Effect of Steady‐State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open‐Label, Fixed‐Sequence Crossover Study

Abstract

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P-450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady-state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single-center, open-label, fixed-sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1-3 and days 10-12. Concomitant administration with faldaprevir led to approximately 9-fold and 34-fold increases in AUC and C , respectively, of atorvastatin and approximately 15-fold and 33-fold increases in AUC and C , respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho-hydroxyatorvastatin and N-desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug-drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided.

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin

“…The study by Hermann et al 42 conducted in healthy subjects treated with multiple doses of 10 mg of ATV for 1 week shows AUC metabolic ratios close to the ones reported in the present study for the active (0.11 for p-OH-ATV, and 0.54 for o-OH-ATV) and inactive metabolites (2.54 for ATV-LAC, 0.42 for p-OH-ATV-LAC, and 1.85 for o-OH-ATV-LAC). Other single oral dose administration studies of ATV reported only the metabolic ratios of AUC for the active metabolite o-OH-ATV, with values of 1.25, 41 1.19, 43 or 0.77 44 and, therefore, close to the value of 1.32 reported in the present study.…”

“…The single oral administration of ATV (20, 40, or 80 mg) to the healthy subjects group (n = 15; Table 3 and Figure 1) resulted in pharmacokinetic parameters of unchanged ATV similar to those reported by Huang et al 41 in the investigation of healthy subjects treated with a single oral dose of 10 mg ATV.…”

Effects of Multiple‐Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin

“…Since aprocitentan was well tolerated, use of a healthy subject population was justified. While the measured plasma concentrations and PK parameters of rosuvastatin alone were similar to published data, [20][21][22] the initial intended LOQ of 1.0 ng/mL was insufficient to reliably characterize the t 1…”

“…Since aprocitentan was well tolerated, use of a healthy subject population was justified. While the measured plasma concentrations and PK parameters of rosuvastatin alone were similar to published data, [20][21][22] the initial intended LOQ of 1.0 ng/mL was insufficient to reliably characterize the t 1 2 , and therefore the method was revalidated to lower the LOQ to 0.04 ng/mL. The t 1 2 of rosuvastatin proved to be variable during the study as indicated by a wide 90%CI around the geometric mean.…”

Severe rosuvastatin accumulation with rhabdomyolysis due to drug interactions and low cardiac output syndrome

“…Rosuvastatin is a substrate of OATP1B1, and interactions have been described with OATP inhibitors. Notably, the interaction with faldaprevir, an OATP‐inhibiting anti‐HCV medication, can lead to increases in AUC and Cmax of rosuvastatin of 15‐ and 33‐fold, respectively …”