Development of a dosing algorithm integrating pharmacogenetic markers and inflammation for individualization of initial voriconazole maintenance doses

Antimicrobial Agents and Chemotherapy, vol. 70, pp. e0027826

Abstract

ABSTRACT Achieving early therapeutic trough concentrations (Cmin) of voriconazole (VRC) is crucial for treatment efficacy and to avoid side effects. Since VRC Cmin are influenced by numerous determinants, this multicenter retrospective study aimed to develop a multiparametric dosing algorithm for individualizing initial VRC maintenance doses. Individual data regarding VRC Cmin from adult patients and associated parameters (age, sex, underlying disease [presence of hematological disease/other], weight, dose, route of administration, indication: curative/prophylactic, cytochrome [CYP]2C19 and 3A genotypes, C-reactive protein [CRP], transaminases, bilirubin, and proton pump inhibitor treatment) were collected from six previously published studies and routine care data from seven laboratories (building cohort). A mixed-effects model predicting VRC Cmin was developed on this building cohort using a stepwise cross-validation procedure and then externally validated on an independent cohort (validation cohort). The building and validation cohorts included 977 VRC Cmin in 277 patients and 47 VRC Cmin in 33 patients, respectively. The initial model, which integrated VRC daily dose, CYP2C19 genotype, and CRP, was enriched by two additional covariates: age and underlying disease. The final model had an R ² of 0.69 but tended to underestimate low VRC Cmin and overestimate high VRC Cmin. Finally, a formula derived from this final model was proposed and integrated into an Excel sheet to individualize initial VRC maintenance doses. The developed predictive model allowed for the creation of a multiparametric dosing algorithm for the individualization of initial VRC maintenance doses. The benefit of this algorithm will soon be evaluated in a prospective pilot study to improve initial VRC exposure.

Authors 21

1. Elodie Gautier‐Veyret

   Inserm · Hôpital Européen Georges-Pompidou · Université Grenoble Alpes

   Affiliation as printed

   Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

   Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

   Univ. Grenoble Alpes, CHU Grenoble Alpes, Laboratoire de Pharmacologie, Pharmacogénetique et Toxicologie

   Univ. Grenoble Alpes, INSERM U1300, HP2 Laboratory

2. Othilie Giannoni

   University of Geneva · University Hospital of Geneva

   Affiliation as printed

   Pharmacie des Hôpitaux Universitaire de Genève

   Section des Sciences Pharmaceutiques, Institut des Sciences Pharmaceutiques de Suisse Occidentale, Université Genève Suisse

3. Marc Manceau

   Inserm · Université Grenoble Alpes

   Affiliation as printed

   Univ. Grenoble Alpes, Inserm CIC1406, CHU Grenoble Alpes

4. Capucine Arrivé

   Inserm · Université Grenoble Alpes

   Affiliation as printed

   Univ. Grenoble Alpes, CHU Grenoble Alpes, Laboratoire de Pharmacologie, Pharmacogénetique et Toxicologie

   Univ. Grenoble Alpes, INSERM U1300, HP2 Laboratory

5. Sylvia D. Klomp Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

6. Matthieu Roustit

   Inserm · Université Grenoble Alpes

   Affiliation as printed

   Univ. Grenoble Alpes, Inserm CIC1406, CHU Grenoble Alpes

7. Fabien Lamoureux

   Inserm · Hôpital Européen Georges-Pompidou · Normandie Université

   Affiliation as printed

   Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

   Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

   UNIROUEN, INSERM U1096, CHU Rouen, Department of Pharmacology, Normandie University

8. Benjamin Hennart

   Centre Hospitalier Universitaire de Lille · Hôpital Européen Georges-Pompidou

   Affiliation as printed

   CHU Lille, Service de Toxicologie et Génopathies

   Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

   Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

9. Caroline Solas

   Inserm · Aix-Marseille Université · Hôpital de la Timone · Institut de Recherche pour le Développement · Unité des Virus Emergents

   Affiliation as printed

   Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

   Laboratoire de Pharmacocinétique et Toxicologie, Hôpital La Timone, Aix-Marseille University, APHM, UMR "Emergence des Pathologies Virales" Inserm 1207 IRD 190

10. Sarah Baklouti

    Hôpital Européen Georges-Pompidou · Hôpital Purpan

    Affiliation as printed

    Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

    Laboratoire de Pharmacocinétique et Toxicologie, IFB, Hôpital Purpan

    Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

11. Céline Verstuyft

    Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou

    Affiliation as printed

    Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

    Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

    Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris

12. Christelle Boglione‐Kerrien

    Centre Hospitalier Universitaire de Rennes

    Affiliation as printed

    Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes University Hospital

    Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

13. Jesse Joachim Swen Aachen Department of Clinical Pharmacy and Toxicology

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

14. Nicolas Pallet

    Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou

    Affiliation as printed

    Réseau Francophone de Pharmacogénétique (RNPGX), Hôpital Européen Georges-Pompidou (HEGP)

    Service de Biochimie, Assistance Publique Hôpitaux de Paris, Assistance Publique Hôpitaux de Paris

15. Anette Veringa

    University Medical Center Groningen · University of Groningen · OLVG

    Affiliation as printed

    Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen

    Department of Clinical Pharmacy, OLVG

16. Jan‐Willem C. Alffenaar

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen

17. Takahiro Yamada

    Hamamatsu University School of Medicine

    Affiliation as printed

    Department of Hospital Pharmacy, Hamamatsu University School of Medicine

18. Takafumi Naito

    Shinshu University Hospital

    Affiliation as printed

    Department of Pharmacy, Shinshu University Hospital

19. Françoise Stanke‐Labesque

    Inserm · Université Grenoble Alpes

    Affiliation as printed

    Groupe Suivi Thérapeutique Pharmacologique-Personnalisation des traitements (STP-PT) de la Société Française de Pharmacologie et Thérapeutique (SFPT)

    Univ. Grenoble Alpes, CHU Grenoble Alpes, Laboratoire de Pharmacologie, Pharmacogénetique et Toxicologie

    Univ. Grenoble Alpes, INSERM U1300, HP2 Laboratory

20. Charles Khouri

    Inserm · Centre Hospitalier Universitaire de Grenoble · Université Grenoble Alpes

    Affiliation as printed

    Univ. Grenoble Alpes, Inserm CIC1406, CHU Grenoble Alpes

    Univ. Grenoble Alpes, Pharmacovigilance Unit, Grenoble Alpes University Hospital

21. on behalf of the Therapeutic Drug Monitoring and Personalization Treatment group of the French Society of Pharmacology and Therapeutics and the French-Speaking Network of Pharmacogenetics (RNPGx)