Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Effect of various doses of alisporivir alone or in combination with Peg‐IFN on the early viral kinetics: a modeling approach
Jérémie Guedj, Thi Huyen Tram Nguyen, France Mentré, Micha Levi, Nikolai Naoumov, Jing Ju

Last modified: 2014-06-09


Alisporivir (ALV) is a first in class cyclophilin inhibitor in clinical development with potent activity against hepatitis
C virus (HCV) [1]. Here we aimed to estimate the antiviral effectiveness of combination treatment with ALV and
pegylated interferon (Peg‐IFN) in patients infected with different HCV genotypes (GT). For that purpose we
analyzed the pharmacokinetic (PK) of both drugs and the viral kinetics observed in 88 patients treated for four
weeks with different doses of ALV (200, 600 or 1000 mg) +/‐ weekly injections of Peg‐IFN (DEBIO‐025‐A2203) [2].
The PK of ALV was best described by a two compartment model with Michaelis‐Menten elimination and timedependent
bioavailability. Further we found a significant interaction between both drugs at 1000 mg ALV that was
attributed to a decreased elimination of ALV in presence of Peg‐IFN. PK model predictions were then plugged into
a viral kinetic model [3]. A model assuming multiplicative effect of both agents in blocking viral production could
well fit the viral load data and allowed to tease out the effects of ALV and Peg‐IFN. GT was found to significantly
affect Peg‐IFN effectiveness, εIFN (median ε= 86.3% and 99.1% in HCV GT‐1/4 and GT‐2/3, respectively, p=10‐7) and
the infected cells’ half‐life (median t1/2 =0.22 vs 0.39 day‐1 in GT‐1/4 and GT‐2/3, respectively, p=10‐6). ALV’s
effectiveness, εALV, was not significantly different across GT, and was very effective at doses larger than 600 mg
QD (median εALV= 50.5%, 89.4%, 97.1% and 93.6% in 200, 600 and 1000 mg bitherapy and 1000 mg monotherapy,
respectively). Lastly, this model was used to simulate various dosing regimen with IFN‐free treatment in HCV GT‐
2/3 patients and could well predict the virological response observed, making this model a useful tool to predict
the effects of ALV, used alone or in combination with other agents, and to predict optimal treatment duration.


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2. Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska‐Drapalo A, et al. The cyclophilin
inhibitor Debio‐025 shows potent anti–hepatitis C effect in patients coinfected with hepatitis C and human
immunodeficiency virus. Hepatology; 2008;47(3):817–26.
3. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo
and the antiviral efficacy of interferon‐alpha therapy. Science; 1998 Oct 2;282(5386):103–7.