Introduction
Methods
Study Design
Study Participants
Dosing and Sampling Schedules
Pharmacokinetic Assessments
Pharmacodynamic Assessments
Safety Assessments
Statistical Analysis
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H0 (null hypothesis): AUCinf ratio less than 0.80 or greater than 1.25.
-
H1 (alternative hypothesis): AUCinf ratio 0.80 or greater and 1.25 or less.
Results
Study Population
Study | ||||||
---|---|---|---|---|---|---|
15L-CL-008 (n = 22) | 15L-CL-009 (n = 22) | 15L-CL-010 | 15L-CL-018 | |||
Amenamevir 200 mg (n = 22) | Amenamevir 400 mg (n = 22) | Amenamevir 200 mg (n = 18) | Amenamevir 400 mg (n = 19) | |||
Age (years) | 30.0 ± 8.4 | 31.9 ± 7.9 | 36.3 ± 9.5 | 34.1 ± 10.9 | 30.3 ± 9.4 | 29.5 ± 8.5 |
Race | ||||||
White | 13 (59.1%) | 16 (72.7%) | 16 (72.7%) | 18 (81.8%) | 13 (72.2%) | 12 (63.2%) |
Black or African American | 6 (27.3%) | 3 (13.6%) | 6 (27.3%) | 3 (13.6%) | 4 (22.2%) | 3 (15.8%) |
Asian | 0 | 0 | 0 | 0 | 0 | 0 |
Other | 3 (13.6%) | 3 (13.6%) | 0 | 1 (4.5%) | 1 (5.6%) | 4 (21.1%) |
Weight (kg) | 78.2 ± 10.6 | 77.6 ± 8.9 | 74.2 ± 11.1 | 74.6 ± 9.1 | 74.0 ± 8.8 | 77.7 ± 9.3 |
Height (m) | 1.77 ± 0.05 | 1.76 ± 0.06 | 1.75 ± 0.05 | 1.75 ± 0.05 | 1.77 ± 0.05 | 1.79 ± 0.05 |
BMI (kg/m2) | 25.0 ± 2.5 | 25.1 ± 2.7 | 24.1 ± 3.2 | 24.3 ± 2.8 | 23.6 ± 2.6 | 24.3 ± 2.6 |
Pharmacokinetics
Effects of Ketoconazole on Amenamevir Pharmacokinetics
Parameter | Study | |||
---|---|---|---|---|
15L-CL-008 | 15L-CL-009 | |||
Amenamevir alone (n = 22) | Amenamevir + ketoconazole (n = 22) | Amenamevir alone (n = 22) | Amenamevir + rifampicin (n = 22) | |
AUCinf (ng h/mL)a
| 19,917 ± 5561 | 51,483 ± 12048 | 18,658 ± 4935 | 3115 ± 930 |
C
max (ng/mL)a
| 1448 ± 329 | 1886 ± 448 | 1325 ± 282 | 563 ± 218 |
t
max (h)b
| 4.0 (1.0–5.0) | 4.0 (3.0–6.0) | 3.0 (0.5–5.0) | 1.75 (1.0–5.0) |
t
½ (h) | 8.1 ± 1.9 | 17.5 ± 2.9 | 8.0 ± 1.2 | 2.9 ± 0.6 |
CL/F (L/h) | 20.8 ± 5.9 | 8.0 ± 2.1 | 22.1 ± 5.9 | 133.5 ± 40.0 |
LS GMRc
| Amenamevir + ketoconazole vs amenamevir alone | Amenamevir + rifampicin vs amenamevir alone | ||
AUCinf
| 2.58 (2.32–2.87) | 0.17 (0.15–0.19) | ||
C
max
| 1.30 (1.17–1.45) | 0.42 (0.37–0.49) |
Effects of Rifampicin on Amenamevir Pharmacokinetics
Effects of Amenamevir on Midazolam Pharmacokinetics
Parameter | Amenamevir 200 mg | Amenamevir 400 mg | ||
---|---|---|---|---|
Midazolam alone (n = 22) | Midazolam + amenamevir (n = 22) | Midazolam alone (n = 22) | Midazolam + amenamevir (n = 22) | |
AUCinf (ng h/mL)a
| 104.5 ± 64.7 | 74.8 ± 37.5 | 107.5 ± 55.8 | 57.3 ± 25.7 |
C
max (ng/mL)a
| 26.3 ± 13.7 | 25.9 ± 19.1 | 30.2 ± 22.7 | 19.0 ± 12.9 |
t
max (h)b
| 1.5 (0.5–3.0) | 1.0 (0.3–4.0) | 1.5 (0.3–3.0) | 1.0 (0.5–4.0) |
t
½ (h) | 5.7 ± 2.5 | 4.8 ± 1.9 | 5.3 ± 1.8 | 4.3 ± 1.4 |
CL/F (L/h) | 80.1 ± 37.0 | 109.0 ± 43.4 | 78.2 ± 39.2 | 143.8 ± 68.0 |
LS GMRc
| Midazolam + amenamevir 200 mg vs midazolam alone | Midazolam + amenamevir 400 mg vs midazolam alone | ||
AUCinf
| 0.72 (0.65–0.79) | 0.53 (0.47–0.61) | ||
C
max
| 0.98 (0.82–1.18) | 0.63 (0.50–0.80) |
Effects of Amenamevir on Warfarin Pharmacokinetics
Parameter | (S)-Warfarin | (R)-Warfarin | ||||||
---|---|---|---|---|---|---|---|---|
Warfarin alone (n = 18) | Warfarin + amenamevir 200 mg (n = 18) | Warfarin alone (n = 17) | Warfarin + amenamevir 400 mg (n = 15) | Warfarin alone (n = 18) | Warfarin + amenamevir 200 mg (n = 18) | Warfarin alone (n = 17) | Warfarin + amenamevir 400 mg (n = 15) | |
AUCinf (ng h/mL)a
| 48,072 ± 19,712 | 46,725 ± 18,437 | 50,329 ± 24,609 | 45,032 ± 23,503 | 69,581 ± 18,385 | 67,092 ± 18,315 | 75,652 ± 18,160 | 68,723 ± 12,736 |
C
max (ng/mL)a
| 1194 ± 132 | 1217 ± 134 | 1168 ± 162 | 1251 ± 237 | 1197 ± 133 | 1240 ± 134 | 1187 ± 149 | 1262 ± 232 |
t
max (h)b
| 4.0 (2.0–4.0) | 4.0 (1.0–4.0) | 4.0 (1.0–4.0) | 2.0 (1.0–4.0) | 4.0 (2.0–4.0) | 4.0 (1.0–12.0) | 4.0 (2.0–12.0) | 4.0 (2.0–12.0) |
t
½ (h) | 34.6 ± 8.6 | 35.0 ± 7.1 | 36.4 ± 12.2 | 36.4 ± 9.7 | 42.0 ± 7.0 | 39.7 ± 6.3 | 45.7 ± 8.5 | 40.8 ± 6.0 |
CL/F (L/h) | 0.25 ± 0.07 | 0.26 ± 0.07 | 0.25 ± 0.08 | 0.27 ± 0.08 | 0.17 ± 0.04 | 0.18 ± 0.04 | 0.16 ± 0.04 | 0.17 ± 0.03 |
LS GMRc
| (S)-Warfarin + amenamevir 200 mg vs (S)-warfarin alone | (S)-Warfarin + amenamevir 400 mg vs (S)-warfarin alone | (R)-Warfarin + amenamevir 200 mg vs (R)-warfarin alone | (R)-Warfarin + amenamevir 400 mg vs (R)-warfarin alone | ||||
AUCinf
| 0.97 (0.94–1.01) | 0.92 (0.89–0.96) | 0.96 (0.94–0.99) | 0.91 (0.88–0.95) | ||||
C
max
| 1.02 (0.98–1.06) | 1.08 (1.02–1.15) | 1.04 (1.01–1.07) | 1.07 (1.01–1.13) |
Pharmacodynamics
Effects of Amenamevir on Warfarin Pharmacodynamics
Parameter | Amenamevir 200 mg | Amenamevir 400 mg | ||
---|---|---|---|---|
Warfarin alone (n = 18) | Warfarin + amenamevir 200 mg (n = 18) | Warfarin alone (n = 17) | Warfarin + amenamevir 400 mg (n = 15) | |
AUCPT;0–168 h (s h)a
| 2480 ± 246 | 2411 ± 199 | 2556 ± 254 | 2425 ± 163 |
PTmax (s) | 17.2 ± 2.3 | 17.3 ± 2.5 | 17.9 ± 2.4 | 16.7 ± 1.9 |
tPTmax (h) | 36.0 ± 12.4 | 35.9 ± 12.3 | 39.5 ± 14.6 | 36.0 ± 13.6 |
LS mean ratiob
| Warfarin + amenamevir 200 mg vs warfarin alone | Warfarin + amenamevir 400 mg vs warfarin alone | ||
AUCPT;0–168 h
| 0.97 (0.94–1.00) | 0.96 (0.95–0.98) | ||
PTmax
| 1.00 (0.96–1.04) | 0.95 (0.93–0.97) |