Potent cytochrome P450 2C19 genotype–related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir

Mikus, Gerd; Schöwel, Verena; Drzewinska, Magdalena; Rengelshausen, Jens; Ding, Reinhard; Riedel, K.; Burhenne, Jürgen; Weiß, Johanna; Thomsen, T.; Haefeli, Walter E.

doi:10.1016/j.clpt.2006.04.004

Cited by 144 publications

(122 citation statements)

References 36 publications

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“…Mean plasma concentration-time profile of the metabolites OH-voriconazole and DiOH-voriconazole after oral (open symbols) and intravenous (closed symbols) administration of a single 400 mg dose of voriconazole to 20 healthy participants participants compared with EM is similar to the previously reported differences observed after oral administration [3,4,6,9].To switch from the i.v. to oral route of administration without dose adjustment is possible in general due to the high bioavailability of all CYP2C19 genotypes.…”

Section: Figuresupporting

confidence: 72%

“…Because these enzymes are responsible for the main metabolic pathways of many drugs, there is a considerable potential for drug interactions, including both inhibition and induction of voriconazole metabolism by other drugs. Indeed, inhibition of voriconazole metabolism by omeprazole [1,5] or ritonavir [6] and induction by phenytoin [7] or St John's wort [8] have been reported.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

Scholz

Oberwittler²,

Riedel³

et al. 2009

Brit J Clinical Pharma

164

156

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetic variability of voriconazole is largely caused by CYP3A4-and CYP2C19-mediated metabolism.• Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment. WHAT THIS STUDY ADDS• For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported.• In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype.• Enterohepatic circulation of both hydroxylated metabolites must be anticipated. AIMSThe aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole. METHODSIn a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy. RESULTSAbsolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min -1 (30.5, 67.1) vs. 6.1 ml min -1 (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity. CONCLUSIONSIndependent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.

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Section: Figuresupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

Scholz

Oberwittler²,

Riedel³

et al. 2009

Brit J Clinical Pharma

164

156

View full text Add to dashboard Cite

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“…Coadministration of drugs with strong inhibitory effects on CYP3A4, such as ritonavir, a human immunodeficiency virus protease inhibitor, prevents metabolism of voriconazole by CYP3A4 enzymes and thereby leads to higher voriconazole concentrations with the risk of increased adverse events such as hepatotoxicity. 9 Indeed, hepatotoxicity is a dose-limiting adverse event in patients taking voriconazole, which is often observed. Moreover, clinically significant hepatic dysfunction occurs in more than 10% of patients receiving regular doses of voriconazole and is a major cause of discontinuation of this drug.…”

Section: Discussionmentioning

confidence: 99%

“…Among the drugs which are metabolized by CYP2C19 enzymes are cytostatics, proton pump inhibitors, antidepressants, sedative, beta blockers, antiviral and anti-fungal agents. [2][3][4][5][6][7][8][9] Recently, it was demonstrated that PMs of CYP2C19 showed a decrease in platelet responsiveness to clopidogrel. 10 In another study, it was reported that patients treated with antidepressants and genotyped as PMs for CYP2D6 and CYP2C19, remained in hospital for longer (median 57.5 versus 40.0 days) compared to IMs.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

Elmaagacli

Koldehoff

Steckel

et al. 2007

Bone Marrow Transplant

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The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato-and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50718.6% for PMs compared to 25.173.7% for EMs (Po0.018) and 22.7 75.6% for IMs (Po0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graftversus-host disease grade 2-4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.

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“…69 Interestingly, the coexistence of multiple CYP polymorphisms in the same patient do not necessarily have an additive effect on the metabolism of voriconazole. [70][71][72] Metabolism of voriconazole results in several metabolites, the major circulating metabolite being the N-oxide of voriconazole, 65 formed predominantly by CYP3A4 and 2C19, with a smaller contribution from 2C9. 73 Production of the methyl hydroxylated metabolite is due solely to CYP3A4.…”

Section: Anidulafunginmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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Potent cytochrome P450 2C19 genotype–related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir

Abstract: Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.

Cited by 144 publications

References 36 publications

Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

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