<p>Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors</p>

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.

Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib

“…Zhu et al have investigated the potential of apatinib as a perpetrator on the pharmacokinetics of nifedipine and warfarin in advanced solid tumor patients. The results indicated that concomitant administration of apatinib led to an obvious increase to nifedipine and warfarin exposure ( Zhu et al, 2020 ). Due to the risk of pharmacokinetic DDI based on enzyme inhibition by apatinib, a dynamic PBPK model is needed for further dosing recommendations when apatinib is co-administered with CYP3A4, CYP2D6, or CYP2C9 substrates.…”

Application of physiologically-based pharmacokinetic/pharmacodynamic models to evaluate the interaction between nifedipine and apatinib

“…The in vitro studies indicated that nifedipine was a typical substrate of CYP3A4 which was almost completely metabolized by CYP3A4 (Guengerich et al, 1986). The research conducted by Zhu et al (2020) has confirmed that co-administration of nifedipine with apatinib significantly increased the AUC 0-48h and C max of nifedipine by 83% and 64%, respectively. Coadministration of apatinib with nifedipine could cause exposure changes of nifedipine in vivo.…”

“…Summary of the input data are listed in Table 2. Apatinib was reported to exert potent inhibition on CYP3A4 in a competitive way (Zhu et al, 2020). In the DDI models between nifedipine and apatinib, the K i was set to 0.12, with the f umic at 0.65 (Bao et al, 2018;Zhu et al, 2020).…”

“…However, the detailed evaluation of apatinib as a perpetrator in CYP450-based DDIs is lacking. Apatinib was reported to exert potent inhibition on CYP3A4 and CYP2C9 with the IC 50 values of 1.80, 0.83, and 0.44 μM for midazolam hydroxylation, testosterone hydroxylation, and tolbutamide hydroxylation, respectively (Zhu et al, 2020). Thus, apatinib might affect the plasma exposures of CYP3A4 and CYP2C9 substrates when using combination therapy causing clinical efficacy and safety issues.…”

Apatinib combined with Keytruda treatment induces apoptosis of gastric carcinoma cells through CES4/miR‐616‐5p/DUSP2 axis

“…Apatinib, as a selective vascular endothelial growth factor receptortyrosine kinase inhibitor, has an inhibitory effect on various solid tumours, such as advanced hepatocellular carcinoma and GC. [3][4][5] Long non-coding RNAs (lncRNAs) are a kind of non-coding RNA with a length of more than 200 nucleotides. LncRNAs regulate the expression of genes from multiple levels such as chromatin remodelling, transcription and post-transcription.…”