Drug interactions and protease inhibitors used in the treatment of hepatitis C: How to manage?

Pons, Sarah Talavera; Lamblin, Géraldine; Boyer, Anne; Sautou, V.; Abergel, Armand

doi:10.1007/s00228-014-1679-9

Cited by 8 publications

(4 citation statements)

References 44 publications

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“…This transporter is involved in the hepatic influx of some drugs such as statins (pravastatin, rosuvastatin) . Simeprevir, daclatasvir, ledipasvir, paritaprevir and ritonavir are all substrates and inhibitors of the OATP1B1 transporter, whereas sofosbuvir, ombitasvir and dasabuvir are not substrates . In healthy subjects, administration of a single dose of rosuvastatin with simeprevir or daclatasvir at 60 mg once daily or 3D regimen results in a respectively AUC increase by 181%, 58% and 159%, by blocking their hepatic uptake .…”

Section: Resultsmentioning

confidence: 99%

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Managing drug–drug interactions with new direct‐acting antiviral agents in chronic hepatitis C

Pons

Boyer

Lamblin

et al. 2016

Brit J Clinical Pharma

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Keywords direct-acting antiviral, drug-drug interaction, hepatitis C, management Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 269-293 269

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Section: Resultsmentioning

confidence: 99%

“…Understanding pharmacokinetic mechanisms is an essential prerequisite to manage DDI . In this review we summarise pharmacokinetics and DDI with new DAA agents against hepatitis C: simeprevir, daclatasvir, ledipasvir/sofosbuvir and 3D regimen, with a view to help clinicians manage DDI issues.…”

Section: Introductionmentioning

confidence: 99%

Managing drug–drug interactions with new direct‐acting antiviral agents in chronic hepatitis C

Pons

Boyer

Lamblin

et al. 2016

Brit J Clinical Pharma

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“…Previously, first-line treat-ment options were limited to pegylated interferon-, ribavirin-and first-generation protease inhibitor-containing regimens [2]. Interferon-and ribavirin-based therapies were non-specific to HCV and caused moderate to severe side effects universally, while firstgeneration protease inhibitors also had moderate to high potential for drug-drug interactions [3]. Newer therapies against specific viral targets use direct-acting antiviral agents (DAA), small-molecule inhibitors that can be categorized on the basis of their viral targets.…”

Section: Introductionmentioning

confidence: 99%

Validation of a Genotype-Independent Hepatitis C Virus Near-Whole Genome Sequencing Assay

Lapointe

Dong

et al. 2021

Viruses

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Despite the effectiveness of direct-acting antiviral agents in treating hepatitis C virus (HCV), cases of treatment failure have been associated with the emergence of resistance-associated substitutions. To better guide clinical decision-making, we developed and validated a near-whole-genome HCV genotype-independent next-generation sequencing strategy. HCV genotype 1–6 samples from direct-acting antiviral agent treatment-naïve and -treated HCV-infected individuals were included. Viral RNA was extracted using a NucliSens easyMAG and amplified using nested reverse transcription-polymerase chain reaction. Libraries were prepared using Nextera XT and sequenced on the Illumina MiSeq sequencing platform. Data were processed by an in-house pipeline (MiCall). Nucleotide consensus sequences were aligned to reference strain sequences for resistance-associated substitution identification and compared to NS3, NS5a, and NS5b sequence data obtained from a validated in-house assay optimized for HCV genotype 1. Sequencing success rates (defined as achieving >100-fold read coverage) approaching 90% were observed for most genotypes in samples with a viral load >5 log10 IU/mL. This genotype-independent sequencing method resulted in >99.8% nucleotide concordance with the genotype 1-optimized method, and 100% agreement in genotype assignment with paired line probe assay-based genotypes. The assay demonstrated high intra-run repeatability and inter-run reproducibility at detecting substitutions above 2% prevalence. This study highlights the performance of a freely available laboratory and bioinformatic approach for reliable HCV genotyping and resistance-associated substitution detection regardless of genotype.

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“…HCV protease inhibitors, when used in combination with ribavirin and peginterferon alpha, were the first of a new generation of directacting drug treatments for combating HCV (1)(2). However, during development, telaprevir was found to precipitate a number of drug-drug interactions (DDI) (3). In particular, attention was drawn to the profound interaction between telaprevir and the immunosuppressant, tacrolimus (4).…”

Section: Introductionmentioning

confidence: 99%

Reversible, Time-Dependent Inhibition of CYP3A-Mediated Metabolism of Midazolam and Tacrolimus by Telaprevir in Human Liver Microsomes

et al. 2015

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-Purpose Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM). Methods We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite -VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature. Results The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4-and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates. This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus. Conclusions The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir.

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Drug interactions and protease inhibitors used in the treatment of hepatitis C: How to manage?

Cited by 8 publications

References 44 publications

Managing drug–drug interactions with new direct‐acting antiviral agents in chronic hepatitis C

Managing drug–drug interactions with new direct‐acting antiviral agents in chronic hepatitis C

Validation of a Genotype-Independent Hepatitis C Virus Near-Whole Genome Sequencing Assay

Reversible, Time-Dependent Inhibition of CYP3A-Mediated Metabolism of Midazolam and Tacrolimus by Telaprevir in Human Liver Microsomes

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