Pharmacokinetic analysis of plasma ampreloxetine exposure indicated that the terminal half-life was 30–40 h, reached steady state after 6 days, and accumulated three- to four-fold with once-daily dosing. |
Population pharmacokinetic modeling identified sex and smoking status as statistically significant covariates indicating that cytochrome P450 1A2-based metabolism is the key mechanism for ampreloxetine elimination. |
Based on the pharmacokinetic/pharmacodynamic relationship, a once-daily ampreloxetine dose of 10 mg is predicted to achieve sustained norepinephrine transporter engagement during the entire dosing interval. |
1 Introduction
2 Materials and Methods
2.1 Ethical Conduct of the Study
2.2 Study Designs
2.2.1 Single-Ascending Dose
2.2.2 Multiple-Ascending Dose
2.2.3 Attention-Deficit/Hyperactivity Disorder Study
2.2.4 Fibromyalgia Study
2.3 Pharmacokinetic Analyses
2.3.1 Bioanalysis of Pharmacokinetic Samples
2.3.2 Non-Compartmental Analysis
2.3.3 Population Pharmacokinetic Analysis
2.3.4 Population Pharmacokinetic-Pharmacodynamic Simulation
3 Results
3.1 Ampreloxetine Pharmacokinetic Profile in Healthy Volunteers
Dose level (mg) | Cmax (ng/mL) | Tmaxa (h) | Tlaga (h) | AUC0–24 (ng*h/mL) | AUC0–t (ng*h/mL) | t1/2 (h) | CL/F (L/h) | VZ/F (L) | |
---|---|---|---|---|---|---|---|---|---|
2 | Mean | 0.925 | 12 | 1 | 15.8 | 36.3 | 29.5 | 56.4 | 2397 |
SD | 0.335 | 8.00, 12.0 | 0.5, 1.5 | 5.6 | 11.1 | 4.6 | 22.3 | 916 | |
n | 6 | 6 | 6 | 6 | 6 | 3 | 3 | 3 | |
4 | Mean | 2.09 | 8 | 1 | 32.8 | 87.6 | 36.0 | 38.7 | 1983 |
SD | 0.34 | 8.00, 10.0 | 0.5, 1.0 | 4.3 | 11.4 | 6.4 | 6.4 | 353 | |
n | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | |
8 | Mean | 5.02 | 12 | 0.50 | 85.6 | 231 | 34.5 | 38.2 | 1659 |
SD | 1.4 | 8.05, 14.0 | 0, 1.0 | 22.5 | 98 | 12.8 | 17.4 | 386 | |
n | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | |
20 | Mean | 8.59 | 12 | 0.5 | 142 | 445 | 41.0 | 52.2 | 2745 |
SD | 2.45 | 8.00, 14.0 | 0, 2.0 | 43 | 195 | 12.2 | 33.8 | 1034 | |
n | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | |
50 | Mean | 26.4 | 12 | 0.5 | 461 | 1430 | 40.9 | 39.9 | 2337 |
SD | 5.7 | 8.00, 14.0 | 0, 1.0 | 105 | 530 | 8.8 | 15 | 1046 | |
n | 6 | 6 | 6 | 6 | 6 | 5 | 5 | 5 |
Dose level (mg) | Cmax (ng/mL) | Tmaxb (h) | AUC0–4 (ng*h/mL) | t1/2 (h) | CL/F (L/h) | VZ/F (L) | AR | Ctrough (ng/mL) | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Day 4 | Day 6 | Day 8 | Day 10 | Day 12 | |||||||||
4 | Mean | 7.88 | 8 | 150 | 43.1 | 29.9 | 1833 | 4.98 | 3.4 | 4.03 | 4.16 | 4.67 | 4.47 |
SD | 2.39 | 8.00, 8.00 | 47 | 4.1 | 13.2 | 737 | 0.84 | 1.09 | 1.46 | 1.39 | 1.61 | 1.47 | |
n | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 6 | 6 | 5 | 5 | 5 | |
10 | Mean | 18.2 | 6.01 | 336 | 37.7 | 36.4 | 1880 | 3.18 | 8.36 | 12.3 | 13.1 | 12.1 | 11.5 |
SD | 8.7 | 6.00, 8.00 | 156 | 6.2 | 17.7 | 726 | 0.45 | 3.56 | 6.8 | 6.4 | 5.7 | 5.6 | |
n | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | |
20 | Mean | 30.5 | 8 | 600 | 37.6 | 35.7 | 2068 | 3.74 | 14.6 | 18.5 | 20.2 | 21.9 | 20.8 |
SD | 9.6 | 5.50, 12.0 | 169 | 3.3 | 10.1 | 614 | 0.78 | 4.9 | 7.1 | 6.6 | 5.4 | 5 | |
n | 6 | 6 | 6 | 5 | 6 | 5 | 6 | 6 | 6 | 6 | 6 | 6 | |
20 | Mean | 52.5 | 7.03 | 1019 | 37.1 | 23.7 | 1528 | 4.38 | 21.9 | 28.5 | 29.2 | 29.5 | 30.8 |
(older)c | SD | 22.8 | 6.00, 8.00 | 469 | 4.4 | 11.4 | 532 | 1.41 | 7.2 | 10.1 | 12.2 | 15.3 | 15.5 |
n | 6 | 6 | 6 | 4 | 6 | 4 | 6 | 6 | 6 | 6 | 6 | 6 | |
40 | Mean | 74.5 | 8 | 1346 | 34.3 | 34.7 | 1611 | NA | 36.9 | 49.9 | 44.1 | 46.3 | 45 |
SD | 36.2 | 6.00, 10.0 | 570 | 7.3 | 15 | 496 | NA | 12 | 19.7 | 18.9 | 21.3 | 15.3 | |
n | 6 | 6 | 6 | 6 | 6 | 6 | NA | 6 | 6 | 6 | 6 | 6 |
3.2 Ampreloxetine Pharmacokinetics in Subjects with Attention-Deficit/Hyperactivity Disorder and Fibromyalgia
Treatment arm | Dose level (mg) | PK collection dayc | ||||
---|---|---|---|---|---|---|
8 | 15 | 29 | 43 | |||
Ampreloxetine 5 mg | 5 | Mean | 4.53 | 5.11 | 4.85 | 4.91 |
SD | 2.18 | 2.86 | 3.43 | 3.91 | ||
%CV | 48 | 56 | 71 | 80 | ||
Min | 1.33 | 0.190 | 0 | 0 | ||
Max | 10.2 | 13.5 | 17.4 | 17.5 | ||
n | 93 | 91 | 85 | 81 | ||
Ampreloxetine 20 mg | 10a | Mean | 13.4 | 13.2 | 12.0 | 12.4 |
SD | 6.50 | 6.20 | 7.76 | 10.0 | ||
%CV | 48 | 47 | 65 | 81 | ||
Min | 4.72 | 4.74 | 1.27 | 3.55 | ||
Max | 27.5 | 24.1 | 27.9 | 41.0 | ||
n | 14 | 13 | 13 | 13 | ||
20b | Mean | 9.29 | 20.1 | 20.3 | 18.2 | |
SD | 4.50 | 11.2 | 13.4 | 14.9 | ||
%CV | 48 | 56 | 66 | 82 | ||
Min | 1.37 | 0.208 | 0 | 0 | ||
Max | 21.1 | 56.4 | 63.4 | 81.2 | ||
n | 79 | 75 | 66 | 66 |
Treatment arm | PK collection day | |||
---|---|---|---|---|
8 | 15 | 29 | 43 | |
Ampreloxetine 5 mg | ||||
Mean | 2.42 | 6.32 | 5.54 | 5.31 |
SD | 1.43 | 3.39 | 3.67 | 3.63 |
%CV | 59 | 54 | 66 | 68 |
Min | 0 | 0 | 0 | 0 |
Median | 2.45 | 5.99 | 5.07 | 5.15 |
Max | 7.10 | 15.4 | 15.2 | 13.7 |
n | 112 | 107 | 100 | 98 |
Ampreloxetine 20 mg | ||||
Mean | 9.93 | 28.0 | 23.4 | 21.0 |
SD | 6.06 | 16.1 | 16.1 | 15.5 |
%CV | 61 | 58 | 69 | 74 |
Min | 0 | 0 | 0 | 0 |
Median | 9.33 | 26.6 | 22.6 | 18.0 |
Max | 24.8 | 79.0 | 87.2 | 76.3 |
n | 113 | 107 | 93 | 90 |
3.3 Population Pharmacokinetic Analysis
Description | Population estimate (%RSE) | Inter-subject variability %CV (%RSE) |
---|---|---|
Dose lag (h) | 1.74 (1.52) | – |
CL/F (L/h) | 47.2 (3.72) | 50.4 (10.9) |
V1/F (L) | 2040 (6.25) | 38.4 (31.9) |
Q/F (L/h) | 15.4 (20.1) | – |
V2/F (L) | 357 (16.6) | – |
Ka (L/h) | 0.2 (7.17) | 34.1 (48.1) |
Sex effect on CL [if female] (L/h) | − 16.9 (11.6) | – |
Smoking effect on CL (L/h) | 16.0 (16.1) | – |
Sex effect on V1 [if female] (L) | − 720.0 (18.1) | – |
Proportional residual error (%) | 24.7 (8.7) | |
Additive residual error (ng/mL) | 0.199 (24.0) |