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. 2025 Mar 29;95(1):49.
doi: 10.1007/s00280-025-04772-x.

Influence of interleukin-6 on the pharmacokinetics and pharmacodynamics of osimertinib in patients with non-small cell lung cancer

Hayato Yokota  1 , Kazuhiro Sato  2 , Sho Sakamoto  2 , Yuji Okuda  2 , Masahide Takeda  2 , Yumiko Akamine  1 , Katsutoshi Nakayama  2 , Masatomo Miura  3   4
Affiliations

Influence of interleukin-6 on the pharmacokinetics and pharmacodynamics of osimertinib in patients with non-small cell lung cancer

Hayato Yokota et al. Cancer Chemother Pharmacol. .

Abstract

Purpose: The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC).

Methods: Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis.

Results: The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021).

Conclusion: A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.

Keywords: Area under the plasma concentration–time curve; Interleukin-6; Osimertinib; Overall survival; Polymorphism; Trough concentration.

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Conflict of interest statement

Declarations. Ethics approval: The study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Akita University School of Medicine (approval number: 2826). Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Correlation between the IL-6 level and osimertinib concentration. The trough plasma concentration (C0) (A) and AUC0 − 24 (B) of osimertinib
Fig. 2
Fig. 2
Influence of the IL-6 rs1800796G > C polymorphism on the IL-6 level at 15 days after osimertinib therapy initiation. Comparisons of the IL-6 level (A) between the G allele and C/C genotype and (B) among the G/G, G/C, and C/C genotypes. The boxes represent the interquartile ranges, with the bold horizontal lines and numbers next to the boxes indicating the medians. The ends of each whisker (vertical lines) represent the smallest and largest values that were not outliers. Outliers (circles) are the values between 1.5 and 3 quartiles from the end of the box
Fig. 3
Fig. 3
Kaplan–Meier curves for (A) overall survival (OS) and (B) progression-free survival (PFS) in patients with the IL-6 rs1800796 G allele (dotted line) or C/C genotype (solid line)
See this image and copyright information in PMC

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