Pharmacogenetic Analysis of Voriconazole Treatment in Children
Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum co...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/6/1289 |
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| author | Romy Tilen Paolo Paioni Aljoscha N. Goetschi Roland Goers Isabell Seibert Daniel Müller Julia A. Bielicki Christoph Berger Stefanie D. Krämer Henriette E. Meyer zu Schwabedissen |
| author_facet | Romy Tilen Paolo Paioni Aljoscha N. Goetschi Roland Goers Isabell Seibert Daniel Müller Julia A. Bielicki Christoph Berger Stefanie D. Krämer Henriette E. Meyer zu Schwabedissen |
| author_sort | Romy Tilen |
| collection | DOAJ |
| description | Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure <i>SwissPK</i><sup>cdw</sup>, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections. |
| first_indexed | 2024-03-09T22:44:10Z |
| format | Article |
| id | doaj.art-1063935f041f4117ae1ad62a4e36bbe6 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:44:10Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-1063935f041f4117ae1ad62a4e36bbe62023-11-23T18:31:18ZengMDPI AGPharmaceutics1999-49232022-06-01146128910.3390/pharmaceutics14061289Pharmacogenetic Analysis of Voriconazole Treatment in ChildrenRomy Tilen0Paolo Paioni1Aljoscha N. Goetschi2Roland Goers3Isabell Seibert4Daniel Müller5Julia A. Bielicki6Christoph Berger7Stefanie D. Krämer8Henriette E. Meyer zu Schwabedissen9Division of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, SwitzerlandDivision of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, SwitzerlandBiopharmacy, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, SwitzerlandBiopharmacy, Department of Pharmaceutical Sciences, University Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandBiopharmacy, Department of Pharmaceutical Sciences, University Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandInstitute of Clinical Chemistry, University Hospital Zurich, Rämistr. 100, 8091 Zurich, SwitzerlandPaediatric Research Centre, University Children’s Hospital Basel, Basel, Spitalstrasse 33, 4056 Basel, SwitzerlandDivision of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, SwitzerlandBiopharmacy, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, SwitzerlandBiopharmacy, Department of Pharmaceutical Sciences, University Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandVoriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure <i>SwissPK</i><sup>cdw</sup>, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections.https://www.mdpi.com/1999-4923/14/6/1289childrenpediatric pharmacologyvoriconazoletherapeutic drug monitoringpharmacogeneticsnon-linear mixed effects modelling |
| spellingShingle | Romy Tilen Paolo Paioni Aljoscha N. Goetschi Roland Goers Isabell Seibert Daniel Müller Julia A. Bielicki Christoph Berger Stefanie D. Krämer Henriette E. Meyer zu Schwabedissen Pharmacogenetic Analysis of Voriconazole Treatment in Children Pharmaceutics children pediatric pharmacology voriconazole therapeutic drug monitoring pharmacogenetics non-linear mixed effects modelling |
| title | Pharmacogenetic Analysis of Voriconazole Treatment in Children |
| title_full | Pharmacogenetic Analysis of Voriconazole Treatment in Children |
| title_fullStr | Pharmacogenetic Analysis of Voriconazole Treatment in Children |
| title_full_unstemmed | Pharmacogenetic Analysis of Voriconazole Treatment in Children |
| title_short | Pharmacogenetic Analysis of Voriconazole Treatment in Children |
| title_sort | pharmacogenetic analysis of voriconazole treatment in children |
| topic | children pediatric pharmacology voriconazole therapeutic drug monitoring pharmacogenetics non-linear mixed effects modelling |
| url | https://www.mdpi.com/1999-4923/14/6/1289 |
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