Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

DiCenzo, Robert; Peterson, Derick R.; Cruttenden, Kim; Mariuz, Peter; Rezk, Naser L.; Hochreiter, Jill; Gelbard, Harris A.; Schifitto, Giovanni

doi:10.1128/aac.00194-08

Cited by 16 publications

(11 citation statements)

References 22 publications

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“…In concentration time profiles of existing plasma samples, the C max and AUC of RTV [34, 35] were similar as previously reported [29]. Metabolite profiles showed formation rate limited clearance except for R5 indicating a lower clearance.…”

Section: Discussionsupporting

confidence: 84%

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Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Kaspera

Kirby

Sahele

et al. 2014

Biochemical Pharmacology

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Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, KI/kinact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro-in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2- specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp®. A modest (2-6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.

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Section: Discussionsupporting

confidence: 84%

“…): measured by depletion 1 [6, 34] 2 inhibition measured with specific probes in Supersomes [27] [11] 3 R<0.2 4 Linear scaled according to k inact /K I, see materials and methods, n.d.: not determined) 5 95% confidence interval. …”

Section: Figurementioning

confidence: 99%

Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Kaspera

Kirby

Sahele

et al. 2014

Biochemical Pharmacology

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“…A class III study in 11 HIV‐positive subjects (eight evaluable) taking lopinavir/ritonavir 400/100 found that lopinavir AUC increased on average by 38% (90% CI −2% to 94%) after administration of valproic acid 500 mg/day for 7 days (DiCenzo et al., 2004). A class III study of HIV‐positive subjects showed no effect of valproic acid on atazanavir (12 subjects) or ritonavir (9 subjects) levels (DiCenzo et al., 2008).…”

Section: Analysis Of the Evidencementioning

confidence: 99%

Antiepileptic drug selection for people with HIV/AIDS: Evidence‐based guidelines from the ILAE and AAN

Birbeck

French²,

Perucca

et al. 2012

Epilepsia

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Summary A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED–ARV interactions. Key findings from this literature search included the following: AED–ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme‐inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

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“…177 Another prospective study containing ritonavir and atazanavir found no significant results when co-administered with valproic acid. 178 However, 2 studies did find DDIs with valproic acid when the PI combination product lopinavir/ritonavir was co-administered. In the case report, the patient experienced decreased valproic acid concentrations, likely due to ritonavir-induced metabolism, which resulted in clinical symptoms of mania/hypomania.…”

Section: Carbamazepinementioning

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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Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

Cited by 16 publications

References 22 publications

Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Antiepileptic drug selection for people with HIV/AIDS: Evidence‐based guidelines from the ILAE and AAN

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

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