Introduction
Methods
Subjects
Study Design
Study | OCA administration | Probe substrate administration | CYP/transporter | ||
---|---|---|---|---|---|
Dose | Days | Probe substrate (oral dose) | Days | ||
I | 10 and 25 mg QD | Day 5 through day 23 | Caffeine (200 mg) Midazolam (2 mg) | Day 3 and day 21 Day 1 and day 19 | CYP1A2 CYP3A |
II | 10 and 25 mg QD | Day 8 through day 27 | Warfarin (25 mg) | Day 1, day 21 | CYP2C9 (S-warfarin) CYP1A2, CYP3A (R-warfarin) |
III | 10 and 25 mg QD | Day 5 through day 28 | Dextromethorphan (30 mg) Omeprazole (20 mg) | Day 1, day 18 Day 4, day 21–28 | CYP2D6 CYP2C19 |
IV | 10 and 25 mg QD | Day 6 through day 23 | Rosuvastatin (20 mg) | Day 1, day 19 | BCRP/OATP1B1/OATP1B3 |
V | 10 and 25 mg QD | Day 6 through day 23 | Digoxin (0.25 mg) | Day 1, day 19 | P-gp (MDR1) |
Study I: Specific Substrates for CYP1A2 (Caffeine) and for CYP3A (Midazolam)
Study II: Specific Substrates for CYP2C9 (S-warfarin) and for CYP1A2 and CYP3A (R-warfarin)
Study III: Specific Substrates for CYP2D6 (Dextromethorphan) and for CYP2C19 (Omeprazole)
Study IV: BCRP, OATP1B1, and OATP1B3 Substrate (Rosuvastatin)
Study V: P-gp Substrate (Digoxin)
Analytical Methods
Pharmacokinetic and Pharmacodynamic Parameters
Statistical Analysis
Results
Subjects
Study I
N = 48 | Study II
N = 44 | Study III
N = 48 | Study IV
N = 48 | Study V
N = 48 | |
---|---|---|---|---|---|
Age, years | 35.0 (9.5) | 35.0 (9.4) | 32.9 (8.5) | 37.9 (9.5) | 35.4 (8.7) |
Sex, n (%) | |||||
Female | 22 (46%) | 15 (34%) | 17 (35%) | 12 (25%) | 14 (29%) |
Male | 26 (54%) | 29 (66%) | 31 (65%) | 36 (75%) | 34 (71%) |
Race, n (%) | |||||
White | 28 (58%) | 27 (61%) | 24 (50%) | 32 (67%) | 23 (48%) |
Other | 20 (42%) | 17 (39%) | 24 (50%) | 16 (33%) | 25 (52%) |
Ethnicity, n (%) | |||||
Not Hispanic or Latino | 37 (77%) | 29 (66%) | 39 (81%) | 28 (58%) | 35 (73%) |
Height, cm | 170.1 (8.4) | 170.6 (8.0) | 170.8 (8.0) | 171.5 (10.8) | 170.7 (8.5) |
Weight, kg | 75.2 (12.3) | 76.3 (10.6) | 76.2 (11.8) | 78.1 (12.7) | 75.0 (11.8) |
BMI, kg/m2
| 25.9 (2.9) | 26.1 (2.3) | 26.0 (2.9) | 26.4 (2.4) | 25.7 (2.9) |
Discontinuationsa
| |||||
Overall, n (%) | 3 (6%) | 1 (2%) | 1 (2%) | 0 (0%) | 0 (0%) |
10 mg OCA, n (%) | 0 (0%) | 0 (0%) | 1 (4%) | 0 (0%) | 0 (0%) |
25 mg OCA, n (%) | 3 (13%) | 1 (4%) | 0 (0%) | 0 (0%) | 0 (0%) |
Pharmacokinetic Evaluation
Treatment | 10 mg OCA | 25 mg OCA | ||
---|---|---|---|---|
n
| GLSM ratio (90% CI) |
n
| GLSM ratio (90% CI) | |
Study I: caffeine (CYP1A2) | ||||
AUC∞ (h ng/mL) | 24 | 1.417 (1.350–1.488) | 21 | 1.654 (1.557–1.757) |
C
max (ng/mL) | 24 | 1.061 (1.014–1.111) | 21 | 1.099 (1.043–1.159) |
Study I: midazolam (CYP3A) | ||||
AUC∞ (h ng/mL) | 23 | 1.020 (0.930–1.119) | 23 | 1.259 (1.135–1.397) |
C
max (ng/mL) | 24 | 1.017 (0.919–1.126) | 23 | 1.173 (1.052–1.309) |
Study II: S-warfarin (CYP2C9) | ||||
AUC∞ (h ng/mL) | 21 | 1.126 (1.097–1.155) | 22 | 1.181 (1.142–1.220) |
C
max (ng/mL) | 21 | 1.120 (1.052–1.193) | 22 | 1.058 (0.990–1.131) |
Study II: R-warfarin (CYP1A2 and 3A4) | ||||
AUC∞ (h ng/mL) | 21 | 1.209 (1.163–1.256) | 22 | 1.324 (1.274–1.375) |
C
max (ng/mL) | 21 | 1.109 (1.042–1.181) | 22 | 1.052 (0.985–1.123) |
Study III: dextromethorphan (CYP2D6) | ||||
AUC∞ (h ng/mL) | 19 | 0.891 (0.747–1.063) | 19 | 0.895 (0.785–1.021) |
C
max (ng/mL) | 23 | 0.879 (0.725–1.065) | 24 | 0.826 (0.728–0.937) |
Study III: omeprazole (CYP2C19) | ||||
AUC∞ (h ng/mL) | 21 | 1.321 (1.217–1.434) | 19 | 1.366 (1.242–1.502) |
C
max (ng/mL) | 23 | 1.327 (1.167–1.508) | 24 | 1.148 (0.965–1.366) |
Study IV: rosuvastatin (BCRP/OATP1B1/OATP1B3) | ||||
AUC∞ (h ng/mL) | 24 | 1.219 (1.125–1.321) | 23 | 1.296 (1.158–1.450) |
C
max (ng/mL) | 24 | 1.272 (1.150–1.408) | 24 | 1.258 (1.092–1.451) |
Study V: digoxin (P-gp) | ||||
AUC∞ (h ng/mL) | 24 | 1.012 (0.954–1.073) | 24 | 1.073 (0.994–1.157) |
C
max (ng/mL) | 24 | 0.967 (0.869–1.076) | 24 | 1.236 (1.083–1.411) |
CYP1A2 (Caffeine)
CYP3A (Midazolam)
CYP2C9 (S-warfarin)
CYP1A2 and CYP3A (R-warfarin)
CYP2D6 (Dextromethorphan)
CYP2C19 (Omeprazole)
BCRP, OATP1B1, and OATP1B3 (Rosuvastatin)
P-gp Substrate (Digoxin)
Pharmacodynamic Evaluation
Analyte | OCA 10 mg | OCA 25 mg | ||
---|---|---|---|---|
AUEC |
E
max
| AUEC |
E
max
| |
PT, n
| 21 | 21 | 22 | 22 |
GLSM ratio (90% CI) | 0.967 (0.946–0.988) | 0.888 (0.851–0.927) | 0.981 (0.962–1.000) | 0.927 (0.895–0.960) |
aPPT, n
| 21 | 21 | 22 | 22 |
GLSM ratio (90% CI) | 0.991 (0.978–1.004) | 0.990 (0.976–1.005) | 1.001 (0.980–1.022) | 1.004 (0.975–1.034) |
INR, n
| 21 | 21 | 22 | 22 |
GLSM ratio (90% CI) | 0.967 (0.947–0.988) | 0.889 (0.852–0.927) | 0.982 (0.963–1.002) | 0.928 (0.896–0.962) |