Emilie Hénin, 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].
Poster: CNS
Eef Hoeben II-39 Prediction of Serotonin 2A Receptor (5-HT2AR) Occupancy in Man From Nonclinical Pharmacology Data. Exposure vs. 5-HT2AR Occupancy Modeling Used to Help Design a Positron Emission Tomography (PET) Study in Healthy Male
Subjects.
E. Hoeben (1), V. Sinha (2), P. de Boer (3), K. Wuyts (4), H. Bohets (5), E. Scheers (5), X. Langlois (6), P. Te Riele (6), and H. Lavreysen (6)
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse Belgium
Objectives: JNJ-mGluR2 PAM, a positive allosteric modulator of the metabotropic glutamate receptor-2 and 5-HT2AR antagonist, is currently in development for the treatment of disorders of the central nervous system [1,2]. To understand the pharmacological profile of JNJ-mGluR2 PAM and to define exposure vs. 5-HT2AR occupancy relationship in man, a PET study was performed in healthy male subjects [3].To help in designing a PET study, 5-HT2AR occupancies in man were predicted based on in vitro and in vivo nonclinical
pharmacology data in the rat.
Methods: In vitro functional and radioligand binding experiments were performed to investigate the in vitro activity and binding of JNJ-mGluR2 PAM and its major metabolite (M47) to human 5-HT2AR. Receptor occupancy assays were conducted in rats to evaluate JNJ-mGluR2 PAM occupancy to 5-HT2AR in vivo. Plasma concentrations vs. 5-HT2AR modeling was performed in rat and used to predict the 5-HT2AR occupancy in man. The relationship between predicted 5-HT2AR occupancy and simulated plasma concentrations in man was used to predict 5-HT2AR occupancy in man at clinical doses of 50 to 700 mg.
Results: In vitro preclinical experiments showed that JNJ-mGluR2 PAM is a weak 5-HT2AR antagonist. In rats, JNJ-mGluR2 PAM is rapidly metabolized to M47 which is a relatively potent and selective 5-HT2AR
antagonist. Modeling experiments suggested that M47 significantly contributes to the 5-HT2AR binding in the rat but in humans only limited metabolism to M47 has been observed. Accounting for the different contributions of parent and metabolite and the differences in free fraction in rat vs. man, 5-HT2AR
occupancy could be predicted in man based on exposure vs. 5-HT2AR modeling in the rat. At clinical doses of 50 to 700 mg, predicted 5-HT2AR occupancy in man ranged between 5% and 25%. The human PET data confirmed minimal 5-HT2AR occupancy by JNJ-mGluR2 PAM in man, which is not expected to be clinically relevant.
Conclusions: 5-HT2AR occupancy could be predicted in man based on nonclinical pharmacology data in the rat, taking into account the difference in free fraction and the different contributions of parent and
metabolite in rat vs. man. At clinical doses, predicted 5-HT2AR occupancy in man was low and in good agreement with observed 5-HT2AR occupancy in man. This modeling work illustrated the "translatability" of in vitro and in vivo preclinical information to 5-HT2AR occupancy in man.
References:
[1] Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat. Rev. Drug. Discov. 2005; 4:131-144.
[2] Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 2007; 13:1102-1107.
[3] Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J. Nucl. Med. 1998; 39(1):208-214.
Poster: Absorption and Physiology-Based PK