Jennifer J. Bonner (1), Nicola Hannaway (2), Nicola Wyatt (2), Yvette Drew (1,2), Alastair Greystoke (1,2)
(1) Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; (2) Freeman Hospital, The Newcastle upon Tyne NHS Trust, Newcastle upon Tyne, United Kingdom
Objectives: Although the elderly comprise the majority of cancer patients (1), they are under-represented in clinical trials of anticancer agents (2,3), particularly in the Phase I trials where doses are determined. This may be one of the reasons why they have higher rates of side-effects. Physiologically-based pharmacokinetic (PBPK) modelling and simulation may assist in dose selection and exposure prediction in these patients but requires a virtual geriatric population with realistic information on parameters that change with advancing age and the presence of cancer.
Whether physiological changes that potentially affecting PK may change with cancer type as well as with age is not known. Therefore we assessed basic parameters that would impact on PBPK modelling in non-small cell lung and ovarian cancer patients over the age of 70 years and compared them to simulated healthy individuals in the same age range.
Methods: Anonymised patient data was obtained from 228 non-small cell lung cancer patients and 113 patients with ovarian cancer. Relationships between height and age, weight and height, and glomerular filtration rate (GFR) and age were assessed by nonlinear regression. The slope and intercept values from the height and weight curves were used to simulate height and weight values for 1,000 virtual geriatric subjects within Simcyp version 14.1. Comparisons of patient GFR, serum albumin, and haematocrit by cancer type were performed by one-way ANOVA with Tukey’s multiple comparisons test.
Results: GFRs were significantly lower in the ovarian cancer group than in the lung cancer group (mean 57.49 mL/min vs. 67.68 mL/min, p<0.001) as were albumin concentrations (mean 36.87 g/L vs. 39.17 g/L, p<0.01) and haematocrits (mean 0.36 vs. 0.38, p<0.01). All laboratory parameters were significantly different from simulated healthy individuals. As expected an inverse linear relationship between age and GFR was observed for both the lung and ovarian cancer groups.
Conclusions: These results show that laboratory parameters that may significantly affect PK differ significantly in cancer patients from simulated healthy individuals of the same age, and may also differ by cancer type. These findings underscore the need for cancer type-specific virtual populations for modelling and simulation in elderly patients with cancer.
References:
[1] Talarico, L., G. Chen, and R. Pazdur, Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. Journal of Clinical Oncology, 2004. 22(22): p. 4626-4631.
[2] Hutchins, L.F., et al., Underrepresentation of patients 65 years of age or older in cancer-treatment trials. The New England Journal of Medicine, 1999. 341(27): p. 2061-2067.
[3] Murthy, V.H., H.M. Krumholz, and C.P. Gross, Participation in cancer clinical trials: race-, sex-, and age-based disparities. Journal of the American Medical Association, 2004. 291(22): p. 2720-2726.
Reference: PAGE 25 (2016) Abstr 6029 [www.page-meeting.org/?abstract=6029]
Poster: Drug/Disease modeling - Oncology