Pharmacokinetic Drug-Drug Interactions With Drugs Approved by the U.S. Food and Drug Administration in 2020: Mechanistic Understanding and Clinical Recommendations

Abstract

Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechaniDrug-drug interaction (DDI) data for small molecular drugs approved by the U.S. Food and Drug Administration in 2020 (N = 40) were analyzed using the University of Washington Drug Interaction Database. The mechanism(s) and clinical relevance of these interactions were characterized based on information available in the new drug application reviews. About 180 positive clinical studies, defined as mean area under the curve ratios (AUCRs) {greater than or equal to} 1.25 for inhibition DDIs or pharmacogenetic studies and {less than or equal to} 0.8 for induction DDIs, were then fully analyzed. Oncology was the most represented therapeutic area, including 30% of 2020 approvals. As victim drugs, inhibition and induction of CYP3A explained most of all observed clinical interactions. Three sensitive substrates were identified: avapritinib (CYP3A), lonafarnib (CYP3A), and relugolix (P-gp), with AUCRs of 7.00, 5.07, and 6.25 when co-administered with itraconazole, ketoconazole, and erythromycin, respectively. As precipitants, three drugs were considered strong inhibitors of enzymes (AUCR {greater than or equal to} 5): cedazuridine for cytidine deaminase, and lonafarnib and tucatinib for CYP3A. No drug showed strong inhibition of transporters. No strong inducer of enzymes or transporters was identified. As expected, all DDIs with AUCRs {greater than or equal to} 5 or {less than or equal to} 0.2 and almost all those with AUCRs of 2-5 and 0.2-0.5 triggered dosing recommendations in the drug label. Overall, all 2020 drugs found to be either sensitive substrates or strong inhibitors of enzymes or transporters were oncology treatments, underscoring the need for effective DDI management strategies in cancer patients often receiving poly-therapy. Significance Statement This minireview provides a thorough and specific overview of the most significant pharmacokinetic-based DDI data observed (or expected) with small molecular drugs approved by the U.S. Food and Drug Administration in 2020. It will help to better understand mitigation strategies to manage the DDI risks in the clinic.