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Personalized Medicine, Pharmacogenetics, and Clopidogrel: Unraveling Variability of Response
Table 1
Studies on CYP450 Variants, Clopidogrel Pharmacokinetics, Pharmacodynamics, and/or Clinical Outcome
| Population and Treatment | Alleles Under Study | Assay | Pharmacokinetics or Pharmacodynamics | Clinical Outcome | Notes | |
|---|---|---|---|---|---|---|
| Shuldiner et al. (4) | 429 healthy Amish subjects 300 mg LD and 75 mg for 7 days |
Genome wide association, no pre-specified genotypes | ADP-LTA (20 μM) | 2C19*2 loss-of function allele (hetero or homozygous) associated with lower LTA inhibition | n.a. | 12% of variability in LTA response to clopidogrel depends on 2C19*2. No effect of ABCB1 or 2C19*17 gain-of-function |
| 277 PCI candidates 75 mg/od MD | C19*2 | ADP-LTA (20μM) | 2C19*2 loss-of function allele associated with lower LTA inhibition | HR 2.42 (1.18–4.99) for cardiovascular endpoints at 1 yr associated with 2C19*2 | 132 our of 277 patients lost at follow up, no control for compliance, low number of 2C19*2 carriers evaluable at 1 yr, low number of event | |
| Mega et al. (18) | 162 healthy subjects treated with 75, 300, 600 mg | 2C19 loss- or gain-of-function variants, 2B6, 2C9, 3A4/5, 1A2 | ADP-LTA (20 μM), AUC | Lower AUC and lower platelet inhibition with the CYP2C19*2, with a gradient effect. Smaller effect also for CYP2B6. | n.a. | Overlap between wild type and heterozygotes for LTA-ADP. |
| 1477 ACS patients from the TRITON- TIMI trial, 300 mg LD, 75 mg MD | n.a. | n.a. | 12.1% of primary outcomes in 395 patients with at least one 2C19 variants, 8% in 1064 non-carriers. HR: 1.53 (1.07–2.19) No effect of other genotypes |
For *2 carriers only, HR 1.42 (0.98 – 2.04) p=0.04. Unknown whether there was a gradient effect of 1 versus 2 loss-of-function alleles |
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| Simon et al. (22) | 2208 patients from registry on 75 mg MD | ABXB1, 3A5, 2C19, P2RY12 | n.a. | n.a. | At 1 yr follow-up, ABCB1 CC homozygous: HR 1.72 (1.20–2.47). Any two of 2C19 loss-of-function: HR 1.98 (1.10–3.58) |
3A5, ITGB3, and P2RY12 had no effect. No protective effect for the 2C19*17 gain-of-function allele. |
| Collet et al. (23) | 259 MI patients aged < 54, 75 mg MD | 2C19*2 | n.a. | n.a. | At 1 yr follow-up, 15 events in 186 non-carriers and 11 events in 73 2C19*2 carriers (1 or 2 alleles) HR: 3.69 (1.69–8.05) |
Low number of events, compliance unknown, more b-blockers used in non carriers (p=0.05). No differences in deaths, only MI and stent thrombosis |
| Sibbings et al. (24) | 2485 post-PCI patients, 600 mg LD, endpoint: stent thrombosis at 30 days | 2C19*2 | n.a. | n.a. | 10 thromboses over 1805 non- carriers, 7 events over 680 carriers (1 or 2 alleles). HR: 3.86 (1.47–10.14) | No control for compliance. Low number of events, 17 out of 2485 patients (0.7%). 2% homozygous for *2 variant. Worse outcome for homozygous (p for trend) |
| Varenhorst et al. (19) | 47 CAD patients 600 mg LD, 75 mg MD and 51 patients on prasugrel |
2C19, 2B6, 2C9, 3A4/5, 1A2 | metabolite concentration, AUC, VASP, VN on repeated occasions | In carriers of at least one loss-of- function 2C19 allele (*2, *4, *8): lower AUC and platelet inhibition assessed by both tests. No effect of 2C9, 2B6, 3A5 | n.a. | Prasugrel not influenced by CYP genotypes |
| Tiroch et al. (28) | 925 patients with acute MI, 75 mg MD | 2C19*17 | n.a. | n.a. | 18% relative reduction in MACE in the *17 gain-of-function carriers | Bleeding risk associated with a better bioactivation of clopidogrel unknown. PK and PD unknown. |
| Trenk et al. (19) | 797 PCI candidates, studied at 600 mg LD and 75 mg MD (before hospital discharge) from the EXCELSIOR trial | 2C19*2 | ADP-LTA (5–20 μM), flow cytometry post 20μM ADP | Higher residual platelet activation post LD or MD in 2C19*2 carriers (homozygous and heterozygous) | No effect of 2C19*2 on clinical outcome on multivariate analysis, predictive value of LTA-ADP only | Use of an arbitrary threshold (14% maximal aggregation). Two measurements per patient |
| Frere et al. (25) | 603 NSTEMI patients studied in the cath lab after 600 mg LD | 2C19, 3A4/5 | VASP, 10 μM ADP-LTA, flow cytometry post ADP | Higher ADP-LTA, VASP-PRI and P-selectin expression in heterozygotes and homozygotes for 2C19*2 alleles. No effect for 3A4/5 | n.a. | BMI significantly higher in hyper- responsive patients. 1% absolute difference in LTA, 9% absolute difference for VASP, 0.04 units for P-selectin between wild-type and heterozygous |
| Hulot et al. (26) | 28 healthy subjects, 75 mg for 7 days | 2C19, 2B6, 1A2, 3A4/5 | VASP and ADP-LTA | No effect of 2B6, 3A5, 1A2 2C19*1/*2 subjects had poor inhibition | n.a. | None of the *1/*2 subjects responded by ADP-LTA, while showed a significant inhibition by VASP, although lower than *1/*1 |
| Brandt et al. (21) | 74 healthy subjects, 300 mg or prasugrel 60 mg | 2C9, 2C19, 2B6, 1A2, 3A4/5 | AUC, Cmax, ADP-LTA | No effect of 3A5/4, 1A2, 2B6, 2C19*2 and 2C9 loss of function alleles had low AUC, Cmax and IPA | n.a. | Prasugrel independent of CYP genotype |
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Abbreviations: AUC, area under the curve; PCI, percutaneous coronary intervention; MD, maintenance dose; LD, loading dose; ADP-LTA, adenosine diphosphate–light transmittance aggregometry; BMI, body mass index; Cmax, maximal plasma concentration; IPA, inhibition of platelet aggregation; VASP-PRI: vasoactive stimulated phosphoprotein-platelet reactivity index; PK, pharmacokinetics; PD, pharmacodynamics; HR, hazard ratio; CAD, coronary artery disease; MACE, major adverse cardiovascular events; P2RY12, purinergic receptor P2Y, G–protein coupled, 12; n.a., not available.
