Quantification of second generation direct-acting antivirals daclatasvir, elbasvir, grazoprevir, ledipasvir, simeprevir, sofosbuvir and velpatasvir in human plasma by UPLC-MS/MS

Seyen, Minou van; Teulen, Marga; Erp, Nielka P. van; Burger, David M.

doi:10.1016/j.jchromb.2019.01.024

Cited by 32 publications

(21 citation statements)

References 13 publications

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“…10 , 13 , 20 The LLOQ was established for the detection of trough levels and pharmacokinetic evaluation for each compound in HCV patients (with higher exposure than healthy volunteers). 17 As a result, the analysis method was not sufficiently sensitive to be able to determine the grazoprevir plasma concentrations for all healthy volunteers following a single dose of 100 mg of grazoprevir administered under fasted conditions. 13 , 20 In our opinion, the results are reliable and valid because the power is sufficient to evaluate absence of difference in AUC with a total of nine evaluable subjects, so the missing data has no clinically relevant consequences for the conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…The calibration range was 3.0–1500 μg/L for elbasvir and grazoprevir in plasma. 16 , 17 Pharmacokinetic parameters were determined by non-compartmental analysis in WinNonlin (version 8.1, Certara, Princeton, NJ, USA). AUCs were calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations (linear-up/log-down).…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

Pijnenburg¹,

Seyen²,

Abbink

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Finding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended. Objectives To investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet. Methods We conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72. Results Mean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial. Conclusions Pharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

Pijnenburg¹,

Seyen²,

Abbink

et al. 2020

Journal of Antimicrobial Chemotherapy

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“…Plasma was transferred into polypropylene tubes and stored at −80°C until bioanalysis. VEL, SOF, and GS‐331007 plasma concentrations were analyzed by the use of a validated ultra‐high‐performance liquid chromatography mass spectrometry method . Validation was established over the range of 7.5–1,500 μg/L for VEL, 5.0–2,500 μg/L for SOF, and 25–5,000 μg/L for GS‐331007.…”

Section: Methodsmentioning

confidence: 99%

“…VEL, SOF, and GS-331007 plasma concentrations were analyzed by the use of a validated ultra-high-performance liquid chromatography mass spectrometry method. 20 Validation was established over the range of 7.5-1,500 μg/L for VEL, 5.0-2,500 μg/L for SOF, and 25-5,000 μg/L for GS-331007. The precision for low, medium, and high quality control samples was <10%.…”

Section: Statisticsmentioning

confidence: 99%

Concomitant Intake of Coca‐Cola to Manage the Drug–Drug Interaction Between Velpatasvir and Omeprazole Studied in Healthy Volunteers

Seyen¹,

Colbers²,

Abbink

et al. 2019

Clin Pharma and Therapeutics

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We aimed to evaluate the effect of the acid beverage Coca‐Cola on the pharmacokinetics of velpatasvir (VEL) when given with omeprazole. This was an open‐label, randomized, crossover trial in 11 healthy adults. A single dose of sofosbuvir/velpatasvir (SOF/VEL) 400/100 mg was administered alone (reference) or with omeprazole 40 mg once daily with water (intervention I); in the intervention II arm, omeprazole 40 mg was combined with 250 mL of Coca‐Cola. Geometric mean ratios (GMRs) were calculated for VEL area under the concentration‐time curve from zero to infinity (AUC 0−inf) and maximum plasma concentration (Cmax). VEL exposure was reduced by 26.7% when SOF/VEL was coadministered with omeprazole vs. reference: GMRs (90% confidence interval (CI)) were 73.3% (55.6–96.8) and 69.1% (52.3–91.2) for AUC 0‐inf and Cmax, respectively. Intake of SOF/VEL with Coca‐Cola compensated for the interaction with omeprazole and resulted in a higher VEL exposure. GMRs (90% CI) were 161.6% (122.4–213.3) for AUC 0‐inf and 143.9% (109.0–190.0) for Cmax. Therefore, Coca‐Cola can be used to overcome the drug–drug interaction between VEL and omeprazole.

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“…The importance of multianalyte bioanalytical methods [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ] has been emphasized already in our above stated review papers. Various newly published research papers have also demonstrated successful use of LC-MS/MS methods for the simultaneous analysis of 7–16 antiviral agents [ 21 , 22 , 23 , 24 , 25 , 26 ]. Moreover, detailed MS/MS characterization of antivirals addressing selected reaction monitoring (SRM) data and also structure elucidation of individual fragments have been presented in extensive review articles for antivirals for HIV treatment [ 27 ], antivirals against hepatitis [ 28 ], and against herpes, influenza, and other viral infections [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Determination of Antiviral Drugs and Their Metabolites Using Micro-Solid Phase Extraction and UHPLC-MS/MS in Reversed-Phase and Hydrophilic Interaction Chromatography Modes

et al. 2021

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Two new ultra-high performance liquid chromatography (UHPLC) methods for analyzing 21 selected antivirals and their metabolites were optimized, including sample preparation step, LC separation conditions, and tandem mass spectrometry detection. Micro-solid phase extraction in pipette tips was used to extract antivirals from the biological material of Hanks balanced salt medium of pH 7.4 and 6.5. These media were used in experiments to evaluate the membrane transport of antiviral drugs. Challenging diversity of physicochemical properties was overcome using combined sorbent composed of C18 and ion exchange moiety, which finally allowed to cover the whole range of tested antivirals. For separation, reversed-phase (RP) chromatography and hydrophilic interaction liquid chromatography (HILIC), were optimized using extensive screening of stationary and mobile phase combinations. Optimized RP‑UHPLC separation was carried out using BEH Shield RP18 stationary phase and gradient elution with 25 mmol/L formic acid in acetonitrile and in water. HILIC separation was accomplished with a Cortecs HILIC column and gradient elution with 25 mmol/L ammonium formate pH 3 and acetonitrile. Tandem mass spectrometry (MS/MS) conditions were optimized in both chromatographic modes, but obtained results revealed only a little difference in parameters of capillary voltage and cone voltage. While RP-UHPLC-MS/MS exhibited superior separation selectivity, HILIC-UHPLC-MS/MS has shown substantially higher sensitivity of two orders of magnitude for many compounds. Method validation results indicated that HILIC mode was more suitable for multianalyte methods. Despite better separation selectivity achieved in RP-UHPLC-MS/MS, the matrix effects were noticed while using both chromatographic modes leading to signal enhancement in RP and signal suppression in HILIC.

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Quantification of second generation direct-acting antivirals daclatasvir, elbasvir, grazoprevir, ledipasvir, simeprevir, sofosbuvir and velpatasvir in human plasma by UPLC-MS/MS

Cited by 32 publications

References 13 publications

Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

Concomitant Intake of Coca‐Cola to Manage the Drug–Drug Interaction Between Velpatasvir and Omeprazole Studied in Healthy Volunteers

Determination of Antiviral Drugs and Their Metabolites Using Micro-Solid Phase Extraction and UHPLC-MS/MS in Reversed-Phase and Hydrophilic Interaction Chromatography Modes

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