The Relationship Between Efficacy and Safety of Osimertinib Blood Concentration in Patients With EGFR Mutation-positive Lung Cancer: A Prospective Observational Study

Abstract

Background/Aim: Osimertinib blood levels and their impact on treatment continuation in patients with EGFR mutation-positive lung cancer is not known. This study investigated the drug blood levels and risk factors affecting treatment continuation. Patients and Methods: Fifty-six patients with recurrent and inoperable epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who received Osimertinib (80 mg once daily, daily dose) between October 1, 2016, and August 31, 2021, were included. Patients were classified into two groups using a cutoff blood level of 155 ng/ml. The primary endpoint was the relationship between Osimertinib exposure and efficacy, and secondary endpoints were the relationship between Osimertinib exposure and side effects, and the effect of covariates on efficacy and blood levels. Results: The median progression-free survival (PFS) for evaluable patients in the steady-state trough concentration (C min ss ) ≥155 ng/ml and C min ss <155 ng/ml groups was 18.7 months and 31.2 months. Serum albumin (Alb) levels were 3.73±0.40 g/dl and 3.93±0.28 g/dl (p=0.030), respectively, and in multivariate analysis, Alb <3.7 g/dl was associated with a hazard ratio of p=0.013), indicating that Alb <3.7 g/dl significantly shortened PFS. Conclusion: Free blood concentration of Osimertinib may have been increased by a combination of factors, including decreased hepatic metabolic function and decreased albumin production caused by systemic inflammation in patients with cancer. However, there was no effect of Osimertinib C min ss on PFS.

Integrated PBPK-EO modeling of osimertinib to predict plasma concentrations and intracranial EGFR engagement in patients with brain metastases

“…3 ). The observed effects of these key parameters identified by the PBPK-EO model on plasma C trough and intracranial EO trough are consistent with clinical observations 14 , 53 , 56 . Overall, the findings from the PBPK-EO model emphasize the substantial influence of these factors on OSI exposure and target engagement in BRT, highlighting their critical role in guiding personalized treatment approaches for patients with brain metastases.…”

“…The sensitivity analysis has underscored the significance of albumin levels as sensitive parameters for C trough in plasma and BRT among all selected parameters. Notably, multiple clinical studies have established a strong association between plasma albumin levels and clinical efficacy 56 . Furthermore, the wide variability in albumin levels among patients (ranging from 2.0 to 58 g/L) has been observed 48 , 49 , potentially leading to substantial variations in plasma exposure and efficacy.…”

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach

“…In certain clinical studies ( Brown et al, 2017 ; Boosman et al, 2022 ; Hashino et al, 2023 ), when patients’ plasma C trough levels for OSI were divided into only two groups, the relationship between exposure and efficacy was not observed. This is likely because clinical efficacy requires a minimal plasma C trough , while excessive C trough levels can lead to adverse events and result in shorter progression-free survival (PFS).…”

“…Table 1 provides a summary of the modeling parameters utilized in the PBPK model ( Dixon et al, 2003 ; Barter et al, 2013 ; Dickinson et al, 2016 ; Pilla Reddy et al, 2018 ; Schwenger et al, 2018 ; Alsmadi et al, 2021 ; An et al, 2021 ; Hashino et al, 2023 ; Pharmaceuticals and Medical Devices Agency PMDA, 2023 ). Rodgers and Rowland, and PK-Sim’s standard methods provided the human tissue distribution and cellular permeability estimate for OSI.…”

“…For the remaining three metabolizing enzymes, their expression levels in patients were calculated assuming a ratio of 0.7 compared to the healthy population. The plasma albumin levels were set at 0.45 g/dL in the healthy population and 0.31 g/dL in the diseased population, based on information from published papers ( Dixon et al, 2003 ; Hashino et al, 2023 ). Finally, the f up and blood-to-plasma concentration ratio (R bp ) in NSCLC patients were determined using Eqs 1 – 3 : …”