Ripretinib

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

FDA approved drugs -> Active ingredient

In the prelicensure placebo-controlled clinical trial in patients with refractory and extensively treated GIST, ALT elevations arose in 13% of ripretinib- vs 5% of placebo-treated subjects. ALT elevations were generally transient and mild, and were above 5 times the ULN in only 1% of treated patients and did not require dose modification or discontinuation. Bilirubin elevations were reported in 22% of ripretinib treated patients but only 7.5% of placebo controls. The bilirubin elevations were transient and mild, but were not characterized as to their timing, severity and whether conjugated or unconjugated (direct or indirect). In the open label and controlled trials supporting the approval of ripretinib, there were no instances of clinically apparent liver injury, hepatic failure, or deaths from liver injury. Since its approval in the United States and Europe, there have been no reported cases of clinically apparent liver injury associated with ripretinib therapy.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ripretinib

Ambiguous-DILI-concern

4

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

As a broad-spectrum kinase inhibitor, ripretinib inhibits various gene mutations, increasing progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST). It is effective in treating mutations that are resistant to chemotherapy with other kinase inhibitors, such as imatinib. Ripretinib has the propensity to cause cardiac dysfunction and new primary cutaneous malignancy. It is important to measure cardiac ejection fraction before and during treatment as well as to perform regular dermatological assessments.

Protein kinases play important roles in cellular function, and their dysregulation can lead to carcinogenesis. Ripretinib inhibits protein kinases including wild type and mutant platelet-derived growth factor receptor A (PDGFRA) and KIT that cause the majority of gastrointestinal stromal tumor (GIST). In vitro, ripretinib has been shown to inhibit PDGFRB, BRAF, VEGF, and TIE2 genes. Ripretinib binds to KIT and PDGFRA receptors with mutations on the exons 9, 11, 13, 14, 17 and 18 (for KIT mutations), and exons 12, 14 and 18 (for PDGFRA mutations). The “switch pocket” of a protein kinase is normally bound to the activation loop, acting as an “on-off switch” of a kinase. Ripretinib boasts a unique dual mechanism of action of binding to the kinase switch pocket as well as the activation loop, thereby turning off the kinase and its ability to cause dysregulated cell growth.