Highly sensitive determination of HCV protease inhibitors boceprevir (SCH 503034) and telaprevir (VX 950) in human plasma by LC–MS/MS

Farnik, Harald; El-Duweik, Juliane; Welsch, Christoph; Sarrazin, Christoph; Lötsch, Jörn; Zeuzem, Stefan; Geißlinger, Gerd; Schmidt, Helmut

doi:10.1016/j.jchromb.2009.10.013

Cited by 23 publications

(12 citation statements)

References 10 publications

(13 reference statements)

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“…The MS/MS spectra were the same as that reported in previous studies (Farnik et al, 2009;Penchala et al, 2013) and telaprevir-R-IS had the same spectra as telaprevir-IS. Data acquisition, processing, and storage were performed using Xcalibur software, version 1.3 (Thermo Scientific, San Jose, CA, USA).…”

Section: Lc/ms/ms Instrumentation and Conditionssupporting

confidence: 61%

“…Given these pharmacologic characteristics, there is a potential role for therapeutic drug monitoring in the clinical use of telaprevir (Dolton et al, 2013). To facilitate clinical pharmacology studies of telaprevir, simple, fast and sensitive analytical methods are needed, but few methods are currently available (Farnik et al, 2009;D'Avolio et al, 2013;Penchala et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R‐isomer in human plasma

Chen

Bushman

McAllister

et al. 2014

Biomedical Chromatography

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The purpose of this study was to validate a reversed-phase high-performance liquid chromatographic (HPLC), tandem mass spectrometry (MS/MS) assay for the determination of telaprevir and its R-diastereomer (VRT-127394) in acidified and nonacidified human plasma. The chromatographic baseline separation of telaprevir and telaprevir-R was performed on a Waters XBridge(TM) BEH Shield C18 , 2.1 × 75 mm column with a 2.5 µm particle size, under isocratic conditions consisting of a mobile phase of 50:45:5 water-acetonitrile-isopropanol with 1% ammonia at 0.2 mL/min. This method utilized a stable isotope internal standard with 11 deuterium atoms on the structure of the telaprevir molecule (telaprevir-d11). An internal standard for the telaprevir-R (telaprevir-R-d11) was also prepared by incubating telaprevir-d11 in basic solution, which facilitated isomer inter-conversion. The detection and quantitation of telaprevir, telaprevir-R, telaprevir-IS and telaprevir-R-IS was achieved by positive ion electrospray (ESI+) MS/MS detection. The assay quantifiable limit was 5.0 ng/mL when 0.100 mL of acidified human plasma was extracted. Accuracy and precision were validated over the calibration range of 5.0-5000 ng/mL. It was demonstrated using patient samples that, contrary to previous recommendations, quantitation of telaprevir does not require acidified plasma.

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Section: Lc/ms/ms Instrumentation and Conditionssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R‐isomer in human plasma

Chen

Bushman

McAllister

et al. 2014

Biomedical Chromatography

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“…PI concentrations in serum were determined using ultraperformance liquid chromatography coupled with tandem mass spectrometry with lower limits of quantification (LOQ) of 5 ng/ml and 10 ng/ml for boceprevir and telaprevir, respectively (19). The PI concentrations were converted to mol/liter for analysis using molar masses of 519.68 g/mol and 679.85 g/mol for boceprevir and telaprevir, respectively.…”

Section: Methodsmentioning

confidence: 99%

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

Laouénan

Marcellin

Lapalus

et al. 2014

Antimicrob Agents Chemother

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Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P ‫؍‬ 0.5), but there was a significant difference in the 50% effective concentrations (EC 50 ) (P ‫؍‬ 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P ‫؍‬ 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day ؊1 ) and was higher in patients who subsequently eradicated HCV (P ‫؍‬ 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.

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“…Thus, the major achievement of our preanalytical treatment was to optimize the biological extraction procedure for all three drugs together. HCV PIs, BOC, and especially TVR are characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography, as evidenced by the limited number of reports on the assay of these new drugs that have been published so far (27,28,37). In our study, several chromatographic substrates (C 18 , propylcyano, bridged ethyl siloxane/silica hybrid [BEH], pentafluorophenyl, hydrophilic interaction liquid chromatography [HILIC], etc.)…”

Section: Discussionmentioning

confidence: 99%

“…To that end, an LC-MS/MS assay for the simultaneous measurement of TVR and BOC has been described (27) that uses the unrelated compound dimethyl celecoxib as an internal standard (IS) and a gradient program that does not allow the separation of TVR from VRT-127394, the virologically inactive C-21 epimer metabolite of TVR. A report published in abstract form by Chakilam et al (28) briefly described the separation of TVR and its isomer VRT-127394 by a liquid-liquid extraction method with toluene, followed by evaporation under nitrogen of the organic solvent and reconstitution in a heptane-acetone mixture prior to HPLC-MS/MS analysis.…”

mentioning

confidence: 99%

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

Aouri

Moradpour

Cavassini

et al. 2013

Antimicrob Agents Chemother

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g New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.

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Highly sensitive determination of HCV protease inhibitors boceprevir (SCH 503034) and telaprevir (VX 950) in human plasma by LC–MS/MS

Cited by 23 publications

References 10 publications

Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R‐isomer in human plasma

Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R‐isomer in human plasma

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

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