Effect of Liver Disease on Hepatic Transporter Expression and Function

Thakkar, Nilay; Slizgi, Jason R.; Brouwer, Kim L. R.

doi:10.1016/j.xphs.2017.04.053

Cited by 92 publications

(72 citation statements)

References 202 publications

(220 reference statements)

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“…Although simeprevir exposure was increased by 1.7‐fold when administered in combination with odalasvir, compared with simeprevir administered alone in a healthy volunteer drug–drug interaction study, results from cohort 1 indicated that there is no significant interaction in HCV‐infected patients. The difference in interaction effect may be related to the effect of liver disease on hepatic transporters . In the phase IIb PILLAR study of simeprevir in combination with pegIFN and ribavirin, simeprevir doses of 75 and 150 mg QD were evaluated in treatment‐naïve, HCV‐infected patients, and no significant difference in SVR rates was observed, only a trend for higher SVR with the higher dose in some difficult‐to‐cure subpopulations .…”

Section: Discussionmentioning

confidence: 99%

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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This open‐label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct‐acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6‐12‐week oral regimens of 400‐800 mg once daily (QD) AL‐335 + 50 mg QD/every other day odalasvir ± 75‐150 mg QD simeprevir were evaluated in treatment‐naïve, HCV genotype (GT)1/3‐infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV‐RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment‐emergent adverse events occurred, one of which (a Mobitz type 1 second‐degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1‐infected patients receiving 3‐DAA for 6‐8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1‐infected patients receiving 2‐DAA or GT3‐infected patients receiving 3‐DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance‐associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment‐naïve subjects without cirrhosis, AL‐335 + odalasvir + simeprevir for 6‐8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2‐DAA regimen in GT1‐infected subjects and the 3‐DAA regimen in GT3‐infected subjects.

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Section: Discussionmentioning

confidence: 99%

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

et al. 2018

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“…The effect of the DDI on viral‐load reduction can only be evaluated when this DAA combination is evaluated in patients. In addition, differences in metabolism and transporter expression between healthy volunteers and HCV‐infected patients may limit extrapolation of results . Another limitation is that the effect of simeprevir on the pharmacokinetics of odalasvir was estimated without taking into account odalasvir accumulation over time; therefore, the data presented assume steady‐state of odalasvir.…”

Section: Discussionmentioning

confidence: 99%

“…grade 3) and aspartate aminotransferase (peak 3. and transporter expression between healthy volunteers and HCVinfected patients may limit extrapolation of results. 21 Another limitation is that the effect of simeprevir on the pharmacokinetics of odalasvir was estimated without taking into account odalasvir accumulation over time; therefore, the data presented assume steadystate of odalasvir. This can be corrected for by comparing data between Groups 1 and 2 after 7 days of treatment with odalasvir.…”

Section: Safetymentioning

confidence: 99%

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

Kakuda¹,

McClure²,

Westland³

et al. 2018

Pharmacology Res & Perspec

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This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC 0‐24 h) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC 0‐24 h increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC 0‐24 h, whereas odalasvir with/without simeprevir increased ALS‐022227 AUC 0‐24 h 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0‐24 h increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

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“…In addition to investigating PK in healthy volunteers, there should be close attention to understanding the compound’s PK characteristics in hepatically impaired populations. Several pathophysiological changes, which regularly occur in individuals with cirrhosis and PH, can significantly impact drug disposition in this population (Table ) . The 2003 U.S. Food and Drug Administration (FDA) Guidance for Industry recommends a formal PK study in hepatically impaired individuals if (1) hepatic metabolism and/or excretion accounts for >20% of the absorbed drug’s or its active metabolite’s disposition, or (2) the test compound is either known or suspected to have a narrow therapeutic window, or (3) there is insufficient information about the compound’s metabolism and excretion and its predicted therapeutic window.…”

Section: Pharmacokinetic and Pharmacodynamic Evaluation In Ph Clinicamentioning

confidence: 99%

“…Several pathophysiological changes, which regularly occur in individuals with cirrhosis and PH, can significantly impact drug disposition in this population ( Table 2). (18)(19)(20)(21)(22)(23) The 2003 U.S. Food and Drug Administration (FDA) Guidance for Industry (24) recommends a formal PK study in hepatically impaired individuals if (1) hepatic metabolism and/or excretion accounts for >20% of the absorbed drug's or its active metabolite's disposition, or (2) the test compound is either known or suspected to have a narrow therapeutic window, or (3) there is insufficient information about the compound's metabolism and excretion and its predicted therapeutic window. However, a formal PK study in hepatically impaired individuals may not be necessary if a compound is entirely renally excreted with no involvement of the liver, or if a drug is gaseous or volatile and its active metabolite(s) are primarily eliminated by the lungs.…”

Section: Pharmacokinetic and Pharmacodynamic Evaluation In Ph Clinicamentioning

confidence: 99%

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

et al. 2019

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Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

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Effect of Liver Disease on Hepatic Transporter Expression and Function

Cited by 92 publications

References 202 publications

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

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