Ritonavir‐Boosted Atazanavir, Methadone, and Ventricular Tachycardia: 2 Case Reports

Gallagher, David P.; Kieran, Jennifer; Sheehan, G; Lambert, John S.; Mahon, Niall; Mallon, Patrick

doi:10.1086/589869

Cited by 20 publications

(13 citation statements)

References 9 publications

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“…ATV is known to produce QT prolongation and TdP in clinical use [8][9][10] . In this study, we demonstrated that ATV directly inhibits both the cellular hERG K + channel current and hERG K + channel protein trafficking at similar concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…In 2013, Santimaleeworagun et al reported that ATV induced first-degree atrioventricular block and ventricular tachycardia [10] . In addition, there has also been a report of QT interval prolongation or the risk of ventricular tachycardia (VT) with combined treatment using ATV and other drugs such as methadone [9] . Recently, it was reported that ATV did not prolong the QTc interval and did not increase QTc dispersion [11] .…”

Section: Discussionmentioning

confidence: 99%

“…Despite the known benefits of ATV, there are concerns about its potential adverse effects of inducing cardiac arrhythmia [2,3] . Similar to other PIs [4][5][6][7] , ATV has previously been reported to be specifically associated with acquired long-QT syndrome, druginduced QT prolongation, and torsades de pointes (TdP) in HIV-infected patients [8][9][10] . However, these results contradict other recently published studies [11,12].…”

Section: Introductionmentioning

confidence: 99%

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The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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Aim: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K + channels expressed in HEK293 cells. Methods: hERG K + currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K + channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. Results: Application of ATV (0.01-30 μmol/L) concentration-dependently decreased hERG K + currents with an IC 50 of 5.7±1.8 μmol/L. ATV (10 μmol/L) did not affect the activation and steady-state inactivation of hERG K + currents. Compared with the wild type hERG K + channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K + currents. Overnight treatment with ATV (0.1-30 μmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. Conclusion: ATV directly blocks hERG K + channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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“…This adversity was not originally reported during the clinical development of the drug and has only rarely been noticed in the post-marketing period. 45 ATV has been shown to prolong the PR interval in electrocardiograms performed on healthy volunteers as well as in HIV-infected patients. Abnormalities in atrioventricular conduction are generally asymptomatic, concentration-dependent and limited to fi rst-degree atrioventricular block.…”

Section: Toxicitymentioning

confidence: 95%

Role of atazanavir in the treatment of HIV infection

Soriano¹

2008

TCRM

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Atazanavir (ATV) is one of the latest protease inhibitors (PI) approved for the treatment of HIV infection. The drug has a relatively long-life (∼7 h) and large inhibitory quotient which allows once daily administration. It is generally well tolerated and the main side effect is hyperbilirubinemia, since ATV inhibits the hepatic uridin-glucoronyl-transferase. A signature mutation at the protease gene, I50L, may confer loss of susceptibility to the drug. Interestingly, it produces hypersusceptibility to all other PIs. When ATV is pharmacokinetically boosted with ritonavir (r) 100 mg/day, a greater genetic barrier for resistance is achieved, and generally more than 3 major PI resistance associated mutations are needed to result in ATV resistance. In drugnaïve subjects, regimens based on ATV/r have shown non-inferiority compared to lopinavir (LPV)/r (CASTLE study) or fosamprenavir/r (ALERT trial), generally with improved tolerance (less diarrhea and dyslipidemia). Given its good tolerance and convenience, ATV has been proven to be successful as a simplifi cation strategy in switch studies (ie, SWAN and SLOAT) conducted in patients with complete virological suppression under other PI-based regimens. Finally, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens, including LPV/r, in rescue interventions in patients failing other PI regimens (ie, studies AI424-045 and NADIS).

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“…259,261 One patient had taken an overdose of flunazepam prior to his episode, 259 while another was positive for cocaine per urine toxicology. 261 Two patients had their current ART discontinued, 259 while another was discharged with a plan to be tapered off of methadone. 261 In general, the benefits of therapy should be weighed against the potential for adverse effects, taking into consideration patient-specific risk factors and whether increased vigilance with respect to cardiac monitoring is warranted.…”

Section: Compounding Adverse Effectsmentioning

confidence: 99%

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

2018

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Psychotropic medications are frequently co-prescribed with antiretroviral therapy (ART), owing to a high prevalence of psychiatric illness within the population living with HIV, as well as a 7-fold increased risk of HIV infection among patients with psychiatric illness. While ART has been notoriously associated with a multitude of pharmacokinetic drug interactions involving the cytochrome P450 enzyme system, the magnitude and clinical impact of these interactions with psychotropics may range from negligible effects on plasma concentrations to life-threatening torsades de pointes or respiratory depression. This comprehensive review summarizes the currently available information regarding drug–drug interactions between antiretrovirals and pharmacologic agents utilized in the treatment of psychiatric disorders—antidepressants, stimulants, antipsychotics, anxiolytics, mood stabilizers, and treatments for opioid use disorder and alcohol use disorder—and provides recommendations for their management. Additionally, overlapping toxicities between antiretrovirals and the psychotropic classes are highlighted. Knowledge of the interaction and adverse effect potential of specific antiretrovirals and psychotropics will allow clinicians to make informed prescribing decisions to better promote the health and wellness of this high-risk population.

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Ritonavir‐Boosted Atazanavir, Methadone, and Ventricular Tachycardia: 2 Case Reports

Cited by 20 publications

References 9 publications

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

Role of atazanavir in the treatment of HIV infection

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

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