Zinnia Parra-Guillen (1) (2), Josep MarÃa Cendrós Carreras (3), Concepción Peraire (3), Rosendo Obach (4), Joan Prunynosa (3), Eric Chetaille (5) and Iñaki F Troconiz (1)
(1) Dept. of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Spain, (2) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (3) Pharmacy and Pharmaceutical Technology Dept., University of Barcelona, Spain, (4) Calle Sabino Arana 58 11º 1ª Barcelona 08028, Spain, (5) Ipsen Innovation. Les Ulis. France.
Objectives: (i) To develop a population model characterizing simultaneously the pharmacokinetic profiles of irosustat en plasma and blood after single and repeated oral administration, and (ii) to study the patient characteristics that might have a significant impact on the pharmacokinetics of irosustat.
Methods: An open label, multicentre, phase I multiple cohort dose escalation study was conducted in postmenopausal women with oestrogen-receptor positive breast cancer [1]. Thirty five patients were recruited into each of the following dose cohorts: 1 (n=3), 5 (n=7), 20 (n=6), 40 (n=13), and 80 (n=6) mg. Irosustat was administered as a single oral dose to each patient followed by an observation period of 7 days. On day 8 each patient received once daily oral administration of irosustat until day 34. Blood samples to determine the concentration of irosustat in both blood and plasma were obtained at specific times after the start of the treatment. Pharmacokinetic analyses were performed using the population approach with the software NONMEM 7.2 [2].
Results: A one compartment model with transit compartment to account for the absorption [3] process was implemented. A concentration-dependent pharmacokinetic profile was also observed and modelled considering instantaneous and reversible binding with limited distribution capacity (AMAX) of the free drug to the red blood cells (RBC).
Inter-subject variability (ISV) was supported on MTT, NN, KA, F1, kel, and a significant negative correlation was found for the ISV of KA and F1. Covariate analysis was also performed observing a significant relationship between relative biovailability and dose.
Based on the results from the model developed irosustat exhibits linear disposition properties at values of plasma concentration (CPL) lower than 32.79 ng/mL and blood to plasma ratio (BPR) of 419 for the 5ng/mL dose, indicating very high affinity for the RBC compartment. Similarly, a blood clearance of 2.7 L/day was estimated, in the case of complete oral bioavailability, and under linear pharmacokinetic conditions suggesting a low clearance of the drug.
Conclusions: A non-linear population pharmacokinetic model capable to describe simultaneously the concentrations of irosustat in plasma and blood over time after single and repeated oral doses in postmenopausal women with oestrogen-receptor positive breast cancer has been developed and evaluated for a dosing range from 5 to 80 mg.
References:
[1] Coombes RC, Cardoso F, Isambert N, Lesimple T, Soulié P, Peraire C, et al. Breast Cancer Res Treat (2013) 140(1):73-82.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011.
[3] Savic RM, Jonker DM, Kerbusch T, Karlsson MO. J Pharmacokinet Pharmacodyn (2007) 34(5):711-726.
Reference: PAGE 23 (2014) Abstr 3212 [www.page-meeting.org/?abstract=3212]
Poster: Drug/Disease modeling - Oncology