the raw dolutegravir concentration-time data, corresponding viral load determinations, and CD4 cell count for each participant in that trial.

Study Data Provided

Study VIIV-ING111521: A Phase 2a, Multicenter, Randomized, Parallel, Double-Blind, Dose Ranging, Placebo-Controlled Study to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1349572 Monotherapy Versus Placebo Over 10 days in HIV-1 Infected Adults (ING111521)

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.