Solanidine‐derived CYP2D6 phenotyping elucidates phenoconversion in multimedicated geriatric patients

British Journal of Clinical Pharmacology, vol. 91, pp. 1842–1852

Abstract

Abstract Aims Phenoconversion, a genotype‐phenotype mismatch, challenges a successful implementation of personalized medicine. The aim of this study was to detect and determine phenoconversion using the solanidine metabolites 3,4‐seco‐solanidine‐3,4‐dioic acid (SSDA) and 4‐OH‐solanidine as diet‐derived cytochrome P450 2D6 (CYP2D6) biomarkers in a geriatric, multimorbid cohort with high levels of polypharmacy. Methods Blood samples and data of geriatric, multimedicated patients were collected during physician counsel (CT: NCT05247814). Solanidine and its metabolites were determined via liquid chromatography/tandem mass spectrometry and used for CYP2D6 phenotyping. CYP2D6 genotyping was performed and activity scores (AS) were assigned. Complete medication intake was assessed. A shift of the AS predicted via genotyping as measured by phenotyping was calculated. Results Solanidine and its metabolites were measured in 88 patients with complete documentation of drug use. Patients had a median age of 83 years (interquartile range [IQR] 77‐87) and the majority (70.5%, n = 62) were female. Patients took a median of 15 (IQR 12‐17) medications. The SSDA/solanidine metabolic ratio correlated significantly with the genotyping‐derived AS ( P < .001) and clearly detected poor metabolizers. In the model adjusted for age, sex, Charlson Comorbidity Index and estimated glomerular filtration rate each additional CYP2D6 substrate/inhibitor significantly lowered the expected AS by 0.53 (95% confidence interval 0.85‐0.21) points in patients encoding functional CYP2D6 variants ( R 2 = 0.242). Conclusions Phenotyping of CYP2D6 activity by measurement of diet‐derived biomarkers elucidates phenoconversion in geriatric patients. These results might serve as a prerequisite for the validation and establishment of a bedside method to measure CYP2D6 activity in multimorbid patients for successful application of personalized drug prescribing.

Authors 10

1. Jens Andreas Sarömba Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

2. Julian Peter Müller Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

3. Jolanta Tupiec Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

4. Anjali A. Roeth Aachen Department of General, Visceral Pediatric and Transplantation Surgery

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of General, Visceral, Pediatric and Transplantation Surgery University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Department of General, Visceral, Pediatric and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

5. Berkan Kurt Aachen Department of Internal Medicine I-Cardiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Internal Medicine I – Cardiology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

6. Florian Kahles Aachen Department of Internal Medicine I-Cardiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Internal Medicine I – Cardiology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

7. Thea Laurentius Aachen Department of Geriatric Medicine (Medical Clinic VI)

   Carl von Ossietzky Universität Oldenburg · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Geriatric Medicine University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Department of Geriatrics Carl von Ossietzky University of Oldenburg Oldenburg Lower Saxony Germany

   Department of Geriatric Medicine, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

   Department of Geriatrics, Carl von Ossietzky University of Oldenburg, Oldenburg, Lower Saxony, Germany

8. Cornelius Bollheimer Aachen Department of Geriatric Medicine (Medical Clinic VI)

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Geriatric Medicine University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Department of Geriatric Medicine, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

9. Julia Stingl Aachen Institute of Clinical Pharmacology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Clinical Pharmacology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

   Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

10. Katja Susanne Just corresponding Aachen Institute of Clinical Pharmacology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Clinical Pharmacology University Hospital RWTH Aachen Aachen North Rhine‐Westphalia Germany

    Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany