Utilization of Omeprazole To Augment Subtherapeutic Voriconazole Concentrations for Treatment of Aspergillus Infections

Abstract

Voriconazole is the preferred antifungal agent for Aspergillus infections. Therapeutic drug monitoring is recommended to achieve target concentrations and prevent toxicity. However, variable pharmacokinetics, cytochrome P450 polymorphisms, and extensive drug-drug interactions can contribute to subtherapeutic concentrations. We report a voriconazole "boosting" effect of omeprazole to achieve target concentrations for the treatment of Aspergillus in a patient who had persistently subtherapeutic trough concentrations. Voriconazole is a triazole antifungal agent that is the mainstay of therapy for invasive Aspergillus infections (2, 5). Multiple factors, such as age, liver function, and cytochrome P450 (CYP) polymorphisms, affect the systemic exposure of voriconazole (6). Additionally, drug interactions, saturable pharmacokinetics, and significant inter-and intrapatient variability produce unpredictable concentrations. Therapeutic drug monitoring (TDM) is therefore necessary to optimize voriconazole concentrations during the management of invasive fungal infections (IFIs), such aspergillosis. However, the optimal target range remains undefined. Pascual et al. observed a higher response rate for patients with IFIs when trough concentrations were Ͼ1 g/ml (4). A retrospective cohort study found that steady-state concentrations of Ͼ2.05 g/ml were associated with an increased invasive aspergillosis survival rate (10/10 versus 8/18, P Ͻ 0.025) (8). In contrast, voriconazole trough concentrations of Ͼ5.5 g/ml were correlated with toxicity (4).Voriconazole concentrations that fall outside the therapeutic range can occur as a result of drug-drug interactions due to extensive metabolism by CYP enzymes. Voriconazole is a major substrate of CYP2C19, an isoenzyme known for polymorphisms (5). Phenotypic expression of CYP2C19 allelic variants ranges from poor metabolism to ultrarapid metabolism (7). Voriconazole systemic concentrations increase in the presence of CYP2C19 inhibitors. Omeprazole, a widely available proton pump inhibitor, competitively inhibits the CYP2C19 enzyme (3). Wood et al. investigated the effect of omeprazole, given orally at standard doses, on voriconazole pharmacokinetics in 16 patients (11). Omeprazole coadministration increased the mean voriconazole peak concentration in plasma and the area under the curve over the dosing interval by 15 and 41%, respectively. Higher trough concentrations also occurred in the omeprazole-cotreated group. Additionally, other prospective clinical observational data suggest that 44% of patients with supratherapeutic voriconazole concentrations (Ͼ5.5 g/ml) were concomitantly receiving omeprazole (4). Here we report a case of the therapeutic use of omeprazole to "boost" subtherapeutic voriconazole concentrations in a patient with chronic intracranial aspergillosis.In June 2011, a 22-year-old immunocompetent male with a history of intracranial Aspergillus infections was admitted to the Parkland Health and Hospital System (Dallas, TX) after brain magnetic resonance imaging (MRI) s...

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

“…PPI treatment, in fact, remained a significant predictor of low VPCs in multivariate analysis. These findings are in contrast to previous findings reporting increased VPCs in cases of concomitant PPI use (8,22,23). Other studies, however, found no effect of PPI treatment on the pharmacokinetics of voriconazole (24).…”

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

“…Several clinical studies evaluating voriconazole therapeutic drug monitoring and factors affecting plasma concentrations have reported an association between concomitant PPI use and elevated voriconazole concentrations (5,12,23). Furthermore, case reports of the occurrence of increased plasma voriconazole concentrations after coadministration of voriconazole with a PPI have also been reported; two of the reports were distinct, in that the studies involved the deliberate use of a PPI to boost voriconazole concentrations into the therapeutic range (19,20,37). For patients in whom higher plasma voriconazole levels are required to improve tissue penetration or to overcome rapid metabolism, PPI-mediated inhibition could be a reasonable solution for achieving target voriconazole concentrations, provided that TDM is available to guide therapy.…”

“…Both voriconazole and PPIs are also vulnerable to the significant pharmacokinetic variability associated with CYP2C19 polymorphisms. Unsurprisingly, increased plasma voriconazole concentrations during coadministration with a PPI have been reported (5,12,19,20). Despite the widespread use of PPIs and the potential for CYP450-mediated interactions with voriconazole (12,17), the net effect of PPIs on voriconazole pharmacokinetics has not been delineated.…”

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