Optimization of sorafenib dosing regimen using the concept of utility
Emilie Hénin, Benoit Blanchet, Michel Tod
EMR HCL/UCBL 3738 CTO, Faculté de Médecine Lyon-Sud, Université de Lyon
Objectives: The utility function allows finding a compromise between drug efficacy and toxicity, balancing the probability of benefit and the probability of risks [1, 2]. Sorafenib is an oral non-specific multi-kinase inhibitor, approved for the treatment of renal and hepatic carcinoma, blocking cell proliferation and angiogenesis by targeting Raf/ERK pathway. Hand-foot Syndrome (HFS) is one of the major dose-limiting toxicity. This work aimed at applying the concept of utility function to determine the optimal regimen of sorafenib, integrating models for efficacy and toxicity.
Methods: Sorafenib-induced efficacy and toxicity in 100 replicates of 100 patients were simulated under various dosing regimen: daily dose ranging between 200 and 2000 mg, fractionated as 1, 2, 3 or 4 occasions.
The pharmacokinetics were described by a one-compartment model with first-order elimination and saturable absorption [3]. The efficacy on tumor growth inhibition (TGI) was sigmoidally linked to the area under the unbound concentration curve at steady state [4]. The risk of HFS was characterized by a latent variable model whose kinetics is impacted by sorafenib accumulated plasma concentration and whose levels are translated into HFS probability [5].
The utility was defined as a weighted sum of the probability of benefit and the probability of non-risk, the weights adding to 1. It aimed at maximizing the percentage of patients showing at least 20% TGI (responders) and minimizing the risk for grade 2 or 3 HFS. The sensitivity to the relative contribution of efficacy and toxicity to the utility was also evaluated.
Results: The usual regimen of sorafenib is 400mg twice daily (800mg per day). The non-linear pharmacokinetics of sorafenib result in greater exposure the more the daily dose is fractionated.
Considering a 60% efficacy-40% toxicity balance, a maximal plateau in utility is obtained for 200mg to 400mg twice daily. Increasing the contribution of efficacy (or the expected TGI for responders) tends to favor the fractionation of the daily dose: e.g. if the efficacy criterion is the % of responders with TGI > 40% or greater, the utility function favors the four times daily regimen.
Conclusion: The utility is a comprehensible concept for the optimization of dosing regimen, allowing the balance between the required response and acceptable risks. This approach relies on the combination of several PK-PD models, and can be extended to multi-scale models.
References
[1] Sheiner, L.B. and K.L. Melmon, The utility function of antihypertensive therapy. Ann N Y Acad Sci, 1978. 304: p. 112-27.
[2] Ouellet, D., et al., The use of a clinical utility index to compare insomnia compounds: a quantitative basis for benefit-risk assessment. Clin Pharmacol Ther, 2009. 85(3): p. 277-82.
[3] Hornecker, M., et al., Saturable absorption of sorafenib in patients with solid tumors: a population model. Invest New Drugs, 2011.
[4] Hoshino-Yoshino, A., et al., Bridging from preclinical to clinical studies for tyrosine kinase inhibitors based on pharmacokinetics/pharmacodynamics and toxicokinetics/toxicodynamics. Drug Metab Pharmacokinet. 26(6): p. 612-20.
[5] Hénin, E., et al., A latent-variable model for Sorafenib-induced Hand-Foot Syndrome (HFS) in non-selected patients to predict toxicity kinetics according to sorafenib administrations. PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe, 2012. 21: p. Abstr 2494 [www.page-meeting.org/?abstract=2494].
