In Vivo pharmacokinetic interactions of ribociclib with rivaroxaban and apixaban in rats: implications for increased drug exposure and dose adjustments

Abstract

Background: Apixaban (API) and rivaroxaban (RIVA) are orally available inhibitors of coagulation factor Xa and are commonly used to treat cancer-related venous thrombosis. Ribociclib (RIBO), a first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR⁺/HER2^-) advanced breast cancer, is an inhibitor of CYP3A4, P-gp, and BCRP. Given the potential for these drugs to be co-administered in clinical settings, there is limited information regarding the pharmacokinetic drug-drug interactions (DDIs) between ribociclib and these anticoagulants. This study aimed to evaluate the extent of DDIs between ribociclib and rivaroxaban or apixaban in rats and to explore the optimization of drug dosing strategies.

Methods: Male Sprague-Dawley rats were divided into 9 groups (n = 6), receiving ribociclib, apixaban, rivaroxaban, ribociclib with rivaroxaban, ribociclib with apixaban, and combinations with reduced doses and time intervals. Blood concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetic parameters such as AUC, C_max, CL_z/F, and V_z/F.

Results: Ribociclib significantly increased exposure to both rivaroxaban and apixaban, with a greater impact on rivaroxaban. Specifically, ribociclib increased the AUC_0-t, AUC_0-∞ and C_max of rivaroxaban (normal dose) by about 2.4-fold, 2.1-fold and 1.8-fold, while increasing apixaban exposure by about 60.82%, with a trend towards an increase in C_max that was not statistically significant. When co-administered with ribociclib, even at a reduced dosage of 1 mg/kg, rivaroxaban exhibited a significant increase in exposure, with the AUC increasing by 2.3-fold and C_max by 1.3-fold. Despite the reduction in dosage, the pharmacokinetic effect of ribociclib on rivaroxaban persisted. While administration of rivaroxaban 12 h after ribociclib resulted in a less pronounced increase in exposure compared to the normal-dose group. The results of qRT-PCR showed that ribociclib reduced the expression of Cyp3a1 and Abcg2 in rat intestine.

Discussion: This research highlights the need for careful consideration of dosing regimens to minimize toxicity risk and optimize the safety of clinical co-administration of ribociclib with rivaroxaban.

Keywords: apixaban; cancer-associated venous thromboembolism; drug-drug interaction; ribociclib; rivaroxaban.

FIGURE 1

The mass spectra of RIBO (A) and RIBO-d₆ (B).

FIGURE 2

Representative chromatograms of RIBO (A), and RIBO-d₆ (B). Ⅰ, a blank rat plasma sample; Ⅱ, a blank rat plasma sample spiked with the working solution at LLOQ level and IS; Ⅲ, a rat plasma sample after oral administration of 60 mg/kg RIBO.

FIGURE 3

Mean plasma concentration-time profiles of RIVA alone and in combination with multiple doses and timed administration of RIBO.

FIGURE 4

The mean plasma concentration-time graphs of API after oral administration alone and following multiple doses of RIBO.

FIGURE 5

Mean plasma concentration-time profiles of RIBO after oral administration alone and following multiple doses of RIVA or API.

FIGURE 6

Relative mRNA expression in liver and intestine. (A) Effect of multiple-doses RIBO administration on mRNA expression of Cyp3a1 in liver and intestine; (B) Effect of multiple-doses RIBO administration on mRNA expression of Abcb1a and Abcg2 in intestine. **P < 0.01.