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Pharmacokinetic-Pharmacodynamic Modeling and Simulation of the Virologic Response of Dolutegravir in HIV-Infected Patients with Integrase Inhibitor Resistant Virus
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Reported by Jules Levin
16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy.
Washington DC, USA, 26-28 May 2015
I. Song1, K. Adkison1, M. Lovern2, J. Chiu2, J. Huang3, C. Vavro4, M. Ait-Khaled5, B. Wynne6, S. Min7
1GSK, CPMS, Research Triangle Park, USA; 2Quantitative Soluations, East Coast Office, Bridgewater, USA; 3GSK, Clinical Statistics, Toronto, Canada; 4GSK, ID Clinical Virology, Research Triangle Park, USA; 5GSK, MD ID, Stockley Park, United Kingdom; 6GSK, MD ID, Upper Marion, USA; 7GSK, MD ID, Research Triangle Park, USA
Background: Dolutegravir (DTG), a integrate inhibitor (INI), is currently approved at the 50mg twice daily (BID) dose for the treatment of HIV-1 infections in patients with integrase-resistant (INIr) virus based on demonstrated efficacy and safety in 3 studies (VIKING, VIKING-3, VIKING- 4). The objective of this analysis was to (1) describe the DTG exposure-Week 24 viral response relationship and (2) use model-based simulations to assess the impact of a higher dose of DTG or co-administration with food (known to increase DTG exposures) or enzyme inducing drugs and metal cation-containing dietary supplements (known to lower DTG plasma exposures) on response in the overall INI-r population, as well as subpopulations harboring the less sensitive Q148 viral mutations.
Materials & Methods: Using pooled data from 247 subjects, the probability of virology responder (response rate) at Week 24 as defined by Snapshot/TLOVR (HIV-1-RNA<50c/mL) was modeled as a logistic function of DTG plasma exposure (Cmin or Cavg estimated by an existing PopPK model) and covariates of interest including baseline viral load, baseline integrase resistance (fold change in IC50, integrase mutation category), phenotypic or genotypic susceptibility score of background antiretroviral therapy, prior raltegravir/elvitegravir use and duration of use, HIV risk factors, CDC category, baseline CD4+. Model building was performed in NONMEM and covariates were selected based on forward inclusion and backward elimination. The final model was validated by comparing the model predictions to the observed responses. Simulations based on observed and simulated subjects were performed to predict response rates for various scenarios including 100mg BID and dosing with food, metal cation-containing dietary supplements, or enzyme-inducing drugs.
Results: The logistic regression analysis based on either Cmin or Cmax arrived at the same final model, where baseline integrase mutation category, baseline viral load, and baseline CD4 were significant covariate effects. Based on the simulations, increasing dose from 50mg BID to 100mg BID assuming dose-proportional PK and a 45% increased exposure when dosed with food (best case scenario that conservatively assumed observed cases were fasted) is predicted to increase the Week 24 median predicted response rate from 80% to 88% for the 'No Q148' category, from 60% to 71% for the 'Q148+1' category, and from 30% to 48% for the 'Q148+32' category, respectively, using the Cmin-based model.
However there was significant overlap in the 90%
prediction intervals between 50mg BID and 100mg BID for all three mutation categories, and DTG PK was previously shown to be less than dose-proportional from 50mg to 100mg. Coadministration with strong inducers resulted in lower predicted response rates for the 50mg BID regimen by 5%, 8%, and 5% in the No Q148, Q148 + 1, and Q148 + ≥2 mutation categories. Co-administration with metal-cation dietary supplements was predicted to have a negligible impact on virologic response.
Conclusions: A logistic regression model was developed and validated to describe the relationship between the virologic response at Week 24 and DTG exposure in INI-r subjects. The simulation results support the current dose recommendation of 50mg BID for the treatment of HIV infection in patients with integrase-resistant viruses.
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