Farina Hellmann (1), Gareth Veal (2), Georg Hempel (1)
(1) Department of Pharmaceutical and Medical Chemistry, University of Muenster, Germany; (2) Northern Institute for Cancer Research, Newcastle University, United Kingdom
Introduction: Ewing sarcoma is a very aggressive bone tumour, which often occurs in adolescents or young adulthood [1]. The incidence of treatment-associated toxicity varies significantly between children, adolescents and adults [2]. These toxicities are often worse in young children and reduce with advancing age. Furthermore, the survival rates differ between age groups with younger patients having a better outcome as compared to older patients [3]. The standard induction therapy of Ewing sarcoma patients contains the drugs vincristine, ifosfamide, doxorubicin, etoposide and cyclophosphamide. Population pharmacokinetic modelling of these drugs can help to further elucidate the age-dependent differences in toxicity and survival of Ewing sarcoma patients and therefore, improve the therapy.
Objectives:
- Investigation of a possible age-dependency in the clearance of vincristine, ifosfamide, doxorubicin, etoposide and cyclophosphamide in Ewing sarcoma patients
- Analysis of possible predictors of treatment-associated toxicity in Ewing sarcoma patients such as age and gender
- Development of improved strategies regarding toxicity and survival for the treatment of Ewing sarcoma patients
Methods: The Northern Institute for Cancer Research (NICR) at Newcastle University is running an ongoing clinical pharmacology study to investigate differences in drug disposition between Ewing sarcoma patients of different ages and the early prediction of vincristine, ifosfamide, doxorubicin and etoposide (VIDE) toxicity in this patient population (short title: PK 2013 01; EUDRACT Number: 2013-000052-17). In total, 120 adolescent Ewing sarcoma patients treated with standard dose induction chemotherapy VIDE or vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE), will be recruited to the PK 2013 01 study. Blood samples are collected from patients at defined time points for the quantification of all drugs mentioned above on a single course of VIDE or VDC/IE treatment. The plasma concentrations are used to develop population pharmacokinetic models with NONMEM® for the drugs.
Results: For etoposide, a two compartment model with a combined error model was developed based on the 247 plasma concentrations of 58 patients. All pharmacokinetic parameters are scaled to the body surface area of the patients. The model estimates for clearance and central volume of distribution are 1.97 L/h/1.55 m² and 5.59 L/1.55 m², respectively. The peripheral clearance amounts to 0.947 L/h/1.55 m² and the peripheral volume of distribution is determined as 3.76 L/1.55 m². All pharmacokinetic parameters have a residual standard error (RSE) below 30 % indicating an adequate precision. In the current etoposide model, no other covariates investigated, including age or gender, exhibited a significant effect on one or more pharmacokinetic parameters. Following completion of patient recruitment the dataset for the entire patient population will be used to revise the model. However, these preliminary data suggest that no age-dependent differences in etoposide pharmacokinetics can be detected in this patient population.
Conclusion: No differences in the pharmacokinetics of etoposide with age or gender were identified following analysis of preliminary data. Additional analyses are ongoing for the drugs vincristine, ifosfamide, doxorubicin and cyclophosphamide
References:
[1] Lawlor E R, Sorensen P H (2015) Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog 20(3-4): 155–171
[2] Juergens C, Weston C, Lewis I et al (2006) Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47(1): 22–29
[3] Ladenstein R, Pötschger U, Le Deley M C et al (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28(20): 3284–3291
Reference: PAGE 28 (2019) Abstr 8947 [www.page-meeting.org/?abstract=8947]
Poster: Drug/Disease Modelling - Oncology