In vivo evaluation of the pharmacokinetic interactions between almonertinib and rivaroxaban, almonertinib and apixaban

Abstract

Background: Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations. Rivaroxaban and apixaban are a selective, direct factor Xa inhibitor used to treat venous thromboembolism (VTE), which is a frequent complication of NSCLC. Rivaroxaban and apixaban are substrates of CYP3A4, P-gp and BCRP, whereas almonertinib is an inhibitor of P-gp and BCRP. Rivaroxaban or apixaban are often prescribed together with almonertinib in NSCLC patients, but clear information on pharmacokinetic drug interaction is lacking. Therefore, this study aimed to unravel the extent of interactions between almonertinib-rivaroxaban and almonertinib apixaban in rats, and whether the pharmacokinetic interaction can be mitigated by rivaroxaban and apixaban dose adjustment. Methods: Rats were divided into ten groups (n = 6) that received rivaroxaban (2 mg/kg) (group 1), apixaban (0.5 mg/kg) (group 2), almonertinib (15 mg/kg) (group 3, group 4), almonertinib with rivaroxaban (2 mg/kg) (group 5), almonertinib with rivaroxaban (1 mg/kg) (group 6), almonertinib with apixaban (0.5 mg/kg) (group 7), almonertinib with apixaban (0.25 mg/kg) (group 8), rivaroxaban (2 mg/kg) with almonertinib (group 9), apixaban (0.5 mg/kg) with almonertinib (group 10). The concentrations of drugs were determined by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The levels of messenger RNA were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Results and Discussion: The results indicate that almonertinib increased the C_max and AUC_0-t of 2 mg/kg rivaroxaban by 3.30 and 3.60-fold, 1 mg/kg rivaroxaban by 1.28 and 1.90-fold. Almonertinib increased the C_max and AUC_0-t of 0.5 mg/kg apixaban by 2.69 and 2.87-fold, 0.25 mg/kg apixaban by 2.19 and 2.06-fold. In addition, rivaroxaban also increased systemic exposure to almonertinib. The results of qRT-PCR showed that almonertinib reduced the expression of Cyp3a1 in liver and intestine, and Abcb1a, Abcg2 in intestine and kidney. The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.

Keywords: UPLC-MS/MS; almonertinib; apixaban; drug-drug interactions; pharmacokinetics; rivaroxaban.

FIGURE 1

Chemical structure of rivaroxaban (A), apixaban (B), almonertinib (C), rivaroxaban-d₄ (D) and sorafenib-d₃ (E).

FIGURE 2

Product ion mass spectrum of rivaroxaban (A), rivaroxaban-d₄ (B), almonertinib (C), sorafenib-d₃ (D), and apixaban (E).

FIGURE 3

Typical chromatograms of (A) rivaroxaban, (B) rivaroxaban-d₄, (C) almonertinib, (D) and sorafenib-d₃ (E) apixaban. I, blank plasma; II, blank rat plasma with mixed working solution at LLOQ level and IS; and III, rat samples obtained after oral administration of rivaroxaban, apixaban or almonertinib.

FIGURE 4

The mean plasma concentration-time profiles of rivaroxaban after oral rivaroxaban alone and following multiple-doses almonertinib. Values are presented as mean ± SD (n = 6).

FIGURE 5

The mean plasma concentration-time profiles of apixaban after oral apixaban alone and following multiple-doses almonertinib. Values are presented as mean ± SD (n = 6).

FIGURE 6

The mean plasma concentration-time profiles of almonertinib after oral almonertinib alone and following multiple-doses rivaroxaban (A) or apixaban (B). Values are presented as mean ± SD (n = 6).

FIGURE 7

Relative expression ratios of mRNA for Cyp3a1 in liver and intestine, Abcb1a, Abcg2 in intestine and kidney of rats. (A) Effect of multiple-dose almonertinib treatment on mRNA expression of Cyp3a1 in liver and intestine. (B) Effect of multiple-dose almonertinib treatment on mRNA expression of Abcb1a in intestine and kidney. (C) Effect of multiple-dose rivaroxaban treatment on mRNA expression of Abcg2 in intestine and kidney. Values are presented as mean ± SD (n = 3). *p < 0.05, **p < 0.01.