Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors

Abstract

Background and Purpose

Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug–drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug–drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.

Methods

A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9–21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.

Results

Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC_0–48h and C_max of nifedipine by 83% (90% confidence interval [CI] 1.46–2.31) and 64% (90% CI 1.34–2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC_0-t and C_max of S-warfarin by 92% (90% CI 1.68–2.18) and 24% (90% CI 1.10–1.39), respectively.

Conclusion

Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug–drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.

Keywords:

• apatinib
• drug-drug interaction
• CYP3A4
• CYP2C9
• nifedipine
• warfarin

Abbreviations

T_max, the time of the maximum concentration; C_max, the maximum observed plasma concentration; AUC_0–t, the area under the plasma concentration–time curve from time 0 to the time of the last measurable concentration; AUC_0–∞, the area under the plasma concentration–time curve from time 0 to infinity; AUC_0–48h, the area under the plasma concentration–time curve from time 0 to 48 h; AUC_0–36h, the area under the plasma concentration–time curve from time 0 to 36 h; t_1/2z, apparent terminal half-life; V_z/F, apparent volume of distribution; CL/F, apparent clearance; GMean, geometric mean; CV, coefficient of variation; Mean; arithmetic mean; SD, standard deviation; CI, confidence interval.

Data Sharing Statement

Individual deidentified participant data are not going to be shared. All available data have been shown in the article. No other study-related document will be made available.

Disclosure

Quan-Ren Wang and Si-Yuan Mao are employees of Jiangsu Hengrui Medicine Co., Ltd. The authors report no other conflicts of interest in this work.