This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We examined whether the CYP2C9*8 allele impacts warfarin clearance through a pharmacokinetic study in warfarin-treated African American patients and an in vitro kinetic study of S-warfarin 7-hydroxylation using cDNA-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and 25% lower R- to S-warfarin plasma concentration in patients with the CYP2C9*8 allele (n=12) compared to CYP2C9*1 homozygotes (n=26). Consistent with these findings, the in-vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein compared to the wild-type protein. These data show that the R150H variant of the CYP2C9*8 allele reduces S-warfarin clearance, thus providing clinical and experimental evidence to explain lower warfarin dose requirements with the CYP2C9*8 allele.

Objectives Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine if omission of the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype affects performance of dosing algorithms in African Americans. Methods In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. Results The warfarindosing.org algorithm over-estimated doses by a median (IQR) of 1.2 (0.02 to 2.6) mg/day in rs12777823 heterozygotes (p<0.001 for predicted versus observed dose), 2.0 (0.6 to 2.8) mg/day in rs12777823 variant homozygotes (p=0.004), and 2.2 (0.5 to 2.9) mg/day in carriers of a CYP2C9 variant (p<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm under-dosed warfarin by 0.8 (−2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (p<0.001) and over-dosed warfarin by 0.7 (−0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (p=0.04). Modifying the warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original warfarindosing.org (p<0.01) or IWPC (p<0.01) algorithm. Conclusions These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff.

Advancements in pharmacogenomics have introduced an increasing number of opportunities to bring personalized medicine into clinical practice. Understanding how and when to use this technology to help guide pharmacotherapy used to treat neuropsychiatric conditions remains a challenge for many clinicians. Currently, guidelines exist to assist clinicians in the use of genetic information for drug selection and/or dosing for the tricyclic antidepressants, carbamazepine, and phenytoin. Additional language in the product labeling suggests that genetic information may also be useful for assessing the starting and target doses, as well as drug interaction potential, for a number of other medications used to treat psychiatric and neurological conditions. In this review, we outline the current status of pharmacogenomic testing for neuropsychiatric drugs as it pertains to information contained in drug labeling, consensus guidelines, and test panels, as well as considerations related to obtaining tests for patients.