A precision dosing application for docetaxel in metastatic prostate cancer
Claire Villette (1), Hitesh Mistry (1), Fernando Ortega (1), David Orrell (1), Frances Brightman (1), Jim Millen (1), Christophe Chassagnole (1)
(1) Physiomics plc, The Oxford Science Park, Oxford, UK
Introduction: The therapeutic window of chemotherapy drugs is commonly established at a population level and patient dose selection is often simply scaled with Body Surface Area (BSA). Due to large inter-individual physiological variability in term of ADME, this leads to a significant number of patients being under or over-dosed. While a limited number of precision dosing techniques exist to tailor patient-specific treatment, they typically require costly additional PK tests which severely restrict their use in clinical practice.
Objectives: Focusing on docetaxel for advanced metastatic prostate cancer, we have developed a demonstrator for precision dosing which requires a single weekly classical blood test in the first chemotherapy cycle. It will fit within the current clinical practice to improve patient outcome at low cost.
Methods: This tool was developed using publicly available data from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (clinical trial number NCT00617669). This cohort includes 412 patients who were treated with docetaxel between 2008 and 2011 in cycles of 21 days with weekly blood tests in the first cycle.
A population PK/PD model for docetaxel and leukocyte population was assembled based on the literature [1, 2]. Individual patient parameters including docetaxel Area Under the Curve (AUC) were estimated by calibrating this model with weekly measured blood cell counts using a Bayesian approach. Survival and toxicity Cox models were developed using estimated PK/PD parameters as well as biomarker levels. They allowed estimations of gains in prognostic as well as toxicity risks associated with modifying patient dose after the first chemotherapy cycle.
These models were made available through a web application which supports clinicians in their decision to update patient dose. In a typical in-situ scenario, the patient would receive a first cycle of chemotherapy based on standard BSA-guided dose. Before administering the second dose, the clinician would enter the results of their patient’s weekly blood tests in the app, which they would then use to estimate prognostic gains and toxicity risks associated with dose changes. This would help them make an informed dose selection for the second cycle. All subsequent doses would be kept identical unless severe toxicity is observed.
Results: Concordance levels of the order of 0.7 were obtained for the survival and toxicity models, with significant predictive variables including docetaxel AUC, age, patient protein and enzyme levels as well as Prostate Specific Antigen (PSA).
Patients with low estimated hematologic toxicity (neutrophil count not dropping under 0.5 billion/L) presented a median overall survival time of 480 days, against 625 days for patients with higher hematologic toxicity. Patients with low estimated docetaxel AUC (
Conclusion: We have developed a precision dosing app for docetaxel in metastatic prostate cancer which requires a single weekly classical blood test in the first chemotherapy cycle. This app will work as a decision support tool for clinicians, assisting them in adapting docetaxel dose to the patient from the second treatment cycle onwards. That has the potential to significantly improve patient outcome at low cost without disrupting current clinical practice.
References:
[1]: McLeod, H.L., Kearns, C.M., Kuhn, J.G. and Bruno, R., 1998. Evaluation of the linearity of docetaxel pharmacokinetics. Cancer chemotherapy and pharmacology, 42(2), pp.155-159.
[2]: Friberg, L.E., Henningsson, A., Maas, H., Nguyen, L. and Karlsson, M.O., 2002. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. Journal of clinical oncology, 20(24), pp.4713-4721.