A. Janda (1,2), S. Ardanza-Trevijano (2), E. Romero (1), N. Vélez de Mendizábal (3), I.F. Trocóniz (1)
(1) Department of Pharmacy and Pharmaceutical Technology and (2) Department of Physics and Applied Mathematics; University of Navarra, Pamplona, Spain. (3) Indiana University School of Medicine; Indianapolis, IN, USA.
Objectives: Optimizing delivery systems targeting constant drug concentration levels in plasma represents always a challenge, especially for long periods of treatment, and in case of complex non-linear pharmacokinetics/pharmacodynamics (PKPD) systems. Recently we have developed a mechanistic PKPD model for the testosterone (TST) effects of triptoreline (TRP) in prostate cancer patients using data from five different sustained formulations [1]. TST profiles are characterised by an undesired initial flare-up, following by a profound receptor-down regulation eliciting castration (TST <0.5 ng/mL). The objective of the current work is to optimize the release characteristics of a sustained formulation of TRP achieving the following therapeutic goals: (i) limitation in the flare-up to 50% increase with respect to baseline, (ii) minimize time to castration after first injection, and (iii) maximize the castration time after injection.
Methods: The analysis has been performed in three steps. First, a population of individual set of disposition PK, PD, and system-related paremeters is generated [1]. Second, using this set of parameters, the optimal drug absorption and TST profiles for each patient are derived by means of optimal control methods implemented by the softwares PSOPT and GPOPS [2,3]. Finally, and to summarize the absorption properties the optimal (non-parametric) absorption profiles are described using standard absorption models considering several simultaneous absorption processes based on zero and first order kinetics. The individual model parameters are estimated by the R package DEoptim which performs global optimization by differential evolution [4].
Results:The optimal TST profiles obtained reveal that the time to castration can be minimized to 21 days (13 – 36) while the increase of TST levels at the flare is only 30% (0,1% – 50%) with respect to baseline (95% interval confidence between parenthesis). The castration time has been evaluated for different doses of TRP and the administration of 20 mg achieve the castration time longer than 9 months for 95% of patients. Additionally, the therapeutic objectives obtained have been compared to those from the formulations reported in [1] showing an important improvement, especially on the flare-up and the castration time.
Conclusions: The application of optimal control methods profiles are useful techniques for the optimization PK/PD profiles. They are more relevant in physiological systems with complex dynamics where simple simulation exercises tuning parameters are not effective. Moreover, the flexibility of the method allows to deal with multiple and tight therapeutic objectives performing real optimization.
References:
[1] Romero E et al. Pharmacokinetic/Pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer. J Pharmacol Exp Ther. 342: 788-98 (2012).
[2] Rao A. V. et al. .GPOPS: A MATLAB Software for Solving Multiple-Phase Optimal Control Problems Using the Gauss Pseudospectral Method. ACM Transactions on Mathematical Software. 37 (2): 22-39 (2010).
[3] Becerra, V.M. “Solving complex optimal control problems at no cost with PSOPT”. Proc. IEEE Multi-conference on Systems and Control, Yokohama, Japan, September 7-10, 1391-1396 (2010).
[4] K.M. Mullen et al. DEoptim: An R Package for Global Optimization by Differential Evolution”, Journal of Statistical Software (2011), 40 (6): 1- 26.
Reference: PAGE 22 (2013) Abstr 2848 [www.page-meeting.org/?abstract=2848]
Poster: New Modelling Approaches