Patients with chronic kidney disease (CKD) stage 3-5 are polypharmacy patients. Many of these drugs are metabolized by cytochrome P450 (CYP450) and CYP450. Genetic polymorphism is well known to... Show morePatients with chronic kidney disease (CKD) stage 3-5 are polypharmacy patients. Many of these drugs are metabolized by cytochrome P450 (CYP450) and CYP450. Genetic polymorphism is well known to result in altered drug metabolism capacity. This study determined the added value of pharmacogenetic testing to the routine medication evaluation in polypharmacy patients with CKD. In adult outpatient polypharmacy patients with CKD3-5 disease, a pharmacogenetic profile was determined. Then, automated medication surveillance for gene-drug interactions was performed based on the pharmacogenetic profile and the patients' current prescriptions. Of all identified gene-drug interactions, the hospital pharmacist and the treating nephrologist together assessed clinical relevance and necessity of a pharmacotherapeutic intervention. The primary endpoint of the study was the total number of applied pharmacotherapeutic interventions based on a relevant gene-drug interaction. A total of 61 patients were enrolled in the study. Medication surveillance resulted in a total of 66 gene-drug interactions, of which 26 (39%) were considered clinically relevant. This resulted in 26 applied pharmacotherapeutic interventions in 20 patients. Systematic pharmacogenetic testing enables pharmacotherapeutic interventions based on relevant gene-drug interactions. This study showed that pharmacogenetic testing adds to routine medication evaluation and could lead to optimized pharmacotherapy in CKD patients. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Lee, M. van der; Allard, W.G.; Vossen, R.H.A.M.; Baak-Pablo, R.F.; Menafra, R.; Deiman, B.A.L.M.; ... ; Anvar, S.Y. 2021
Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical... Show morePharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read amplicon-based sequencing and cytochrome P450 (CYP) 2D6-mediated tamoxifen metabolism data from a prospective study of 561 patients with breast cancer to train a neural network. The model explained 79% of interindividual variability in CYP2D6 activity compared to 54% with the conventional *-allele approach, assigned enzyme activities to known alleles with previously reported effects, and predicted the activity of previously uncharacterized combinations of variants. The results were replicated in an independent cohort of tamoxifen-treated patients (model R-2 adjusted = 0.66 versus *-allele R-2 adjusted = 0.35) and a cohort of patients treated with the CYP2D6 substrate venlafaxine (model R2 adjusted = 0.64 versus *-allele R-2 adjusted = 0.55). Human embryonic kidney cells were used to confirm the effect of five genetic variants on metabolism of the CYP2D6 substrate bufuralol in vitro. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP2D6 enzyme activity and could potentially enable more accurate prediction of individual drug response. Show less
The RNA-dependent RNA polymerase (RdRp) of turnip yellow mosaic virus (TYMV) was isolated by a simple, new method. An active, template-dependent and specific enzyme was obtained. Although the... Show moreThe RNA-dependent RNA polymerase (RdRp) of turnip yellow mosaic virus (TYMV) was isolated by a simple, new method. An active, template-dependent and specific enzyme was obtained. Although the genomic RNA of TYMV could not be transcribed completely during an in vitro RdRp assay, a complete double-stranded product was obtained when a 3' terminal RNA fragment of 83 nucleotides was used as a template. The reaction product was identified as being of negative polarity by complete digestion With ribonuclease T1. Antibodies directed to part of the N-terminal (Ab140) or C-terminal (Ab66) in vitro autocleavage products of the large non-structural polyprotein of TYMV, could both partially inhibit RdRp activity. Further purification of the RdRp preparation by ion-exchange chromatography resulted in two activity peaks with different protein compositions. Both peak fractions retained high specificity for transcription of TYMV RNA. A protein of approximately 115 kDa was detected by both Ab140 and Ab66. (C) 1997 Elsevier Science B.V. Show less
The pseudoknot or "base-paired loop region" is a widespread structural motif in all kinds of viral RNAs. Detailed structures of hairpin-type pseudoknots, obtained by NMR, are now emerging, but it... Show moreThe pseudoknot or "base-paired loop region" is a widespread structural motif in all kinds of viral RNAs. Detailed structures of hairpin-type pseudoknots, obtained by NMR, are now emerging, but it is still not clear which structural features are responsible for the different functions in processes like translation and replication. Especially noncoding regions are rich sources of pseudoknot structures, where they occur in domains like IRES elements and tRNA-like structures. But also its role in coding regions like in ribosomal -1 frameshifting and read-through is well established, although the precise mechanism of interference with the translational mechanism remains unknown. (C) 1997 Academic Press. Show less
