Adriana Castiñeiras1,4, Gema López Ginés4, Iñaki F. Trocóniz1,2,3
1University of Navarra, 2Navarra Institute for Health Research, IdisNA, 3Institute of Data Science and Artificial Intelligence, DATAI, 4Laboratorios Farmacéuticos Rovi
Introduction. Letrozole is an aromatase inhibitor used as a first line treatment for hormone-dependent breast cancer in post-menopausal women and it is currently marketed as daily oral tablets [1,2,3]. However, non-adherence and/or premature treatment discontinuation are associated to higher mortality risk in these patients [4]. The use of long-acting injectable formulations has emerged as an alternative in order to overcome this non-fulfilled necessity at the same time that help reduce interindividual variability (IIV) and improve bioavailability [5]. In this sense, Laboratorios Farmacéuticos Rovi is developing Letrozole ISM®, a novel polymeric LAI letrozole formulation. Since LAI contain higher doses of drug, it is important to control in vivo behaviour to avoid dose dumping, 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]. Objectives. This study was focused on developing a population pharmacokinetic model to characterize the clinical release performance of Letrozole ISM® as a step to further try to establish an IVIVC. Methods. A phase I clinical trial was carried out in 49 healthy female volunteers. First, the 49 volunteers received a daily oral dose of the marketed letrozole reference formulation (2.5 mg tablets) for 14 days (Phase A) to characterize letrozole disposition during steady-state. After a washing period, the same volunteers received 50 mg (n=21) or 100 mg (n=28) of the LAI formulation as a single intramuscular dose, and the study was prolonged until no letrozole levels could be detected (Phase B). Plasma samples were regularly obtained over the duration of the clinical trial and letrozole was quantified by HPLC-MS/MS. Data were analysed following the population approach using NONMEM 7.5. Drug disposition was characterized using compartmental models. Instantaneous and/or delayed zero and first order input processes from several depot compartments were considered to describe letrozole absorption. Results. From 16 to 20 and 19 to 37 samples were obtained from each volunteer during Phase A and B, respectively. Drug disposition was best characterized with a two-compartment model. After multiple oral dosing, inter-patient variability in relative bioavailability resulted negligible, and drug absorption was described with a first order process associated to a 1.4 h half-life. The estimates of the inter-individual variabilities ranged from 35 to 55%. Variability was estimated for apparent clearance and apparent volume of distribution of the peripheral compartment, and first order rate of absorption, ranging from 35 to 55%. Three absorption processes were required to describe systemic concentration over time after single intramuscular administration. One of them followed zero order kinetics with a typical duration of the process of 3.8 days and accounting for 2.5 % of the absorbed fraction. The rest of the processes followed first order kinetics. One of two began just after injection and was characterized with a first order rate constant and a fraction of the absorbed dose of 0.02 h-1 and 3%, respectively. Finally, most of the absorbed dose followed a slow input process starting typically 145 days after injection. Goodness of fit (GOF) plots and visual-predictive checks (VPC) confirmed good description of the data. Conclusions. The nlme approach was successfully applied to clinical pharmacokinetic data obtained after intramuscular administration of Letrozole ISM®, allowing the characterization of the letrozole absorption process. This constitutes a further step to establish an IVIVC with previously obtained Letrozole ISM® in vitro dissolution data.
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Reference: PAGE 33 (2025) Abstr 11363 [www.page-meeting.org/?abstract=11363]
Poster: Drug/Disease Modelling - Absorption & PBPK