Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 µg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

Analytical validation of a laboratory-development multigene pharmacogenetic assay.

OBJECTIVE: The implementation of pharmacogenetics (PGx) in clinical practice is an essential tool for personalized medicine. However, clinical laboratories must validate their procedures before being used to perform PGx studies in patients, in order to confirm that they are adequate for the intended purposes. METHODS: We designed a validation process for our in-house pharmacogenetic PCR-based method assay. RESULTS: The concordance to reference, repeatability and reproducibility was 100%. Sensitivity and specificity were 100% for the detection of variant diplotypes in CYP2C9, CYP3A5, TPMT, DPYD and UGT1A1 genes. The sensitivity was lower in the detection of CYP2C19 variants due to a limitation in the design that prevents the detection of CYP2C19 *2/*10 diplotype. CONCLUSIONS: The success of implementing clinical pharmacogenetic testing into routine clinical practice is dependent on the precision of genotyping. Limitations must be bearing in mind to guarantee the quality of PGx assays in clinical laboratory practice. We provided objective evidence that the necessary requirements in our laboratory-development assay were fulfilled.

Severe Hyponatremia Is Often Drug Induced: 10-Year Results of a Prospective Pharmacovigilance Program.

We conducted a prospective evaluation of drug-induced severe hyponatremia  (adverse drug reaction (ADR)) through the Prospective Pharmacovigilance Program from Laboratory Signals at Hospital over a period of 10 years. Cases of serum sodium (Na(s)) < 116 mM were recorded from July 2007 to June 2017 (first period). Also cases of Na(s) 116-122 mM were recorded from July 2012 to June 2017 (second period). Drugs were the primary cause of severe hyponatremia. The incidence rate of Na(s) < 116 mM by drugs was increased threefold over the decade. Compared with other causes of hyponatremia, patients with adverse drug reaction-serum sodium (ADR-Na(s)) in the first period were older (79 years (interquartile range (IQR) 68.6-89 vs. 65 years (IQR 48-81); P < 0.001) and were more often women (70.8% vs. 48.9% men, P < 0.001); in the second period were also older (79 years (IQR 65.3-89) vs. 63 years (IQR 46-80.6); P < 0.001) and were more often women (70% vs. 53%, P = 0.002), and ADR-Na(s) occurred more often in summer. The most frequent therapeutic groups of culprit drugs were the cardiovascular system and nervous system. The 65.3% in the first period and 71.2% in the second period of the ADR-Na(s) cases responded to hydration and had been diagnosed with hypovolemic hyponatremia.