Adriana Castiñeiras (1,4), Gema López Ginés (4), Iñaki F Trocóniz (1,2,3)
(1) Department of Pharmaceutical Sciences, Schoof of Pharmacy and Nutrition, University of Navarra, Spain, (2) IdisNA, Navarra Institute for Health Research, Spain, (3) Institute of Data Science and Artificial Intelligence, DATAI, University of Navarra, Spain, (4) Laboratorios Farmacéuticos Rovi, Spain
Introduction/Objectives: Letrozole is an aromatase inhibitor that is currently marketed as oral tablets as a first line treatment for hormone-dependent breast cancer in post-menopausal women[1,2,3]. However, non-adherence and/or premature interruption of treatment are associated to higher mortality risk in these patients[4]. The use of long-acting injectable formulations may help overcome this non-fulfilled necessity, while interindividual variability (IIV) is reduced and bioavailability is improved[5]. In this sense, Laboratorios Rovi is developing Letrozole ISM®, a novel polymeric long-acting injectable formulation of letrozole.
It is important to control in vivo behaviour of long-acting formulations to avoid dose dumping due to their higher doses, as well as to ensure adequate plasma levels along the complete dosing period[6]. Over the last decade, the possibility of evaluating and predicting in vivo response from in vitro data has emerged by the establishment of in vitro-in vivo correlations (IVIVCs)[7,8].
This study was focused on developing a population pharmacokinetic model to characterize the in vivo release performance of Letrozole ISM® as a step to further establish an IVIVC with both in vitro and clinical data.
Methods: Both the target formulation and 2 additional formulations presenting altered Critical Quality Attributes (and showing a faster and slower release of Letrozole in vitro when compared to target release) were studied in Beagle dogs (n=5 per formulation). A Letrozole solution administered intravenously was also studied in the same animal model (n=6). Plasma samples were obtained and Letrozole was quantified by HPLC-MS/MS. Concentration vs time profiles were processed and analysed using the non-linear mixed effects approach (nlme) with NONMEM 7.4.
Results: Systemic disposition on Letrozole was characterized using a one-compartmental model with linear distribution and elimination processes. Complex absorption process after the administration of the long-acting formulation was described considering two depot compartments from which the drug was absorbed into the central compartment following first and zero order processes. Letrozole enterohepatic recirculation was observed and well characterized using a previously described methodology[9]. Values of 19 L and 0.21 L/h were obtained for the volume of distribution and clearance, respectively, for the dose absorbed following the zero order process.
Goodness of fit (GOF) plots and visual-predictive checks (VPC) confirmed acceptable description of the data. A comparative between in vitro dissolution kinetics and in vivo absorption kinetics was performed.
Conclusions: The nlme approach was successfully applied to in vivo pharmacokinetic data obtained after intramuscular administration of Letrozole ISM® to Beagle dogs, allowing the characterization of PK differences when altering the formulation CQAs controlling the release of the active compound. This evaluation, together with the analysis of the Letrozole ISM® in vitro release characteristics, constitutes a further step to establish an IVIVC from in vitro, preclinical and clinical data.
References:
[1] Subramani, R., Nandy, S. B., Pedroza, D. A. & Lakshmanaswamy, R. Role of Growth Hormone in Breast Cancer. Endocrinology 158, 1543–1555 (2017).
[2] SEOM clinical guidelines in advanced and recurrent breast cancer (2018).
[3] https://www.vademecum.es/principios-activos-letrozol-l02bg04.
[4] Yusufov, M. et al. Predictors of increased risk for early treatment non-adherence to oral anti-estrogen therapies in early-stage breast cancer patients. Breast Cancer Res Treat 185, 53–62 (2021).
[5] Chaudhary, K., Patel, M. M. & Mehta, P. J. Long-Acting Injectables: Current Perspectives and Future Promise. Crit Rev Ther Drug Carrier Syst 36, 137–181 (2019).
[6] Bao, Q., Wang, X., Zou, Y., Wang, Y. & Burgess, D. J. In vitro release testing method development for long-acting injectable suspensions. Int J Pharm 622, 121840 (2022).
[7] Mast, M. P. et al. Nanomedicine at the crossroads – A quick guide for IVIVC. Adv Drug Deliv Rev 179, (2021).
[8] Alimpertis, N., Simitopoulos, A., Tsekouras, A. A. & Macheras, P. IVIVC Revised. Pharm Res 41, 235–246 (2024).
[9] Ibarra, M., Vázquez, M. & Fagiolino, P. Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose. J Pharmacokinet Pharmacodyn 41, 363–373 (2014).
Reference: PAGE 32 (2024) Abstr 10837 [www.page-meeting.org/?abstract=10837]
Poster: Drug/Disease Modelling - Absorption & PBPK