TABLE 2.
Results of the candidate gene analysis with SNVs or SNVs and ABCB1 haplotypes on R‐celiprolol, S‐celiprolol, and total celiprolol AUC0–∞
| Pharmacokinetic variable | Covariate/SNV/haplotype | Effect a | p value | Bonferroni adjusted p value | Adjusted R 2 for each step | |
|---|---|---|---|---|---|---|
| Average | 90% CI | |||||
| R‐celiprolol AUC0–∞ | LBW | −8.4% | −11.0%, −5.7% | 1.14 × 10−6 | 0.11 | |
| (ABCB1 SNVs) | ABCB1 c.3435T>C (rs1045642) | −13.4% | −19.7%, −6.6% | 1.84 × 10−3 | 0.0257 | 0.15 |
| SLCO1A2 c.516A>C (rs11568563) | −24.9% | −34.3%, −14.2% | 4.84 × 10−4 | 6.77 × 10−3 | 0.19 | |
| ABCB1 c.2677T>A (rs2032582) | −21.2% | −35.0%, −4.5% | 0.0421 | 0.590 | 0.21 | |
| S‐celiprolol AUC0–∞ | LBW | −8.2% | −10.8%, −5.4% | 2.77 × 10−6 | 0.10 | |
| (ABCB1 SNVs) | SLCO1A2 c.516A>C (rs11568563) | −25.4% | −34.8%, −14.7% | 4.10 × 10−4 | 5.74 × 10−3 | 0.14 |
| ABCB1 c.3435T>C (rs1045642) | −13.2% | −19.5%, −6.3% | 2.50 × 10−3 | 0.0351 | 0.18 | |
| ABCB1 c.2677T>A (rs2032582) | −22.2% | −35.9%, −5.4% | 0.0347 | 0.486 | 0.20 | |
| Total celiprolol AUC0–∞ | LBW | −8.3% | −10.9%, −5.6% | 1.75 × 10−6 | 0.11 | |
| (ABCB1 SNVs) | SLCO1A2 c.516A>C (rs11568563) | −25.2% | −34.6%, −14.4% | 4.42 × 10−4 | 6.19 × 10−3 | 0.14 |
| ABCB1 c.3435T>C (rs1045642) | −13.3% | −19.6%, −6.5% | 2.14 × 10−3 | 0.0300 | 0.19 | |
| ABCB1 c.2677T>A (rs2032582) | −21.7% | −35.5%, −5.0% | 0.0381 | 0.533 | 0.20 | |
| R‐celiprolol AUC0–∞ | LBW | −8.7% | −11.3%, −6.2% | 2.05 × 10−7 | 0.11 | |
| (ABCB1 haplotypes) | ABCB1 H8 (AGCAAC) | −41.0% | −53.4%, −25.2% | 3.02 × 10−4 | 5.14 × 10−3 | 0.15 |
| SLCO1A2 c.516A>C (rs11568563) | −23.0% | −32.3%, −12.3% | 1.03 × 10−3 | 0.0176 | 0.20 | |
| ABCB1 H2 (AGCGAC) | −13.2% | −19.7%, −6.1% | 3.36 × 10−3 | 0.0571 | 0.22 | |
| ABCB1 H7 (AGCTAT) | −22.9% | −37.3%, −5.2% | 0.0390 | 0.662 | 0.24 | |
| S‐celiprolol AUC0–∞ | LBW | −8.5% | −11.1%, −5.9% | 4.97 × 10−7 | 0.10 | |
| (ABCB1 haplotypes) | ABCB1 H8 (AGCAAC) | −42.1% | −54.4%, −26.4% | 2.14 × 10−4 | 3.64 × 10−3 | 0.15 |
| SLCO1A2 c.516A>C (rs11568563) | −23.5% | −32.9%, −12.9% | 8.43 × 10−4 | 0.0143 | 0.19 | |
| ABCB1 H2 (AGCGAC) | −12.8% | −19.4%, −5.6% | 4.79 × 10−3 | 0.0814 | 0.22 | |
| ABCB1 H7 (AGCTAT) | −23.1% | −37.6%, −5.3% | 0.0387 | 0.657 | 0.23 | |
| Total celiprolol AUC0–∞ | LBW | −8.6% | −11.2%, −6.0% | 3.13 × 10−7 | 0.11 | |
| (ABCB1 haplotypes) | ABCB1 H8 (AGCAAC) | −41.5% | −53.9%, −25.9% | 2.52 × 10−4 | 4.28 × 10−3 | 0.15 |
| SLCO1A2 c.516A>C (rs11568563) | −23.3% | −32.6%, −12.6% | 9.26 × 10−4 | 0.0157 | 0.20 | |
| ABCB1 H2 (AGCGAC) | −12.9% | −19.6%, −5.8% | 4.00 × 10−3 | 0.0679 | 0.22 | |
| ABCB1 H7 (AGCTAT) | −23.0% | −37.4%, −5.2% | 0.0387 | 0.658 | 0.24 | |
Abbreviations: AUC0–∞, area under the plasma concentration‐time curve from 0 h to infinity; CI, confidence interval; LBW, lean body weight; SNV, single nucleotide variation.
ABCB1 haplotypes are presented in Figure 2 and are based on the c.61A>G, c.1199G>A, c.1236T>C, c.2677T>G/A, c.3320A>C, and c.3435T>C SNVs.
a
Per minor allele or haplotype copy; per 10% increase in LBW.