Introduction
Materials and methods
Subjects
Study design
Determination of plasma drug concentrations
Pharmacokinetic evaluations
Safety assessments
Pharmacokinetic and statistical analysis
Results
Patients
Parameter | Dextromethorphan (CYP2D6) n = 26 | Tolbutamide + omeprazole (CYP2C9/CYP2C19) n = 20 | Efavirenz (CYP2B6) n = 20 | Repaglinide (CYP2C8) n = 20 |
---|---|---|---|---|
Male, n (%) | 18 (69.2) | 13 (65.0) | 17 (85.0) | 15 (75.0) |
Mean age (SD), years | 30.4 (7.4) | 31.5 (5.8) | 32.1 (7.9) | 29.4 (6.7) |
Ethnicity, n (%) | ||||
Not Hispanic or Latino | 21 (80.8) | 17 (85.0) | 12 (60.0) | 18 (90.0) |
Mean weight (SD), kg | 76.5 (10.5) | 79.3 (12.7) | 78.6 (9.6) | 73.8 (13.8) |
Mean BMI ± SD, kg/m2 | 24.6 (2.9) | 26.1 (2.8) | 25.8 (3.0) | 24.1 (3.5) |
Interaction of dextromethorphan with rolapitant
Treatment | Day | Number | Cmax (ng/mL) | Tmax (h) | AUC0–last (ng h/mL) | AUC0–inf (ng h/mL) | t½ (h) |
---|---|---|---|---|---|---|---|
Mean (CV%) | Median (range) | Mean (CV%) | Mean (CV%) | Mean (CV%) | |||
Dextromethorphan (CYP2D6 substrate) | |||||||
DEX | 1 | 26 | 3.11 (133) | 2.0 (1.0–4.0) | 32.3 (159) | 36.7 (146)a | 7.52 (45.2)a |
DEX + ROL | 7 | 26 | 5.36 (98.6) | 3.0 (1.5–6.0) | 62.1 (125) | 67.4 (120)b | 9.60 (40.5)b |
DEX | 14 | 26 | 5.72 (85.0) | 3.0 (1.5–4.0) | 70.1 (121) | 74.1 (118) | 10.2 (35.2) |
Tolbutamide (CYP2C9 substrate) | |||||||
TOL + OME | 1 | 20 | 43,348 (16.6) | 3.5 (2.0–8.0) | 748,795 (55.8) | 801,801 (74.4) | 10.1 (70.5) |
TOL + OME+ ROL | 7 | 20 | 41,849 (18.6) | 3.0 (1.5–4.0) | 685,748 (69.4) | 765,905 (101) | 10.4 (86.8) |
TOL + OME | 14 | 18 | 429,923 (19.7) | 4.0 (2.0–8.0) | 740,246 (66.5) | 817,760 (93.7) | 10.5 (82.5) |
Omeprazole (CYP2C19 substrate) | |||||||
TOL + OME | 1 | 20 | 410 (62.2) | 1.9 (1.0–12.0) | 1188 (85.9) | 1151 (88.4)c | 1.63 (62.6)c |
TOL + OME+ ROL | 7 | 20 | 606 (61.3) | 2.0 (1.5–4.0) | 1461 (79.8) | 1538 (75.6)d | 2.18 (75.9)d |
TOL + OME | 14 | 18 | 511 (49.5) | 2.0 (0.8–4.0) | 1339 (77.3) | 1429 (75.2)c | 1.57 (35.3)c |
Efavirenz (CYP2B6 substrate) | |||||||
EFV | 1 | 20 | 2592 (22.2) | 3.0 (1.0–5.0) | 68,463 (21.9) | 102,617 (23.8) | 87.6 (44.3) |
EFV + ROL | 10 | 20 | 2103 (19.1) | 3.5 (1.0–8.1) | 69,946 (20.6) | 113,011 (31.8) | 94.7 (42.1) |
EFV | 17 | 20 | 2817 (19.2) | 3.5 (1.0–5.1) | 80,079 (21.3) | 135,904 (35.7) | 101 (41.5) |
Repaglinide (CYP2C8 substrate) | |||||||
REP | 1 | 20 | 3.74 (38.5) | 0.5 (0.5–0.8) | 4.1 (33.7) | 4.4 (34.3)c | 3.01 (30.7)c |
REP + ROL | 3 | 20 | 4.13 (40.6) | 0.5 (0.5–1.0) | 4.6 (33.3) | 5.3 (31.1)e | 3.61 (54.7)e |
REP | 10 | 20 | 4.71 (26.5) | 0.5 (0.5–0.8) | 5.0 (30.5) | 5.6 (33.2)f | 3.76 (59.7)f |
Parameter | Geometric least squares mean | Treatment comparison | Mean ratio | 90% confidence interval | |
Dextromethorphan | Dextromethorphan + rolapitant | ||||
5a: Effect of rolapitant on dextromethorphan PK—day 7 vs day 1 | |||||
C
max
| 1.44 | 3.24 | Rolapitant + DEX vs DEX | 2.25 | (1.87, 2.70) |
AUC(0–last) | 9.26 | 27.84 | Rolapitant + DEX vs DEX | 3.00 | (2.43, 3.72) |
AUC(0–inf) | 12.12 | 31.20 | Rolapitant + DEX vs DEX | 2.58 | (2.13, 3.11) |
5a: Effect of rolapitant on dextromethorphan PK—day 14 vs day 1 | |||||
C
max
| 1.442 | 3.99 | Rolapitant + DEX vs DEX | 2.77 | (2.30, 3.33) |
AUC(0–last) | 9.26 | 36.39 | Rolapitant + DEX vs DEX | 3.93 | (3.18, 4.86) |
AUC(0–inf) | 12.12 | 40.38 | Rolapitant + DEX vs DEX | 3.33 | (2.76, 4.02) |
Parameter | Geometric least squares mean | Treatment comparison | Mean ratio | 90% confidence interval | |
Tolbutamide | Tolbutamide + rolapitant | ||||
5b: Effect of rolapitant on tolbutamide PK—day 7 vs day 1 | |||||
C
max
| 42,718.88 | 41,100.97 | Rolapitant + TOL vs rolapitant | 0.96 | (0.91,1.02) |
AUC(0–last) | 676,029.20 | 602,771.38 | Rolapitant + TOL vs rolapitant | 0.89 | (0.85, 0.94) |
AUC(0–inf) | 694,384.80 | 624,546.67 | Rolapitant + TOL vs rolapitant | 0.90 | (0.85, 0.95) |
5b: Effect of rolapitant on tolbutamide PK—day 14 vs day 1 | |||||
C
max
| 42,718.88 | 41,727.74 | Rolapitant + TOL vs rolapitant | 0.98 | (0.92, 1.04) |
AUC(0–last) | 676,029.20 | 640,009.92 | Rolapitant + TOL vs rolapitant | 0.95 | (0.90, 1.00) |
AUC(0–inf) | 694,384.80 | 661,261.15 | Rolapitant + TOL vs rolapitant | 0.95 | (0.90, 1.01) |
Parameter | Geometric least squares mean | Treatment comparison | Mean ratio | 90% confidence interval | |
Omeprazole | Omeprazole + rolapitant | ||||
5c: Effect of rolapitant on omeprazole PK—day 7 vs day 1 | |||||
C
max
| 337.20 | 485.78 | Rolapitant + OME vs rolapitant | 1.44 | (1.12, 1.86) |
AUC(0–last) | 890.35 | 1088.53 | Rolapitant + OME vs rolapitant | 1.22 | (1.13, 1.32) |
AUC(0–inf) | 914.38 | 1127.10 | Rolapitant + OME vs rolapitant | 1.23 | (1.12, 1.36) |
5c: Effect of rolapitant on omeprazole PK—day 14 vs day 1 | |||||
C
max
| 337.20 | 460.56 | Rolapitant + OME vs rolapitant | 1.37 | (1.05, 1.78) |
AUC(0–last) | 890.35 | 1035.22 | Rolapitant + OME vs rolapitant | 1.16 | (1.07, 1.26) |
AUC(0–inf) | 914.39 | 1047.92 | Rolapitant + OME vs rolapitant | 1.15 | (1.03, 1.27) |
Parameter | Geometric least squares mean | Treatment comparison | Mean ratio | 90% confidence interval | |
Efavirenz | Efavirenz + rolapitant | ||||
5d: Effect of rolapitant on efavirenz PK—day 10 vs day 1 | |||||
C
max
| 2531.37 | 2067.62 | Rolapitant + EFV vs rolapitant | 0.82 | (0.74, 0.90) |
AUC(0–last) | 67,127.93 | 68,601.89 | Rolapitant + EFV vs rolapitant | 1.02 | (0.96, 1.09) |
AUC(0–inf) | 99,812.77 | 107,722.63 | Rolapitant + EFV vs rolapitant | 1.08 | (0.99, 1.17) |
5d: Effect of rolapitant on efavirenz PK—day 17 vs day 1 | |||||
C
max
| 2531.37 | 2769.08 | Rolapitant + EFV vs rolapitant | 1.09 | (1.00, 1.20) |
AUC(0–last) | 67,127.93 | 78,415.00 | Rolapitant + EFV vs rolapitant | 1.16 | (1.10, 1.24) |
AUC(0–inf) | 99,812.77 | 127,843.75 | Rolapitant + EFV vs rolapitant | 1.28 | (1.18, 1.40) |
Parameter | Least squares mean | Treatment comparison | Mean ratio | 90% confidence interval | |
Repaglinide | Repaglinide + rolapitant | ||||
5e: Effect of rolapitant on repaglinide PK—day 3 vs day 1 | |||||
C
max
| 3.53 | 3.76 | Rolapitant + REP vs rolapitant | 1.07 | (0.96, 1.19) |
AUC(0–last) | 3.92 | 4.35 | Rolapitant + REP vs rolapitant | 1.11 | (1.06, 1.16) |
AUC(0–inf) | 4.19 | 4.71 | Rolapitant + REP vs rolapitant | 1.12 | (1.07, 1.18) |
5e: Effect of rolapitant on repaglinide PK—day 10 vs day 1 | |||||
C
max
| 3.53 | 4.56 | Rolapitant + REP vs rolapitant | 1.30 | (1.16, 1.44) |
AUC(0–last) | 3.92 | 4.80 | Rolapitant + REP vs rolapitant | 1.23 | (1.17, 1.28) |
AUC(0–inf) | 4.19 | 5.17 | Rolapitant + REP vs rolapitant | 1.23 | (1.18, 1.30) |