Population pharmacokinetics of ibrutinib and its dihydrodiol metabolite in patients with lymphoid malignancies
Fanny Gallais (1), Loïc Yseabert (2), Anne Quillet-Mary (1), Loïc Dupre (3), Ben Allal (1,2), Etienne Chatelut (1,2), Mélanie White-Koning (1)
(1) Centre de Recherche en Cancérologie de Toulouse (CRCT), Inserm UMR1037, Université Paul Sabater France, (2) Institut Universitaire du Cancer de Toulouse – Oncopole France, (3) Centre de Physiopathologie de Toulouse Purpan (CPTP), Inserm UMR1043, Université Paul Sabatier France.
Introduction: Ibrutinib (Imbruvica®) is a targeted therapy used for the treatment of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. The Bruton Tyrosine kinase (BTK) plays an essential role in the B cell antigen receptor (BCR) pathway, which is involved in these diseases. Ibrutinib binds covalently to BTK, leading to its irreversible inhibition, and therefore alters the BCR pathway (1). Ibrutinib pharmacokinetics (PK) are highly variable between patients. Its oral bioavailability is poor (F=3%) due to high first pass hepatic metabolism. One of its metabolites, dihydrodiol-ibrutinib (DHD-ibrutinib), is 15 times less active than ibrutinib but its concentrations are up to twice those of ibrutinb (2).
Objectives:
- Develop a population PK (popPK) model for ibrutinib and its dihydrodiol metabolite
- Quantify and explain PK interindividual variability (IIV) in this population
Methods: The “PKE3I” study was initiated in 2016 at IUCT-oncopole (Toulouse, France). A total of 93 patients treated by ibrutinib were included in the study and followed for two years. A rich PK sampling (6 samples: before drug intake, 0.5, 1, 2, 4 and 6h after drug intake) was scheduled one month after treatment initiation. In addition, single blood samples were taken at months 2, 3 and 6 to obtain trough concentrations. Concentrations of ibrutinib and its dihydrodiol metabolite were quantified by ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) using a previously developed technique. The lower limit of quantification (LLOQ) was 0.98 ng/mL. A popPK approach was used to develop a compartmental model for ibrutinib and DHD-ibrutinib. The model was developed in Nonmem 7.4, graphical analysis were assessed in R 3.4.2.
Results: A total of 89 patients performed PK blood sampling. Overall, 1501 drug concentrations were included in the popPK analysis. Concentrations below the LLOQ (4% of total concentrations) were set to LLOQ/2=0.49ng/mL. The base model consists in one dosing compartment, 2 compartments for ibrutinib and 2 compartments for DHD-ibrutinib. Absorption was described by a sequential zero-first order process (D1=0.93h, KAI=1.48/h) and a lag time (ALAG1=0.23h). Ibrutinib can be either excreted (CLIBRU/F=208L/h, IIV_CLIBRU=67.6%) or metabolized (KMET/F=182L/h, IIV_KMET=81.6%) into DHD-ibrutinib which is then excreted (CLDHD=188L/h, IIV_CLDHD=52.7%). A link between dosing compartment and DHD-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism (KA_DHD=1.18/h, IIV_KADHD=63.2%) (3). Non-zero covariance terms in the omega matrix were found to improve the model. Inter-occasion variability (IOV) was evaluated on all PK parameters and found to be statistically significant for CLIBRU (IOV_CLIBRU=48.2%), CLDHD (IOV_CLDHD=22.3%) and central volume of distribution V2 (IOV_V2=40.9%). Proportional residual variability is 35% for ibrutinib and 25% for DHD-ibrutinib. The impact of available morphological, biological and clinical covariates will be assessed using a stepwise approach.
Conclusions: Marostica et al. proposed a first popPK model for ibrutinib (4). Our study improved this model by adding the DHD-ibrutinib metabolite and simultaneously taking into account ibrutinib and DHD-ibrutinb concentrations. The final model fits the data well. Interindividual variability was quantified. Covariates remain to be tested to explain this variability. This PK model will further be used for PKPD modelling. The objective will be to describe lymphocyte dynamics under ibrutinib treatment.
References:
[1] Wiestner A. Targeting B-Cell receptor signaling for anticancer therapy: the Bruton’s tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol Off J Am Soc Clin Oncol. 1 janv 2013;31(1):128-30.
[2] imbruvica-epar-public-assessment-report_en.pdf [Internet]. [10-01-2018]. Disponible sur: https://www.ema.europa.eu/documents/assessment-report/imbruvica-epar-public-assessment-report_en.pdf
[3] Bertrand J, Laffont CM, Mentré F, Chenel M, Comets E. Development of a complex parent-metabolite joint population pharmacokinetic model. AAPS J. sept 2011;13(3):390-404
[4] Marostica E, Sukbuntherng J, Loury D, de Jong J, de Trixhe XW, Vermeulen A, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. janv 2015;75(1):111-21.
