High turbulence liquid chromatography online extraction and tandem mass spectrometry for the simultaneous determination of suberoylanilide hydroxamic acid and its two metabolites in human serum

Du, Lihong; Musson, Donald G.; Wang, Amy Qiu

doi:10.1002/rcm.1984

Cited by 43 publications

(48 citation statements)

References 15 publications

(14 reference statements)

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“…The mechanism of HDAC inhibition for RMD, which acts as a prodrug with intracellular reduction of an intramolecular disulfide bond and subsequent binding of the free sulfhydryl groups to a Zn 2ϩ ion in the active site of target HDAC enzymes, is distinct from other HDACi, such as SAHA (52). The apparently superior activity of RMD may also reflect differences in drug pharmacokinetics and cell exposures in a comparison of RMD administered via 4-h intravenous infusion (46,53) with the potentially short and varied exposures and rapid pharmacokinetics of orally administered SAHA (34,40,54,55). We have previously shown robust upregulation of acetylated histone levels, similar to that measured here for rhesus CD4 ϩ T cells treated with RMD (Fig.…”

Section: Discussionsupporting

confidence: 74%

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy

Prete

Oswald

Lara

et al. 2016

Antimicrob Agents Chemother

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dReplication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n ‫؍‬ 5) or saline (n ‫؍‬ 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4 ؉ T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy.A lthough combination antiretroviral therapy (cART) can suppress viral replication in human immunodeficiency virus type 1 (HIV-1)-infected patients to levels below the limits of quantification for standard clinical assays, recrudescent virus emerges upon treatment interruption in virtually all patients who initiate therapy during the chronic phase of infection, even after many years of treatment and virologic suppression (1, 2). A long-lived residual virus pool persists despite apparently effective treatment (3-7). For this reason, current cART does not represent a definitive treatment for HIV infection, and lifelong treatment is required in the vast majority of infected patients. Despite the fact that cART can substantially improve the life expectancy of HIV-1-infected individuals, there are concerns about the development of viral drug resistance and drug-related toxicities in patients with such long-term treatment. In addition, the financial burden of lifelong cART is considerable (8), and recent studies have indicated that well-suppressed patients still have elevated levels of immune activation with increased non-AIDS morbidities and reduced life expectancies compared with those of uninfected people (9-21). These considerations have motivated a substantial scientific research effort to identify treatments that will result in either the eradication of residual virus or in the durable control of viral replication in the absence of cART.A number of different potential in vivo sources of replicationcompetent virus that can reemerge upon treatment cessation...

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Section: Discussionsupporting

confidence: 74%

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy

Prete

Oswald

Lara

et al. 2016

Antimicrob Agents Chemother

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“…Serum and urine vorinostat and two of its inactive metabolites (O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid) were analyzed using a turbulent flow on-line extraction format for analyte isolation followed by reversed-phase high-performance liquid chromatography with tandem mass spectrometric detection (15).…”

Section: Methodsmentioning

confidence: 99%

A Study to Determine the Effects of Food and Multiple Dosing on the Pharmacokinetics of Vorinostat Given Orally to Patients with Advanced Cancer

Rubin

Agrawal

Friedman

et al. 2006

Clinical Cancer Research

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108

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Purpose: This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics. Experimental Design: Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose. Results: The apparent t 1/2 of vorinostat was short (f1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and T max was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting. Conclusions: Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.

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“…Blood collection procedures have been reported previously (14). Serum was assessed for vorinostat using a turbulent flow online extraction format for analyte isolation followed by reverse-phase highperformance liquid chromatography with tandem mass spectrometric detection as described previously (16).…”

Section: Translational Relevancementioning

confidence: 99%

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Münster

Rubin

Belle

et al. 2009

Clinical Cancer Research

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Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C max of vorinostat. Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC 0-∞ and C max values attained were on the order of ∼1.93-and ∼1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation. (Clin Cancer Res 2009;15(22):7077-84)

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High turbulence liquid chromatography online extraction and tandem mass spectrometry for the simultaneous determination of suberoylanilide hydroxamic acid and its two metabolites in human serum

Cited by 43 publications

References 15 publications

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy

A Study to Determine the Effects of Food and Multiple Dosing on the Pharmacokinetics of Vorinostat Given Orally to Patients with Advanced Cancer

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

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