Modeling and Simulation of DEBIO-025 to Support Design of a Dose-Response Monotherapy Study in HIV-1 infected Patients
Prins, K (1), B. Poland (1), V. Nicolas (2), H. Porchet (2), P. Scalfaro (2), R. Bruno (1)
(1) Pharsight, Strategic Consulting Services, Mountain View, CA, USA (2) Debiopharm SA, Lausanne, Switzerland
Introduction: DEBIO-025 is a non-immunosuppressive cyclosporine with potent inhibitory activity on HIV replication in vitro due to the inhibition of cyclophilins.
Objectives: To develop a longitudinal population PK/PD model of the relationship between dose, exposure, and viral load (VL) in patients with HIV-1 infection to:
i) Simulate dose-response and optimal dosing regimen.
ii) Simulate study designs for the next study.
Methods: Data were available from 2 Phase I dose-escalation trials following oral dosing in healthy volunteers (PK only, 16 subjects, 50 to 1600 mg single dose) and in asymptomatic HIV-1 infected patients (PK and VL, 36 patients, 50, 400 and 1200 mg daily for 10 days). The population PK/PD model consisted of a PK model in plasma and in whole blood, a viral inhibition model and a viral dynamics model linked to the viral inhibition (Funk et al., 2001). Viral inhibition and viral dynamics model parameters were estimated (NONMEM) based on the data or obtained from the literature. Simulations of the typical population response over time and associated uncertainty were performed to assess optimal dosing regimen and expected dose-response. Trial design scenarios were simulated integrating both uncertainty and inter-individual variability in the parameters.
Results: A three-compartment PK model with saturable binding to erythrocytes described the PK data adequately. The VL data showed moderate exposure-response relationships. Viral inhibition was best driven by plasma concentrations but DEBIO-025 IC50 was estimated with high uncertainty. The best response of 0.58 Log10 HIV VL decline was obtained after 10 days of treatment with 1200 mg daily. Simulations of the typical population response over time suggested that maximum response was not achieved at day 10. Better efficacy could be obtained by using 1) a loading regimen (e.g. 1200 mg BID followed by 1200 mg OD), 2) a higher dose intensity (e.g. 1200 mg BID) or 3) a longer treatment duration (e.g. 14 days). Comparison of expected VL drop led the team to select a single arm study at the maximum feasible dosing intensity (1200 mg BID for 15 days) vs. placebo. For this regimen the expected probability to achieve a log10 VL drop > 0.5, 0.8 or 1 was 0.88, 0.62 or 0.40. Actual trial results will be presented.
Conclusion: A M&S framework was developed to support the development DEBIO-025 and help the project team to make decisions regarding the design of a learning study to better assess anti-HIV dose-response.
Funk GA, Fischer M, Joos B, et al. 2001, Quantification of in vivo replicative capacity of HIV-1 in different compartments of infected cells, JAIDS 26:397-404.