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Background: CYP2D6 and CYP2C19 are cytochrome P450 enzymes involved in the metabolism of many medications from multiple therapeutic classes. The genes encoding them, CYP2D6 and CYP2C19, have multiple functional variants that have been associated with different levels of enzyme activity. There is evidence that methodology for identifying such variants (genotyping) effectively and efficiently could lead to substantial health care costs savings. There are various genotyping technologies available; we cross-validated several against each other. Methods: Ninety-six samples with a variety of CYP2D6 and CYP2C19 genotypes according to prior AmpliChip CYP450 and TaqMan CYP2C19*17 data were selected from the Genome-based therapeutic drugs for depression (GENDEP) study. Genotyping was performed with TaqMan copy number variant (CNV) analysis using probes specific for three different regions (CYP2D6 only), the next generation sequencing-based Ion S5 AmpliSeq Pharmacogenomics Panel, PharmacoScan, and long-range polymerase chain reaction (XL-PCR) followed by TaqMan single nucleotide variant (SNV) analysis or the Agena MassARRAY. Variant to star allele translation was automated. Results: The inter-platform concordance for CYP2C19 was high (94-98%). For CYP2D6, the IonS5-PharmacoScan concordance was 94% for a range of variants tested apart from those with at least one extra copy of a CYP2D6 gene (occurring at a frequency of 3.8%, 33/853), or a pseudogene-gene conversion (2%, 18/853). Conclusions: Inter-platform concordance for CYP2C19 was high, and, moreover, the Ion S5 and PharmacoScan data were 100% concordant with that from a TaqMan CYP2C19*2 assay. The level of concordance was also good for CYP2D6, apart from those with at least one extra copy of a CYP2D6 gene or a pseudogene-gene conversion. We have also demonstrated feasibility of using a NGS platform for genotyping CYP2D6 and CYP2C19, with automated data interpretation methodology. CYP2D6 and CYP2C19 genotyping may thereby become much more readily accessible, with potential substantial savings in health care costs and public benefit. ### Competing Interest Statement The authors have declared no competing interest.

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