Article Figures & Data
Figures
- Fig. 1.
Apixaban and rosuvastatin interactions in Caco-2 cells. Apixaban (A) and rosuvastatin (B) apparent permeabilities (Papp) across polarized Caco-2 cells in the A-to-B and B-to-A directions. Apixaban and rosuvastatin directional flux was monitored in the absence or presence of rosuvastatin, apixaban, fumitremorgin C (BCRP inhibitor), or verapamil (P-gp inhibitor) applied to both B and A compartments. Data are presented as the mean and S.D. (N = 3). ***P < 0.001; ****P < 0.0001 when compared with control Papp using t test.
- Fig. 2.
Plasma concentration-time curves after simultaneous oral administration of apixaban 2.5 mg (A) and rosuvastatin 5 mg (B) in healthy control subjects (open circles; N = 12) and patients with NAFLD (closed circles; N = 22). Data are presented as the mean ± S.E.M.
- Fig. 3.
Relationships between total body weight and AUC0–12 for apixaban (A) and rosuvastatin (B) in healthy control subjects (open circles; N = 12) and patients with NAFLD (closed circles; N = 22). Pearson’s ρ values, r2 values, and P values are noted.
Tables
- TABLE 1
Participant characteristics
Values are the mean ± S.D., unless otherwise indicated.
Control Group (N = 12) NAFLD Group (N = 22) P Value* NAFLD-No Fibrosis Group (N = 11) P Value* NAFLD-Fibrosis Group (N = 11) P Value* Age (yr) 46.0 ± 9.8 51.3 ± 12.4 0.18 50.9 ± 12.8 0.32 51.7 ± 12.5 0.24 Sex, n (female/male) 10/2 11/11 0.056 7/4 0.28 4/7 0.021 Weight (kg) 65.6 ± 10.3 99.9 ± 21.9 <0.001 93.2 ± 23.5 0.003 106.6 ± 18.8 <0.001 BMI 23.4 ± 2.5 34.0 ± 4.5 <0.001 32.4 ± 3.9 <0.001 35.5 ± 4.8 <0.001 Waist circumference (cm) 76.5 ± 5.0 111.4 ± 17.9 <0.001 109.5 ± 21.8 <0.001 113.1 ± 14.3 <0.001 ALT (U/l) 16.5 ± 7.5 49.4 ± 36.3 <0.001 49.1 ± 32.1 0.007 49.7 ± 41.6 0.024 AST (U/l) 24.0 ± 10.3 33.1 ± 15.5 0.048 30.6 ± 10.3 0.14 35.6 ± 19.6 0.10 GGT (U/l) 16.6 ± 6.3 52.1 ± 40.8 <0.001 43.8 ± 21.5 0.002 60.5 ± 53.6 0.02 Alkaline phosphatase (U/l) 61.3 ± 14.3 77.9 ± 18.1 0.006 79.1 ± 16.8 0.01 76.7 ± 20.1 0.05 Platelets (×109 cells/l) 234 ± 40 262 ± 75 0.16 261 ± 63 0.23 262 ± 89 0.34 Serum creatinine (μM) 69.8 ± 13.8 67.8 ± 12.1 0.67 63.2 ± 11.5 0.23 71.9 ± 11.7 0.70 HgA1c (%) 5.3 ± 0.4 6.3 ± 0.9 <0.001 6.4 ± 1.0 0.004 6.2 ± 0.8 0.004 Diabetes 0/12 8/22 0.017 2/11 0.12 6/11 0.003 Hypertension 0/12 10/22 0.005 4/11 <0.001 6/11 0.003 Dyslipidemia 0/12 11/22 0.003 3/11 0.052 8/11 <0.001 MR fat signal fraction −0.01 ± 0.05 0.27 ± 0.08 <0.001 0.30 ± 0.09 <0.001 0.24 ± 0.08 <0.001 4β HC (ng/ml) 16.9 ± 3.2 11.9 ± 5.4 0.007 13.4 ± 5.9 0.13 10.4 ± 4.5 0.002 Genotypes, n (Frequency %)a SLCO1B1 388A>G 7/5/0 (21) 8/9/5 (43) 0.065 5/3/3 (41) 0.14 3/6/2 (46) 0.075 SLCO1B1 521T>C 8/4/0 (17) 15/7/0 (16) 0.935 7/4/0 (18) 0.89 8/3/0 (14) 0.78 ABCG2 421C>A 7/4/1 (25) 20/2/0 (5) 0.012 10/1/0 (5) 0.054 10/1/0 (5) 0.054 CYP3A4*22 12/0/0 (0) 22/0/0 (0) 11/0/0 (0) 11/0/0 (0) CYP3A5*3 8/3/1 (79) 20/1/1 (93) 0.086 9/1/1 (86) 0.52 11/0/0 (100) 0.023 PNPLA3 I148M 9/3/0 (13) 12/8/2 (27) 0.16 5/5/1 (32) 0.11 7/3/1 (23) 0.36 ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, γ-glutamyltranspeptidase; HgA1c, glycated hemoglobin; Ref, carriers of reference allele; Var, variant allele.
↵a Genotypes are reported in the following pattern: Ref-Ref/Ref-Var/Var-Var.
↵* Two-tailed, t test or χ2 test with comparison with control group.
- TABLE 2
Apixaban pharmacokinetic parameters
Values are the mean ± S.D., unless otherwise indicated.
Control Group (N = 12) NAFLD Group (N = 22) P Value* NAFLD-No Fibrosis Group (N = 11) P Value* NAFLD-Fibrosis Group (N = 11) P Value* AUC0–12 (ng/ml × h) 671 ± 174 545 ± 265 0.15 580 ± 228 0.30 511 ± 304 0.15 AUC0–∞ (ng/ml × h) 840 ± 326 715 ± 351 0.31 725 ± 290 0.38 705 ± 417 0.40 Cmax (ng/ml) 98 ± 31 78 ± 44 0.13 82 ± 40 0.33 74 ± 49 0.17 Tmax (h) 2.6 ± 1.1 2.7 ± 1.3 0.78 2.6 ± 1.1 0.96 2.8 ± 1.4 0.66 t1/2 (h) 4.5 ± 1.5 5.0 ± 1.2 0.34 4.5 ± 0.5 0.97 5.5 ± 1.4 0.12 Xurine,0–12 (μg) 611 ± 148 544 ± 182 0.26 527 ± 176 0.23 562 ± 194 0.51 CLrenal (ml/min) 16.2 ± 5.4 19.6 ± 9.1 0.25 17.3 ± 8.5 0.71 21.8 ± 9.4 0.11 ↵* Two-tailed, t test or χ2 test with comparison with control group.
- TABLE 4
Rosuvastatin pharmacokinetic parameters
Values are the mean ± S.D., unless otherwise indicated.
Control Group (N = 12) NAFLD Group (N = 22) P Value* NAFLD-No Fibrosis Group (N = 11) P Value* NAFLD-Fibrosis Group (N = 11) P Value* AUC0–12 (ng/ml × h) 25.4 ± 11.0 20.1 ± 14.3 0.28 21.5 ± 13.5 0.46 18.6 ± 15.7 0.25 AUC0–∞ (ng/ml × h) 30.7 ± 13.6 25.4 ± 17.0 0.35 27.0 ± 15.4 0.58 23.7 ± 19.2 0.36 Cmax (ng/ml) 3.7 ± 2.0 3.0 ± 2.6 0.42 3.3 ± 2.6 0.70 2.8 ± 2.7 0.39 Tmax (h) 3.9 ± 2.0 3.8 ± 1.9 0.86 3.7 ± 2.1 0.81 3.9 ± 1.8 0.95 t1/2 (h) 4.4 ± 1.2 5.4 ± 2.9 0.21 4.8 ± 1.4 0.54 6.0 ± 4.0 0.25 Xurine,0–12 (μg) 257 ± 107 209 ± 186 0.34 244 ± 230 0.87 174 ± 130 0.11 CLrenal (ml/min) 180 ± 64 178 ± 69 0.93 178 ± 84 0.94 178 ± 53 0.94 ↵* Two-tailed, t test or χ2 test with comparison with control group.
