Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

Sane, Rucha; Steinmann, Gerhard; Huang, Qihong; Li, Yongmei; Podila, Lalitha; Mease, Kirsten; Olson, Stephen; Taub, Mitchell E.; Stern, Jerry O.; Nehmiz, Gerhard; Böcher, Wulf O.; Asselah, Tarik; Tweedie, Donald J.

doi:10.1124/jpet.114.218081

Cited by 33 publications

(27 citation statements)

References 30 publications

(56 reference statements)

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“…Overall, the safety profile observed in this study was consistent with that reported in the faldaprevir clinical trial program in subjects without renal impairment (13)(14)(15)(16)(17). Increased levels of indirect bilirubin were not accompanied by elevations of other markers of liver toxicity, and these clinically irrelevant, transient indirect bilirubin increases are a well-known effect of treatment with faldaprevir, which is an inhibitor of UGT1A1 and hepatic uptake transporters (35).…”

Section: Discussionsupporting

confidence: 74%

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

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e Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC 0 -ؕ ) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.) C hronic hepatitis C virus (HCV) infection is a cause of renal dysfunction and associated with a number of comorbidities that can affect renal function (1, 2).As impaired renal function may influence drug metabolism and pharmacokinetics (PK) (3, 4), dose adjustments might be required in this patient population to avoid excess drug accumulation, which can impact drug efficacy and safety. While the introduction of the NS3/4A protease inhibitors telaprevir and boceprevir represented a significant advance in the management of patients with chronic HCV genotype 1 (GT-1) infection, their use is associated with some disadvantages (5). In addition to being associated with a number of significant serious side effects (including rash, anemia, and gastrointestinal symptoms), these protease inhibitors require three times daily dosing due to short halflives, have a complex drug-drug interaction profile (limiting coadministration with other agents), and are associated with a marked decline in renal function (6-8).In order to improve the safety, efficacy, and convenience of HCV treatments, a number of second-generation direct-acting antivirals (DAAs) for the treatment of patients infected with HCV GT-1 are in clinical development or have recently been approved (9-11). Faldaprevir is a potent HCV NS3/4A protease inhibitor (12), which, in combination with pegylated alpha-2a interferon and ribavirin (RBV) (PR), has been shown to be highly effective for the treatment of chronic HCV GT-1 infection (13-16). In the phase III STARTVerso1 trial, once-daily (QD) faldaprevir (120 mg) plus PR achieved sustained virologic response rates 12 weeks after completion of treatment (SVR12) of ...

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Section: Discussionsupporting

confidence: 74%

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Huang

Moschetti

Lang

et al. 2015

Antimicrob Agents Chemother

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“…In vitro data have shown that CYP3A4 is one of the key enzymes involved in EE/LNG oxidative metabolism in the liver (21), and thus, a likely mechanism for the increased exposure is via altered EE elimination due to the inhibition of CYP3A4 by faldaprevir. Inhibition of UGT1A1 by faldaprevir, reported by Sane and colleagues (15), may affect glucuronidation of synthetic hormones in the liver and could contribute to the increased exposure of EE and LNG reported here.…”

Section: Discussionsupporting

confidence: 51%

“…In vivo data suggest that with a twice-daily (BID) dose of 240 mg in healthy volunteers, faldaprevir is a weak inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4 (13), whereas a dose of 120 mg faldaprevir QD in HCV patients resulted in weak inhibition of CYP3A4 and had no effect on CYP2C9 (14). In vitro data also suggest that faldaprevir inhibits P-glycoprotein (P-gp), UDP-glucuronosyltransferase (UGT1A1), and CYP2C8 (14,15). EE, which has a terminal half-life of 10 to 20 h, is metabolized in the liver by hydroxylation mediated by CYP3A4 and CYP2C9, followed by glucuronidation by UGT1A1 (12).…”

Section: Hronic Hepatitis Caused By Hepatitis C Virus (Hcv) Infectimentioning

confidence: 99%

Effect of the Hepatitis C Virus Protease Inhibitor Faldaprevir on the Pharmacokinetics of an Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers

Sabo¹,

Lang²,

Elgadi³

et al. 2015

Antimicrob Agents Chemother

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Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median t1/2 (terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (∼ 30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number NCT01570244.).

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“…2). Faldaprevir inhibits the bilirubin conjugation enzyme, UGT1A1, and to a lesser extent the bilirubin transporters, OATP1B1, and MRP2 [30]. Increases in bilirubin have also been observed with simeprevir; however, this is predominantly driven by inhibition of OATP1B1 and MRP2 [31].…”

Section: Discussionmentioning

confidence: 99%

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

Ferenci

Asselah

Foster

et al. 2015

Journal of Hepatology

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Background & Aims:The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. Methods: Patients were randomly assigned (1:2:2) to PegIFN/ RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p <0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. Conclusions: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg. Ó

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Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

Cited by 33 publications

References 30 publications

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Effect of the Hepatitis C Virus Protease Inhibitor Faldaprevir on the Pharmacokinetics of an Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

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