1204 Pharmacokinetics, Safety and Tolerability of the HCV Ns5a Inhibitor Abt-267 Following Single and Multiple Doses in Healthy Adult Volunteers

Dumas, Emily O.; Lawal, Adebayo; Menon, R.; Podsadecki, Thomas; Awni, WM; Dutta, Santanu; Williams, L.

doi:10.1016/s0168-8278(11)61206-3

Cited by 19 publications

(12 citation statements)

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“…In addition to daclatasvir, several other NS5A replication complex inhibitors have entered the clinic, including GS-5885, PPI-461, ABT-267, and GSK2336805 (7)(8)(9)(10). In addition, preclinical data have recently been described for several other NS5A replication complex inhibitors, including EDP-239, IDX719, MK-4882, ITMN-9959, and ACH-3102 (11)(12)(13)(14)(15), highlighting the increased focus on this class of HCV DAAs.…”

Section: H Epatitis C Virus (Hcv) Infection Is a Global Health Issuementioning

confidence: 99%

Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885

Wong

Worth

Martin

et al. 2013

Antimicrob Agents Chemother

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c GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log 10 HCV RNA IU/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3/10 subjects at the 1-mg dose and for all subjects dosed at >3 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30-and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred >30-fold reductions in GS-5885 and daclatasvir susceptibilities in vitro. Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials.gov under registration number NCT01193478.) H epatitis C virus (HCV) infection is a global health issue, with approximately 170 million people infected worldwide (1).The standard of care (SOC) has been pegylated alpha interferon and ribavirin until the more recent approval of two NS3 protease inhibitors, telaprevir and boceprevir, for use in conjunction with pegylated alpha interferon and ribavirin (1-3). The last several years have seen a great expansion of new direct-acting antivirals (DAAs) in clinical development to augment or supplant treatment with pegylated alpha interferon and ribavirin. HCV nonstructural protein 5A (NS5A) has emerged as a viable and attractive viral target for small-molecule inhibition. Although there is no known enzymatic activity for NS5A, it is essential for viral replication (4). The first NS5A replication complex inhibitor to show efficacy in the clinic was daclatasvir (BMS-790052) (5). This compound elicited rapid and profound reductions in HCV RNA and validated NS5A as a clinical target. Sequence analysis of clinical isolates following daclatasvir monotherapy identified the main resistanceassociated mutations (RAMs) at NS5A amino acid positions 28, 30, 31, and 93 (6).In addition to daclatasvir, several other NS5A replication complex inhibitors have entered the clinic, including GS-5885, PPI-461, ABT-267, and GSK2336805 (7-10). In addition, preclinical data have recently been described for several other NS5A replication complex inhibitors, including EDP-239, IDX719, MK-4882, , highlighting ...

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Section: H Epatitis C Virus (Hcv) Infection Is a Global Health Issuementioning

confidence: 99%

Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885

Wong

Worth

Martin

et al. 2013

Antimicrob Agents Chemother

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“…Ritonavir has been found to increase levels of ABT-267, an NS5A inhibitor in phase II studies, by greater than 60% in healthy volunteers [51]. This points to the involvement of CYP3A4 in the metabolism of ABT-267, and potential for pharmacokinetic interactions with HIV protease inhibitors and NNRTIs.…”

Section: Other Directly Acting Antivirals In Developmentmentioning

confidence: 98%

Directly acting antivirals for hepatitis C and antiretrovirals

Seden

Back²

2011

Current Opinion in HIV and AIDS

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As a result of DDIs, the concomitant use of some medicines with DAA will be contraindicated, whereas other combinations may require caution, monitoring, or dose modification of the co-administered drug. Management of DDIs with these novel agents will pose a new challenge, and prescriber awareness of the potential for DDIs is fundamental for safe prescribing. Online resources are likely to play a key role in prescriber education and clinical decision-making.

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“…Mean half-life was between 21 and 25 hours.1 Repeated daily dosing of 5 mg suggests that accumulation is expected, with an accumulation ratio of approximately 1.4.15 Coadministration of ombitasvir with ritonavir 100 mg increases the ombi tasvir Cm ax (68%) and AUC (62%) at steady state compared with ombitasvir given alone. 15 Dasabuvir is not expected to inhibit CYP enzymes or induce CYP3A4 expression in vivo. 16 Single oral doses of dasabuvir produce a C at (11% vs 0%, respectively; P < .001), elevated blood bilirubin (8.8% vs 0%, respectively; P = .003), rash (8.8% vs 1.1%, respectively; P = .017), and total bilirubin greater than 3 times the upper limit of normal (ULN) (8.8% vs 0%, respectively; P = .003).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir

et al. 2015

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Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The May 2015 monograph topics are palbociclib, lenvatinib, nivolumab, ferric pyrophosphate citrate solution, and secukinumab. The Safety MUE is on non-opioid injectable pain or fever medications.

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1204 Pharmacokinetics, Safety and Tolerability of the HCV Ns5a Inhibitor Abt-267 Following Single and Multiple Doses in Healthy Adult Volunteers

Cited by 19 publications

References 0 publications

Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885

Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885

Directly acting antivirals for hepatitis C and antiretrovirals

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir

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