A. Janda (1,2), E. Romero (1), N. Vélez de Mendizábal (1), S. Ardanza-Trevijano (2), I.F. Trocóniz (1).
(1) Department of Pharmacy and Pharmaceutical Technology and (2) Department of Physics and Applied Mathematics. University of Navarra, Pamplona, Spain.
Objectives: Triptorelin is a gonadotropin-releasing hormone agonist indicated mainly for the treatment of hormone-dependent prostate cancer. Its testosterone (TST) effects shows a complex dynamic profiles. Based on a semi-mechanistic pharmacokinetic/pharmacokinetic (PK/PD) model already developed[1], the aim of the current work is to derive pharmacokinetic profiles of triptorelin in plasma dealing with optimal TST profiles. This objective is motivated by previous works [2-3] but we apply a more flexible method based on optimal control techniques [4].
Methods: The typical testosterone profile is characterized by an undesired initial flare-up where concentrations of testosterone are greater than baseline (~4 ng/mL). Once testosterone reaches its maximum value, its level decreases to the castration limit (due to a receptor down-regulation phenomena) and keeps below it for a finite period of time. Based on the mentioned PD model, we applied optimal control methods [2] to obtain a pharmacokinetic profile that: (i) minimizes the highest levels of testosterone during the flare-up, (ii) minimizes the time to reach the castration limit and (iii) prolongs the efficacy of the drug (i.e., time below castration limit). This analysis has been performed including the variability in model parameters.
Results: Results form the optimal control analysis reveals that minimum time to reach castration (Tmin_ct) is 19 days, and to achieve Tmin_ct a flare-up of 11 ng/mL is required. Additional results have shown that cab reached at early times of 23 days after drug administration, without almost any flare-up based on a certain PK profile, characterized by a small rate of increase plasma concentration of triptorelin (Tmax = three weeks) up to a 6 ng/mL. Those results together with the value of the CTRP_min descriptor obtained previously [1] allowed to generate an optimal PK profile of triptoreline satisfying the pharmacological imposed constraints.
Conclusions: The optimal control methods is an useful technique that allows to derive from a PD model the desired effect profiles and the corresponding pharmacokinetics to obtain them. Therefore, it can be a very helpful tool to optimized and design new drug formulations.
References:
[1] PAGE 20 (2011) Abstr 2253 [www.page-meeting.org/?abstract=2253].
[2] K. Park, D. Verotta, S. K. Gupta and L. B. Sheiner, Use of a Phamacokinetic/Pharmacodynamic Model to Design an Optimal Dose Input Profile, Journal of Pharmacokinetics and Biopharmaceutics (1998) 26 (4): 471-492.
[3] J-M Gries, N. Benowitz and D. Verotta, Importance of Chronopharmacokinetics in Design and Evaluation of Trandermal Drug Delivery Systems, The Journal of Pharmacology and Experimental Therapeutics, 285 (2): 457-463.
[4] Lenhart and J. Workman, Optimal Control Applied to Biological Models. Chapman and Hall/CRC, 2007.
Reference: PAGE 21 () Abstr 2575 [www.page-meeting.org/?abstract=2575]
Poster: New Modelling Approaches