M. van Eijk (1), N. Loos (1), T.P.C. Dorlo (1), A.H. Schinkel (1), J.H. Beijnen (1,2), A.D.R. Huitema (1,3,4)
(1) Department of Pharmacy & Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam. (2) Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht. (3) Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht. (4) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Introduction
Cabazitaxel is currently approved as an intravenous (IV) formulation for the second line treatment of hormone refractory prostate cancer [1]. Preclinical studies by our group have shown promising systemic cabazitaxel exposure after oral administration when co-administered with the CYP3A4 inhibitor ritonavir to transgenic mice with expression of human CYP3A4 in the liver and intestine (Cyp3aXAV). Subsequent translation to phase I clinical studies conventionally follows the ICH S9 guideline, which recommends the selection of a starting dose in humans based on 1/10th of the severely toxic dose in 10% of the mice [2]. These first-in-human trials with an oral formulation can be optimized by integrating preclinical data with existing pharmacological knowledge through population pharmacokinetic (PK) modelling, thereby providing an a priori estimate for an oral maximum tolerated dose (MTD) in humans. This estimate can ultimately lead to fewer dose-escalation steps and fewer patients required in first-in-human studies with an oral cabazitaxel formulation and more importantly, may result in fewer patients treated at subtherapeutic dose levels.
Objectives:
- Develop a population PK model for oral cabazitaxel co-administered with ritonavir in CYP3A4 transgenic mice.
- Extrapolate critical preclinical parameter estimates into an established model for IV cabazitaxel
- Predict the dose level of oral cabazitaxel that achieves equivalent exposure to IV cabazitaxel in terms of AUC0-inf and time above threshold concentrations of 0.05 µM (tc>0.05) and 0.005 µM (tc>0.005)).
Methods: 371 PK observations were available for both cabazitaxel and ritonavir, which were obtained in 42 Cyp3aXAV mice. Mice were treated with 10 mg/kg of oral cabazitaxel concomitant with either vehicle solution or 25 mg/kg, 10 mg/kg, or 1 mg/kg of the boosting agent ritonavir. Ritonavir and cabazitaxel PK were modelled sequentially following the PPP&D approach [3]. Weight-based allometric scaling was used to scale relevant PK parameters from mice to humans. The scaled preclinically informed PK parameters were imputed in a previously published model for IV cabazitaxel and subsequently used to predict an oral cabazitaxel dose level achieving equivalent exposure in terms of relevant parameters (AUC0-inf, tc>0.05, tc>0.005) to the IV formulation [4].
Results: Oral ritonavir PK in mice was described with a one-compartment model with first-order absorption and elimination. The preclinical PK of cabazitaxel was modelled with a two-compartment model in which the hepatic elimination and first-pass effect of cabazitaxel were estimated using a well-stirred liver model. Inhibition of intrinsic cabazitaxel clearance by ritonavir plasma concentrations was quantified by the inhibition constant (Ki, 4.14 ng/mL) following the assumption of a general competitive inhibition model. Our simulations demonstrated that exposure, equivalent to the 25 mg/m2 IV dose terms of AUC0-inf, tc>0.05 and tc>0.005, was achieved at boosted oral doses of 7.2 mg, 5.9 mg, and 5.7 mg, respectively for a patient of 70 kg. The sensitivity analyses demonstrated that the effect of a 10-fold decrease in the estimate for the Ki was relatively small while a 50-fold increase in Ki resulted in a ~2 fold increase in the median estimate for an equivalent dose as assessed by all metrics.
Conclusions: We have successfully modelled the preclinical PK of oral cabazitaxel co-administered with ritonavir in Cyp3aXAV mice. The preclinical PK model was integrated with a published model for IV cabazitaxel and used to obtain an estimate for an oral dose that achieves equivalent exposure to the registered IV dose in humans. These preclinically informed dose estimates may be used to guide decisions regarding the design of a first-in-human trial with oral cabazitaxel.
References:
[1] Sanofi-Aventis groupe. Summary of Product Characteristics: Jevtana, INN-cabazitaxel,. 2011 https://www.ema.europa.eu/en/medicines/human/EPAR/jevtana. Accessed 2022 March 28.
[2] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH S9 – Non-Clinical evaluation for anti-Cancer pharmaceuticals. Gl. 2013;Step 5:10.
[3] Zhang L, Beal SL, Sheiner LB. Simultaneous vs. Sequential Analysis for Population PK/PD Data I: Best-case Performance. J Pharmacokinet Pharmacodyn. 2003;30(6):387–404.
[4] Ferron GM, Dai Y, Semiond D. Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(3):681–92.
Reference: PAGE 30 (2022) Abstr 10007 [www.page-meeting.org/?abstract=10007]
Poster: Drug/Disease Modelling - Oncology