Sebastiaan C. Goulooze (1,2) and Jennifer H. Martin (2).
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands, (2) School of Medicine and Public Health, University of Newcastle, NSW, Australia.
Objectives: Due to large interpatient variability, therapeutic drug monitoring (TDM) is being considered to individualise cancer treatment with tyrosine kinase inhibitors such as sunitinib[1]. However it remains unclear what impact sunitinib TDM could have on the clinical outcome of eligible patients. The aim of this study was to: (a) estimate the expected improvement in time to tumour progression (TTP) in patients with gastrointestinal stromal tumours (GIST) treated with an initial dose of 37.5 mg/day sunitinib, and (b) assess feasibility of a sunitinib TDM trial by estimating the number of subjects required for sufficient statistical power.
Methods: Simulations were performed in R, based on published models of the pharmacokinetics and pharmacodynamics of sunitinib[2,3]. The dynamics of the impact of drug exposure change on the TTP hazard rate are unknown. Therefore two scenarios were simulated: an optimistic scenario with an immediate impact and a conservative scenario with a very gradual impact. Dose-limiting toxicity (67%) and patient drop-out (biweekly rate of 0.2%) were included in the simulations used to estimate required study size.
Results: Two rounds of TDM reduced the percentage of patients below target exposure levels from 52% to 16%.For patients with an initial exposure below the target, median TTP was estimated at 216 days with a fixed dosing regimen. TDM increased the TTP of eligible patients to 249 days (+15%) and 283 (+31%) days in the ‘gradual’ and ‘immediate’ impact scenario. However, an estimated 1600 (immediate impact) or 3800 (gradual impact) subjects are required for a sunitinib TDM trial to be powered to detect a significant impact on TTP.
Conclusions: Although clinical data on the impact of sunitinib TDM is lacking, the simulations suggest a clinically relevant increase for eligible patients. However, considering the fact that GIST is a rare cancer (and sunitinib not its first line treatment), the number of subjects required for a TDM trial are likely prohibitively high. Pharmacometric modelling and simulation might support evidence-based TDM practices when prospective TDM trials are not feasible due to low number of eligible patients.
References:
[1] Lankheet NA, Kloth JS, Gadellaa-van Hooijdonk CG, Cirkel GA, Mathijssen RH, Lolkema MP, Schellens JH, Voest EE, Sleijfer S, de Jonge MJ, Haanen JB, Beijnen JH, Huitema AD, Steeghs N. Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours. Br J Cancer (2014) 110(10):2441-2449.
[2] Yu H, Steeghs N, Kloth JS, de Wit D, van Hasselt JG, van Erp NP, Beijnen JH, Schellens JH, Mathijssen RH, Huitema AD. Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662. Br J Clin Pharmacol (2015) 79(5):809-819.
[3] Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol (2010) 66(2):357-371.
Reference: PAGE 25 (2016) Abstr 5786 [www.page-meeting.org/?abstract=5786]
Poster: Drug/Disease modeling - Oncology