Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study

Figures

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  Fig. 1. Drug-drug, drug-gene, and drug-drug-gene interactions. The hepatic extensive (normal) metabolism of small molecule drug A (yellow triangles) requires functional drug-metabolising enzyme Z (DME-Z, blue rectangles) for metabolism to metabolite A (blue circles), as shown in I. In II, DME-Z is inhibited by perpetrator drug B (red triangle) leading to reduced drug A metabolism, and hence a drug-drug interaction (DDI). Similarly in III, the function of DME-Z is reduced by genetic variation (red rectangles) conferring a poor metaboliser (homozygous) genotype, leading to reduced drug A metabolism, and hence a drug-gene interaction (DGI). In IV, a drug-drug-gene interaction (DDGI) is depicted whereby both genetic variation (e.g. a heterozygous intermediate metaboliser genotype) and perpetrator drug B conceivably act together to collectively reduce DME-Z function, strongly attenuating drug A metabolism. In V, drug A is primarily metabolised by DME-Z, but also a second enzyme, DME-Y, (flattened red rectangles) involved to a lesser extent is shown. If perpetrator drug B inhibits DME-Z, less drug A is metabolised by DME-Z and so drug A metabolism is more reliant on DME-Y conversion to…

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  Fig. 2. Study cohort selection process. There were 1470 patients included in the PhACS study, of whom 1456 were discharged alive from their index NSTE-ACS; 1357 had array genetic data available following standard quality control procedures; CYP2D6 genotype was available in 728 after determination of copy number variation in those on CYP2D6 substrates; 698 had non-cardiovascular disease (CVD) drugs at discharge recorded in their case report form (CRF) medication appendix, in addition to CVD drugs explicitly required in the CRF; and in 652 patients (the interaction cohort), CVD drugs, non-CVD drugs, and genetic data were available (although patients not on a CYP2D6 substrate did not require CYP2D6 genotype for inclusion in the interaction cohort)

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  Fig. 3. Patient pharmacogene genotypes. Proportions of genotype-based CYP metaboliser phenotypes (a) and non-CYP pharmacogene genotypes (b) observed across the whole cohort with quality-controlled array genetic data available (n = 1357), except for CYP2B6 (n = 1347), F5 (n = 1346), and CYP2D6 (n = 728). The number of patients with CYP2B6, F5, and CYP2D6 available was less due to exclusion of patients with imputed genotypes outside the predefined imputation acceptance range, and determination of CYP2D6 copy number variation in patients on a CYP2D6 drug substrate (see the ‘Methods’ section). Overall, 713 patients had genotypes available for all analysed genes. EM, extensive (normal) metaboliser; IM, intermediate metaboliser; PM, poor metaboliser; RM, rapid metaboliser; UM, ultra-rapid metaboliser; WT, wild-type; HET, heterozygous; HOM, homozygous for the variant allele

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  Fig. 4. Drug- and gene-mediated interactions. This figure shows the total number (%) of interactions identified (a), the number (%) of interactions per patient (b), and the percentage of interactions mediated per enzyme/transporter (c) in 652 post-NSTE-ACS patients. The pie charts on the left display all interactions (of any or unconfirmed strength), whilst predicted substantial interactions only are presented in the charts on the right. In a and b, each interaction was counted only once. In c, some types of interaction were counted more than once in a given patient. These were as follows: DDIs where a perpetrator drug can influence the same victim drug through more than one enzyme/transporter (e.g. verapamil inhibiting atorvastatin at both CYP3A4/5 and P-gp), DDGIs involving more than one enzyme/transporter, and DGGIs. These interactions were included in the count of both involved enzymes/transporters to illustrate them clearly in c only

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  Fig. 5. Interactions mediated by CYP2C9, CYP2C19, CYP2D6, and SLCO1B1. This figure displays the number of identified all (a) and substantial (b) interactions mediated through the three CYP enzymes (2C9, 2C19, 2D6) and transporter (SLCO1B1) that were directly influenced by both drug- and gene-based interactions, in 652 post-NSTE-ACS patients. In this patient cohort, CYP2C19-mediated interactions were the most common due to the high frequency of clopidogrel prescribing and, to a lesser extent, proton pump inhibitors, although many SLCO1B1-based interactions were also found due to atorvastatin and simvastatin