Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.
Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium. souwerke@its.jnj.com.
Sivi
S
Ouwerkerk-Mahadevan
Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
Jan
J
Snoeys
Janssen Infectious Diseases, Beerse, Belgium.
Monika
M
Peeters
Janssen Infectious Diseases, Beerse, Belgium.
Maria
M
Beumont-Mauviel
Janssen Infectious Diseases, Beerse, Belgium.
Alexandru
A
Simion
D004347:Drug Interactions; D006801:Humans; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D000069616:Simeprevir / Q000493:pharmacokinetics*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; D000069616:Simeprevir