Arwa Alghaith1, Jamie Dean1, Joseph Standing2
1Department of Medical Physics and Biomedical Engineering, UCL, 2Institute of Child Health, University College London
Background: Clinical studies combining molecularly-targeted drugs with radiotherapy have largely failed to improve patient outcomes in cancer. A potential reason is the insufficient consideration given to treatment scheduling. Often, schedules are selected based on previous monotherapy or combination regimens with chemotherapy. Mathematical modelling is a viable approach to explore alternative schedules to enhance synergy between therapies and investigate associated toxicities. A population pharmacokinetic (PopPK) model of the PARP-inhibitor olaparib was previously published, primarily based on breast and ovarian cancer data. We evaluated its generalisability to alternative patient populations and investigated the effects of dosing schedules on olaparib concentration at the time of radiotherapy treatment. Aim: To (i) evaluate the ability of the olaparib PopPK model to accurately predict olaparib concentrations in patient populations not used in the model development; and (ii) apply this model to investigate the effects of different dosing schedules in patients treated with concurrent olaparib and radiotherapy. Methods: For evaluating model generalisability, we identified the OPARATIC trial (NCT01390571), which measured olaparib concentrations on the fourth day of dosing in 45 patients with recurrent glioblastoma. Monte Carlo simulations were performed using a non-linear mixed-effects PopPK model for 3 cohorts: 100mg once daily (QD), 150mg QD, and 200mg twice daily (BID). Population predicted plasma concentrations with their associated variability (95% CI) were compared to observed plasma concentrations. For evaluating effects of different dosing schedules, we identified the CONCORDE-A trial (NCT04550104), which administered various olaparib and radiotherapy schedules in patients with non-small cell lung cancer (NSCLC). Olaparib and radiotherapy administration timings were obtained from 13 patients across 3 dose levels (100mg 3 times a week, QD and BID). Population predicted concentrations and their 95% CI were generated for each patient, and plasma and peripheral concentrations were compared. To identify superior schedules, alternative dosing regimens were simulated, to align radiotherapy dosing with the peak peripheral concentration of olaparib. Concentrations at radiotherapy administration were compared between equivalent regimens. Results: For the OPARATIC trial, observed olaparib concentrations ranged from 1.4–10.2 uM (mean±SD, 3.3±1.6) in the 100 mg QD cohort; model simulation yielded a mean of 2.1 uM (95% CI 0.3–10.6). In the 150 mg QD cohort, observed concentrations ranged from 0.3–10.9 uM (mean±SD, 3.4±2.4); model simulation yielded a mean of 3.1 uM (95% CI 0.5–16.0). In the 200 mg BID cohort, observed concentrations ranged from 3.0–12.1 (mean±SD, 6.9±2.0); model simulation yielded a mean of 4.7 uM (95% CI 0.8–24.5). Mean predicted errors for each dose cohort were 1.6, 1.4 and 3.2 uM, respectively. Root mean square errors were 2.7, 3.4, 4.9 uM. Although the central tendency is underpredicted in these patients, the observed concentrations fell within the 95% CI of the simulated concentrations. For the CONCORDE-A trial patients, predicted olaparib peripheral concentrations at radiotherapy administration increased with more frequent dosing, while plasma concentrations remained similar. Comparison of simulated alternative schedules showed that QD olaparib dosing 5 hours before radiotherapy could achieve higher peripheral drug concentrations at the time of radiotherapy administration than the equivalent dose with BID schedules. Conclusion: The olaparib PopPK model was able to predict plasma concentrations in recurrent glioblastoma patients. Alternative scheduling in NSCLC patients shows that higher olaparib concentrations at radiotherapy administration could be achieved than those administered in the CONCORDE-A trial. This research was conducted with support from AstraZeneca UK Limited.
Zhou D, et al. Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-analysis in Oncology Patients. Clin Pharmacokinet. 2019 May;58(5):615-625. Hanna C, et al. Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850. Walls GM, et al. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020 Sep 22;25:61-66.
Reference: PAGE 33 (2025) Abstr 11318 [www.page-meeting.org/?abstract=11318]
Poster: Drug/Disease Modelling - Oncology