Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer

Abstract

BackgroundThe effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. MethodsBlood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. ResultsThere were signi cant correlations of the osimertinib AUC 0-24 with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were signi cant differences in the AUC 0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no signi cant differences in the AUC 0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no signi cant differences in the AUC 0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC 0-24 of osimertinib. ConclusionsAnalysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the e cacy or side effects of osimertinib. However, lower serum albumin values were associated with an increase in the AUC 0 − 24 of osimertinib. After beginning osimertinib therapy, periodic measurement of serum albumin values should be performed.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study

“…The median estimated AUC 0–24 of osimertinib at steady state was consistent or slightly lower than that in previous reports because some patients included in our study received a reduced dose [ 27 , 28 ]. Albumin level was identified as a significant covariate for the clearance of the parent compound and AZ5104 (positive correlation), consistent with a previous report [ 29 ]. C-reactive protein (CRP) is a covariate of osimertinib clearance [ 21 ].…”

“…Our results also indicated that exposures to the osimertinib parent compound and AZ5104 were associated with grade ≥ 2 diarrhea and increase in creatinine level. Similarly, a previous report suggested a linear relationship between the exposure to the parent compound and the occurrence of diarrhea [ 11 ], whereas another report suggested that exposure to the parent compound and grade ≥ 1 diarrhea were not associated [ 29 ]; thus, exposure to the parent compound may be related to higher grade (grade ≥ 2) diarrhea. The potential mechanism responsible for both diarrhea and creatinine increase may be the activation of chloride secretion as a result of EGFR inhibition [ 36 ].…”

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer

“…We did not find a correlation between these genetic polymorphisms and plasma osimertinib concentrations. This finding is in agreement with a previous study, which reported that genetic polymorphisms did not have an effect on plasma drug concentrations (22). Based on these results, ABCB1/ABCG2 genotyping before osimertinib administration might not be necessary to predict its efficacy and adverse events.…”

“…Similar to afatinib, osimertinib is a substrate for P-glycoprotein, encoded by ABCB1, and breast cancer resistance protein, encoded by ATP-binding cassette super-family G member 2 (ABCG2), raising the possibility that individual variations in plasma osimertinib concentrations may occur due to genetic polymorphisms. Although Yokota et al reported that ABC transporter polymorphisms did not contribute to individual variability in osimertinib pharmacokinetics, further studies are needed to resolve this question due to a modest number of enrolled patients (22). Therefore, the present study aimed to clarify the relationship of plasma trough concentrations of osimertinib with efficacy, safety, and associated genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations.…”

“…Osimertinib is metabolized by cytochrome P450, family 3, subfamily A (CYP3A), which also exhibits genetic polymorphisms. In Japanese patients, genetic polymorphisms in CYP3A4*1G and CYP3A5*3 were reported to have no effect on the area under the receiver operating characteristic curve in reported evaluations (22). Additionally, genetic polymorphisms of CYP3A4 were shown to affect plasma concentrations in vitro, suggesting that further investigation of the relationship between the role of genetic polymorphisms in metabolic pathways and plasma osimertinib concentrations is necessary.…”