E. Hoeben (1), A. Vermeulen (1), M. Neyens (1), L. Vijgen (2) and F. De Ridder (3)
Janssen Research and Development, Clinical Pharmacology and Pharmacometrics (1), Clinical Virology (2), Statistics and Decision Sciences (3), Turnhoutseweg 30, B-2340 Beerse, Belgium
Objectives: Prediction of treatment outcome in chronic hepatitis C for patient management has become obsolete due to very high SVR rates and excellent tolerability associated with contemporary interferon free regimens1. Nevertheless, our objective was to evaluate whether the Neumann viral kinetic (VK) model2, previously applied to HCV RNA data on interferon-based therapies, could be used to analyze the HCV RNA decline during treatment with 2 direct-acting antiviral agents (DAAs) and whether VK parameters could still be linked to clinical outcome. Plasma HCV RNA data obtained during 8 or 12 weeks of treatment with simeprevir (SMV) and sofosbuvir (SOF) from the COSMOS (N=167) and OPTIMIST-1 (N=310) and -2 (N=103) trials were used.
Methods: A modification of the classical Neumann-VK model2 was used for the analysis. The model was re-parametrized to obtain the hidden instantaneous virion production (J) and required only 4 parameters (baseline viral load (V0), inhibition of virion production (e), infected hepatocyte death rate (d) and virion clearance (C)) which could be estimated from the observed HCV RNA profiles. The model was fitted to the HCV RNA time profiles in NONMEM3 using the SAEM algorithm. The modified VK model was evaluated using goodness-of-fit plots4. A logistic regression model was used to describe the relationship between the subject’s virion production at the end of SMV/SOF therapy, ie week 8 (J8) or week 12 (J12), and SVR12. J8 and J12 were derived from the individual subject’s estimates of the 4 model parameters.
Results: The VK model captured the HCV RNA profiles well and the VK parameters were well estimated with considerable amount of inter-individual variability; shrinkage of the random effects was limited. For a treatment duration of 12 weeks, there was no relation between J12 and SVR12. For a treatment duration of 8 weeks, the probability of SVR12 decreased with increasing J8, but this relationship was not statistically significant. The relationship was also not strong enough to allow individual predictions of SVR12.
Conclusion: On-treatment VK parameters derived from the adapted Neumann model from patients treated for 8 or 12 weeks with SMV/SOF were not able to predict SVR12. This illustrates the limitations of the Neumann model and is consistent with the observation that on-treatment HCV RNA data have no value to predict efficacy outcome in combination regimens of highly effective DAAs.
References:
[1] Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, Managing, and Treating Adults Infected With Hepatitis C Virus. Hepatology, 62:932-954, 2015.
[2] Neumann, A. U. et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282, 103–107 (1998).
[3] NONMEM Users Guides (1989–2009). Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds). Icon Development Solutions, Ellicott City, MD.
[4] Karlsson MO and Savic RM. Diagnosing model diagnostics. CPT, 82(1):17-20, 2007.
Reference: PAGE 25 () Abstr 6003 [www.page-meeting.org/?abstract=6003]
Poster: Drug/Disease modeling - Infection