ABSTRACT
OBJECTIVE: To review the pharmacology, safety, and efficacy of nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF). METHODS: A literature search was conducted via PubMed using the MeSH term "idiopathic pulmonary fibrosis" combined with the key word "nintedanib." Additional online searches using Google Scholar, Micromedex, and PubMed were performed to obtain prescribing and cost information. RESULTS: One phase II and 2 replicate phase III clinical trials that examined the safety and efficacy of nintedanib for IPF were identified. In patients with IPF, nintedanib was more effective than placebo in slowing the annual rate of decline in forced vital capacity (FVC). Improvements in mortality, quality of life, and risk of acute exacerbations have not been consistently demonstrated in clinical trials. Diarrhea was the most common adverse effect associated with nintedanib use. Outside of these clinical trials, there are limited data evaluating nintedanib for the treatment of IPF. CONCLUSIONS: Nintedanib is a safe and effective treatment option for patients with IPF. Nintedanib slows IPF disease progression by reducing the rate of decline in FVC. Reductions in mortality and acute exacerbations may be present in certain subgroups of patients, but these outcomes require further research. Future studies on nintedanib are needed to explore its use in more advanced stages of IPF, its long-term safety and efficacy, its value in combination with pirfenidone or other therapies for IPF, and its cost-effectiveness in clinical practice.
Subject(s)
Idiopathic Pulmonary Fibrosis/drug therapy , Indoles/administration & dosage , Pyridones/pharmacology , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Diarrhea/chemically induced , Drug Therapy, Combination , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Indoles/adverse effects , Indoles/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokineticsABSTRACT
Acquired drug resistance in cancer continues to be a challenge in cancer therapy, in part due to overexpression of the drug efflux transporter P-glycoprotein (P-gp, MDR1, ABCB1). NSC73306 is a thiosemicarbazone compound that displays greater toxicity against cells expressing functional P-gp than against other cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (CTR1, SLC31A1). Overexpression of P-gp sensitizes LLC-PK1 cells to NSC73306. Cisplatin (IC50 = 77 µM), cyclosporin A (IC50 = 500 µM), and verapamil (IC50 = 700 µM) inhibited cellular accumulation of [(3)H]NSC73306. Cellular hypertoxicity of NSC73306 to P-gp-expressing cells was inhibited by cisplatin in a dose-dependent manner. Cells transiently expressing the cisplatin uptake transporter CTR1 (SLC31A1) showed increased [(3)H]NSC73306 accumulation. In contrast, CTR1 knockdown decreased [(3)H]NSC73306 accumulation. The presence of NSC73306 reduced CTR1 levels, similar to the negative feedback of CTR1 levels by copper or cisplatin. Surprisingly, although cisplatin is a substrate of CTR1, we found that CTR1 protein was overexpressed in high-level cisplatin-resistant KB-CP20 and BEL7404-CP20 cell lines. We confirmed that the CTR1 protein was functional, as uptake of NSC73306 was increased in KB-CP20 cells compared to their drug-sensitive parental cells, and downregulation of CTR1 in KB-CP20 cells reduced [(3)H]NSC73306 accumulation. These results suggest that NSC73306 is a transport substrate of CTR1.
