In this case, the authors employed the Naranjo algorithm adverse drug reaction probability scale to assess whether there was a causal relationship between this event and initiation of simeprevir/sofosbuvir regimen.7 The Naranjo score was 4, indicating a possible link between simeprevir/sofosbuvir initiation and hepatic decompensation and AKI. This case may be the first postmarketing report of significant hepatic decompensation and AKI related to simeprevir/sofosbuvir.
Unlike simeprevir, which undergoes extensive oxidative metabolism by CYP3A in the liver and has negligible renal clearance with < 1% of the dose recovered in the urine, sofosbuvir is extensively metabolized by the kidneys with an active metabolite, GS-331007, and about 80% of the dose is recovered in urine (78% as GS-331007; 3.5% as sofosbuvir).8,9 The potential for drug-drug interaction also was assessed because simeprevir is extensively metabolized by the hepatic cytochrome CYP34 system and possibly CYP2C8 and CYP2C19. Clinically significant interactions could have occurred with diltiazem and morphine, because the coadministration of these medications along with simeprevir, an inhibitor of P-glycoprotein (P-gp), and intestinal CYP3A4, may result in increased diltiazem and morphine plasma concentrations.
Of note, because sofosbuvir is a substrate of P-gp, it may have its serum concentration increased by simeprevir. Inducers and inhibitors of P-gp may alter the plasma concentration of sofosbuvir. The major metabolite, GS-331007, is not a substrate of P-gp. Drugs that induce P-gp may reduce the therapeutic effect of sofosbuvir; however, the FDA-labeling suggests that inhibitors of P-gp may be coadministered with sofosbuvir.
According to simeprevir prescribing information, drug interaction studies have demonstrated that moderate CYP3A4 inhibitors, such as diltiazem (although coadministration have not been studied), increased the maximum serum concentration (Cmax), minumum serum concentration (Cmin), and AUC of simeprevir.7 As a result, concurrent use of simeprevir with a moderate CYP3A4 inhibitors is not recommended. Morphine and simeprevir interaction also is possible via the P-gp inhibition of simeprevir. Morphine concentration may have increased and metabolites may have accumulated, leading to urinary retention and elevated creatinine. In addition, decreased oral intake and subsequent nausea/vomiting may have compounded the renal insult.
Conclusion
Given that updated HCV treatment guidelines include simeprevir/sofosbuvir as an alternative treatment option, clinicians should be aware of hepatic decompensation with markedly elevated bilirubin and AKI during simeprevir and sofosbuvir treatment. Careful consideration is needed prior to the initiation of simeprevir/sofosbuvir, particularly in patients with advanced liver disease or known HCC and baseline renal impairment.