Multiplexed LC-MS/MS method for the simultaneous quantitation of three novel hepatitis C antivirals, daclatasvir, asunaprevir, and beclabuvir in human plasma

Jiang, Hao; Kandoussi, Hamza; Zeng, Jianing; Wang, Jian; Demers, Roger; Eley, Timothy; He, Bing; Burrell, Richard C.; Easter, John A.; Kadiyala, Pathanjali; Pursley, Janice; Cojocaru, Laura; Baker, Chanda; Ryan, John; Aubry, Anne‐Françoise; Arnold, Mark E.

doi:10.1016/j.jpba.2015.01.027

Cited by 55 publications

(24 citation statements)

References 21 publications

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“…Daclatasvir, asunaprevir, and beclabuvir plasma samples were analyzed using a validated liquid chromatography with tandem mass spectrometry assay . The lower limit of quantification (LLOQ) of the assay was 2.0 ng/mL for daclatasvir, asunaprevir, and beclabuvir.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Osawa

Ueno

Shiozaki

et al. 2019

Clinical Pharm in Drug Dev

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A fixed‐dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor) was approved for hepatitis C virus treatment in Japan. The objectives of the analyses were to develop the daclatasvir, asunaprevir, and beclabuvir population pharmacokinetic models for the combination regimen. First, an original population pharmacokinetic model was developed using the data in non‐Japanese hepatitis C virus–infected subjects. The model was subsequently updated after a phase 3 study in Japanese hepatitis C virus–infected subjects was available. A total of 11,382, 11,300, and 10,728 pharmacokinetic records from 1,228 subjects were included for daclatasvir, asunaprevir, and beclabuvir in the updated model, respectively. Daclatasvir and beclabuvir pharmacokinetics (PK) were described by a 1‐compartment model with linear elimination and asunaprevir PK was described by 2‐compartment model with linear elimination. Cirrhosis, baseline, and time‐varying ALT were significant covariates on asunaprevir apparent oral clearance. Asian subjects had greater asunaprevir and beclabuvir exposures than white subjects. The effects of all covariates on daclatasvir PK were modest and not considered clinically significant. With the exception of race on asunaprevir and beclabuvir PK, no other parameters for daclatasvir, asunaprevir and beclabuvir population PK models were meaningfully impacted during the refinement with Japanese subjects.

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Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Osawa

Ueno

Shiozaki

et al. 2019

Clinical Pharm in Drug Dev

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“…Daclatasvir, asunaprevir, and beclabuvir exposures were assessed as the geometric mean of C avgss and predicted from previously described popPK models. Daclatasvir, asunaprevir, and beclabuvir plasma samples were analyzed using a validated liquid chromatography with tandem mass spectrometry assay . The E‐R analysis data set was prepared by merging C avgss predicted from the final popPK model for daclatasvir, asunaprevir, and beclabuvir, with SAS data sets derived from clinical data.…”

Section: Methodsmentioning

confidence: 99%

Exposure‐Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV‐Infected Patients

Ueno

Osawa

Shiozaki

et al. 2019

Clinical Pharm in Drug Dev

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The combination regimen of daclatasvir, asunaprevir, and beclabuvir (3DAA regimen) was developed as a fixed‐dose combination for the treatment of hepatitis C virus (HCV) infection in Japan. The objectives of this analysis were to characterize the relationship between drug exposure and sustained virologic response at posttreatment week 12 (SVR12) in HCV‐infected subjects and to evaluate the impact of demographic covariates and clinical factors on the exposure‐response (E‐R) relationship. The E‐R efficacy analysis was performed with data from phase 2 and phase 3 studies in HCV‐infected subjects treated with the 3DAA regimen. The relationship between the probability of achieving SVR12 and exposure to daclatasvir, asunaprevir, and beclabuvir was described using a logistic regression model and included assessments of the potential covariate effects. The impacts of the covariates on the rate of SVR12 and interactions of covariates with the individual drug effects were tested. The final model for SVR12 included effects of non–genotype‐1a status, resistance‐associated NS5A‐Q30 substitution in genotype‐1a subjects, and baseline RNA level on the intercept, and effect of prior peg‐interferon failure on the beclabuvir slope. Sex, race, age, weight, fibrosis score, alanine transaminase, and cirrhosis status had no statistically significant impact on the rate of SVR12. The individual E‐R relationships with each drug, were relatively flat, and the effects of exposure were not significant. With the exception of the NS5A‐Q30 substitution in genotype‐1a subjects, statistically significant covariate effects had little impact on SVR12 rates. Overall, the E‐R model was developed that captured the high SVR12 rates and the effect of covariates for the 3DAA regimen in HCV‐infected patients.

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“…The plasma concentration of ASV was determined with an API 4000 triple quadrupole mass spectrometer coupled with a Shimadzu HPLC system, following the procedure previously described (Jiang et al, 2015). Briefly, the internal standard (IS) d 9 -ASV (50 lL at 20 ng/mL) was added to 200 lL of plasma or QC samples followed by a brief vortexing.…”

Section: Quantitative Analysis Of Asv In Plasmamentioning

confidence: 99%

“…The organic layer was removed and evaporated to dryness under nitrogen at 40 C. The residue was reconstituted in 150 lL of methanol:water:formic acid (75:25:0.1, v:v:v) and a portion of supernatant (10 lL) was analyzed with LC-MS/MS. Chromatographic conditions and MS detection for ASV and the internal standard were described previously (Jiang et al, 2015).…”

Section: Quantitative Analysis Of Asv In Plasmamentioning

confidence: 99%

Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans

Gong¹,

Eley

et al. 2015

Xenobiotica

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1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV. 2. Following a single oral dose of [(14)C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance. 3. The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.

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Multiplexed LC-MS/MS method for the simultaneous quantitation of three novel hepatitis C antivirals, daclatasvir, asunaprevir, and beclabuvir in human plasma

Cited by 55 publications

References 21 publications

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Exposure‐Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV‐Infected Patients

Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans

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Multiplexed LC-MS/MS method for the simultaneous quantitation of three novel hepatitis C antivirals, daclatasvir, asunaprevir, and beclabuvir in human plasma

Cited by 55 publications

References 21 publications

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV‐Infected Subjects

Exposure‐Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV‐Infected Patients

Characterization of ADME properties of [14C]asunaprevir (BMS-650032) in humans

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Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans