A Drug-Drug Interaction Study Evaluating the Effect of Givosiran, a Small Interfering Ribonucleic Acid (siRNA), on Cytochrome P450 Activity in Liver

This study assessed the impact of givosiran on the pharmacokinetics of substrates of five major CYP450 enzymes in subjects with acute intermittent porphyria (AIP), the most common type of AHP, by using the validated 'Inje cocktail', comprised of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4). We show that givosiran treatment had a differential inhibitory effect on CYP450 enzymes in liver, resulting in a moderate reduction in activity of CYP1A2 and CYP2D6, a minor effect on CYP3A4 and CYP2C19, and a similar weak effect on CYP2C9. To date, this is the first study evaluating the DDI for an oligonucleotide therapeutic and highlights an atypical drug interaction due to the pharmacological effect of givosiran. The results of this study suggest that givosiran does not have a large effect on heme dependent CYP enzyme activity in the liver.PMID:34510420 | DOI:10.1002/cpt.2419
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research