Julie M. Janssen (1), Gertjan J.L. Kaspers (2, 3), Denise Niewerth (3), Bram J. Wilhelm (4), C. Michel Zwaan (5), Jos H. Beijnen (1, 6), Alwin D.R. Huitema (1, 7)
(1) Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands, (2) Princess Maxima Center for Pediatric Oncology/Hematology, Utrecht, The Netherlands, (3) Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands, (4) Clinical Pharmacology & Pharmacy, VU University Medical Center, Amsterdam, The Netherlands, (5) Department of Pediatric Oncology/Hematology, Erasmus-MC Sophia Children’s Hospital, Rotterdam, The Netherlands, (6) Science Faculty, Utrecht University for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands, (7) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
Objectives: Bortezomib is a proteasome inhibitor targeting the 20S proteasome used in the treatment of adult multiple myeloma, and is currently under investigation for treatment of children with relapsed acute lymphoblastic leukemia (ALL). The pharmacokinetic (PK) profile of bortezomib is nonlinear and is characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after intravenous (iv) administration. Furthermore, a marked increase in exposure was observed in the second week of treatment (1, 2, 3). This has previously been explained by extensive binding of bortezomib to proteasomes in erythrocytes and peripheral tissue (4). The primary aim of the current study was to develop a PK model for bortezomib in order to evaluate the currently used dosing regimen in pediatric patients. The secondary aim was to understand the time-dependent change in bortezomib exposure.
Methods: 323 samples of 28 patients (1.0 – 17.5 years old) were available from the ITCC 021/I-BFM-SG-study (EudraCT number: 2009-014037-25). Patients were treated with an iv bortezomib dose of 1.3 mg/m2 in a twice-weekly schedule (administrations on day 1, 4, 8 and 11). PK samples in plasma and cerebrospinal fluid (CSF) were collected after the bortezomib administrations on day 1 and 11 at 7 time points (pre-dose and 15 minutes, 3, 8, 24, 48, 72 hours after dose). A semi-physiological PK model for bortezomib was developed incorporating saturable binding of bortezomib. The Langmuir model was used to describe the non-linear binding of bortezomib in the central compartment. Allometric scaling was applied to all structural model parameters. Correlations between PK parameter estimates and age were investigated to identify a possible maturation effect. Visual assessment of the model was applied by goodness-of-fit plots and prediction-corrected visual predictive check (pcVPC). Uncertainty on model parameters were calculated using the Sampling Importance Resampling (SIR) procedure.
Results: Bortezomib concentrations in CSF were undetectable in the majority of the samples (83.5%). The plasma data was best described by a two-compartment model with large volumes of distribution (V1 = 69.7 L (97.5% confidence interval (CI) 46.0 – 105.0 L) and V2 = 656 L (97.5% CI 417 – 1019 L)) and systemic clearance of 5.95 L/h (97.5% CI 3.56 – 9.24 L/h). Increased concentrations were observed on day 11 compared to day 1. Non-linear binding in the central compartment was best described by a saturable Langmuir model. The population value of the maximal specific binding capacity (Bmax) was 60.7 ng/mL (97.5% CI 35.1 – 105 ng/mL) with 52.1% (97.5% CI 39.8 – 69.3%) inter-individual variability. The corresponding equilibrium dissociation constant (KD) was 60.2 ng/mL (97.5% CI 32.5 – 110 ng/mL). Maturation effect and other covariate effects could not be identified. The goodness-of-fit plots and pcVPC indicated that the developed model adequately captured the PK and variability of the data.
Conclusions: The semi-physiological model adequately described the nonlinear PK of bortezomib in plasma. Saturable binding, probably to erythrocytes, provides an explanation for the increased exposure in the second week of treatment. Additionally, the final model parameters were in agreement with reported adult values.
References:
[1] Horton TM, Pati D, Plon SE et al. A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children’s Oncology Group Study. Pediatr Blood Cancer. 2013;60(3):390-395.
[2] Reece DE, Sullivan D, Lonial S et al. Pharmacokinetic and pharmacodynamics study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol. 2011;67(1):57-67.
[3] Blaney SM, Bernstein M, Neville K et al. Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children’s Oncology Group Study (ADVL0015). J Clin Oncol. 2004;22(23):4804-4806.
[4] Zhang L, Mager DE. Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice. J Pharmacokinet Pharmacodyn. 2005;42(5):541-552.
Reference: PAGE 27 (2018) Abstr 8590 [www.page-meeting.org/?abstract=8590]
Poster: Drug/Disease Modelling - Oncology