In this phase I study, eflapegrastim (Rolontis®), a novel long‐acting granulocyte colony-stimulating factor developed to prevent chemotherapy-induced neutropenia, was evaluated in healthy Japanese and Caucasian subjects. |
A single subcutaneous administration of eflapegrastim 1.1–270 μg/kg was safe and well tolerated in Japanese and Caucasian subjects. |
The Japanese and Caucasian subjects showed similar pharmacokinetic and pharmacodynamic profiles of eflapegrastim 45–135 μg/kg, suggesting that different dosage regimens based on ethnicity may not be required. |
1 Introduction
2 Methods
2.1 Subjects and Study Design
2.2 Safety and Tolerability Assessments
2.3 Bioanalysis
2.4 Pharmacokinetic Assessment
2.5 Pharmacodynamic Assessment
2.6 Statistical Analysis
3 Results
3.1 Subjects
Treatment | Eflapegrastim, μg/kg | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Dose | 1.1 | 3.3 | 10 | 45 | 135 | 270 | ||||
Subjects | Caucasian | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | |
Subject demographics | ||||||||||
Male | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) | 3 (50) |
Ethnicity | ||||||||||
Hispanic or Latino | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Non-Hispanic or Latino | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) |
Age, years | 27.3 ± 4.0 | 31.2 ± 6.6 | 29.3 ± 6.2 | 29.0 ± 5.2 | 28.3 ± 4.1 | 32.5 ± 6.9 | 28.7 ± 4.9 | 31.2 ± 10.1 | 29.8 ± 8.4 | 28.7 ± 5.3 |
Height, cm | 173.8 ± 18.7 | 174.5 ± 9.6 | 167.2 ± 11.7 | 173.2 ± 7.4 | 164.5 ± 10.0 | 172.3 ± 11.7 | 166.8 ± 9.4 | 176.8 ± 5.8 | 165.3 ± 13.8 | 171.8 ± 11.5 |
Body weight, kg | 66.4 ± 27.2 | 68.8 ± 9.4 | 61.7 ± 14.7 | 72.7 ± 9.7 | 61.6 ± 6.7 | 71.4 ± 11.5 | 60.9 ± 15.8 | 77.7 ± 14.0 | 63.4 ± 8.8 | 75.8 ± 11.7 |
BMI, kg/m2 | 21.1 ± 3.3 | 22.5 ± 2.3 | 21.8 ± 2.9 | 24.2 ± 2.0 | 22.9 ± 3.1 | 23.9 ± 2.6 | 21.6 ± 3.9 | 24.9 ± 4.3 | 23.1 ± 1.0 | 25.6 ± 2.5 |
Laboratory tests | ||||||||||
Albumin, gm/dL | 4.2 ± 0.2 | 3.9 ± 0.3 | 4.2 ± 0.3 | 4.2 ± 0.4 | 4.2 ± 0.2 | 3.9 ± 0.4 | 4.3 ± 0.2 | 4.5 ± 0.4 | 4.1 ± 0.3 | 4.3 ± 0.4 |
ALP, IU/L | 68.3 ± 24.2 | 52.5 ± 19.9 | 58.0 ± 15.9 | 53.3 ± 21.1 | 55.2 ± 13.2 | 52.7 ± 17.3 | 52.7 ± 22.9 | 61.2 ± 11.4 | 56.2 ± 7.1 | 59.5 ± 24.7 |
ALT, g/dL | 26.2 ± 10.7 | 16.2 ± 2.6 | 17.3 ± 12.8 | 25.8 ± 23.2 | 16.7 ± 8.5 | 21.8 ± 11.4 | 19.3 ± 13.9 | 19.8 ± 8.8 | 14.8 ± 3.1 | 20.2 ± 11.0 |
AST, IU/L | 22.3 ± 4.3 | 22.5 ± 3.4 | 20.0 ± 4.6 | 28.80 ± 16.6 | 19.2 ± 4.1 | 20.7 ± 6.7 | 19.2 ± 6.9 | 19.2 ± 3.5 | 19.0 ± 4.1 | 19.0 ± 4.5 |
Total bilirubin, mg/dL | 0.7 ± 0.1 | 0.7 ± 0.3 | 0.8 ± 0.3 | 0.8 ± 0.1 | 1.0 ± 0.6 | 0.8 ± 0.4 | 0.7 ± 0.3 | 0.6 ± 0.2 | 0.9 ± 0.3 | 0.6 ± 0.2 |
BUN, mg/dL | 14.0 ± 4.3 | 10.3 ± 3.0 | 9.2 ± 2.5 | 8.5 ± 1.8 | 8.5 ± 1.9 | 10.0 ± 3.3 | 7.8 ± 2.2 | 11.7 ± 3.4 | 10.0 ± 2.5 | 10.7 ± 3.8 |
Total CK, units/L | 112.2 ± 147.8 | 100.7 ± 76.3 | 95.3 ± 43.2 | 375.7 ± 586.6 | 84.7 ± 35.0 | 103.7 ± 37.1 | 77.2 ± 23.3 | 77.8 ± 58.9 | 139.2 ± 92.8 | 83.8 ± 35.1 |
Creatinine, mg/dL | 0.9 ± 0.2 | 0.8 ± 0.1 | 0.8 ± 0.1 | 0.9 ± 0.1 | 0.7 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.3 | 0.9 ± 0.1 | 0.6 ± 0.2 | 0.7 ± 0.2 |
Glucose, mg/dL | 84.0 ± 6.0 | 82.5 ± 5.3 | 91.5 ± 2.8 | 83.2 ± 6.6 | 88.2 ± 5.6 | 79.2 ± 4.1 | 103.5 ± 29.6 | 84.5 ± 4.8 | 85.7 ± 9.2 | 87.7 ± 7.3 |
Potassium, mmol/L | 4.2 ± 0.3 | 4.0 ± 0.3 | 4.0 ± 0.1 | 4.1 ± 0.3 | 4.2 ± 0.5 | 4.0 ± 0.3 | 4.1 ± 0.5 | 4.4 ± 0.2 | 4.1 ± 0.3 | 4.0 ± 0.4 |
Sodium, mmol/L | 138.5 ± 1.4 | 137.8 ± 1.7 | 139.5 ± 1.0 | 137.0 ± 0.9 | 137.7 ± 1.5 | 137.7 ± 1.5 | 139.0 ± 0.9 | 140.2 ± 1.6 | 138.8 ± 1.5 | 138.7 ± 1.2 |
Uric acid, mg/dL | 5.1 ± 1.6 | 4.3 ± 1.0 | 4.8 ± 1.9 | 4.4 ± 1.2 | 5.7 ± 1.2 | 5.1 ± 0.9 | 4.8 ± 1.0 | 5.3 ± 1.6 | 5.3 ± 1.0 | 5.1 ± 1.3 |
Treatment | Pegfilgrastim, mg | Placebo | Total | |||
---|---|---|---|---|---|---|
Dose | 6 | |||||
Subjects | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 4] | [n = 8] | [n = 4] | [n = 8] | [n = 32] | [n = 52] | |
Subject demographics | ||||||
Male | 4 (50) | 4 (50) | 2 (50) | 4 (50) | 16 (50) | 26 (50) |
Ethnicity | ||||||
Hispanic or Latino | 0 (0) | 1 (12.5) | 0 (0) | 0 (0) | 0 (0) | 1 (1.92) |
Non-Hispanic or Latino | 4 (100) | 7 (87.5) | 4 (100) | 8 (100) | 32 (100) | 51 (98.08) |
Age, years | 29.5 ± 4.2 | 31.1 ± 7.7 | 30.8 ± 2.9 | 27.4 ± 5.8 | 29.3 ± 5.2 | 29.8 ± 6.5 |
Height, cm | 167.5 ± 9.9 | 172.8 ± 8.2 | 166.0 ± 9.6 | 169.2 ± 8.5 | 166.2 ± 10.2* | 172.9 ± 10.1* |
Body weight, kg | 62.0 ± 11.7 | 76.1 ± 12.4 | 56.1 ± 10.9 | 71.2 ± 14.0 | 61.2 ± 11.1* | 72.6 ± 14.0* |
BMI, kg/m2 | 21.9 ± 2.5 | 25.4 ± 2.5 | 20.2 ± 1.6 | 24.6 ± 3.4 | 22.0 ± 2.7* | 24.1 ± 3.1* |
Laboratory tests | ||||||
Albumin, gm/dL | 4.3 ± 0.2 | 4.2 ± 0.4 | 4.5 ± 0.2 | 4.2 ± 0.3 | 4.2 ± 0.3 | 4.2 ± 0.4 |
ALP, IU/L | 61.0 ± 8.9 | 56.5 ± 13.0 | 49.0 ± 8.0 | 60.2 ± 16.1 | 55.4 ± 13.7 | 58.1 ± 18.0 |
ALT, g/dL | 16.8 ± 6.6 | 21.6 ± 6.3 | 12.5 ± 1.3 | 20.2 ± 9.0 | 16.4 ± 8.9 | 21.4 ± 11.1 |
AST, IU/L | 20.0 ± 2.6 | 23.1 ± 4.3 | 18.0 ± 1.6 | 22.5 ± 6.5 | 19.2 ± 4.2 | 22.3 ± 7.3 |
Total bilirubin, mg/dL | 1.3 ± 0.5 | 0.7 ± 0.1 | 0.8 ± 0.2 | 0.7 ± 0.2 | 0.9 ± 0.4 | 0.7 ± 0.2 |
BUN, mg/dL | 8.0 ± 2.3 | 11.0 ± 3.4 | 10.2 ± 2.2 | 11.9 ± 3.4 | 8.9 ± 2.3 | 11.0 ± 3.5 |
Total CK, units/L | 89.5 ± 24.2 | 98.0 ± 50.2 | 100.2 ± 79.6 | 130.2 ± 75.1 | 98.0 ± 55.7 | 133.6 ± 214.9 |
Creatinine, mg/dL | 0.8 ± 0.0 | 0.8 ± 0.2 | 0.7 ± 0.1 | 0.9 ± 0.2 | 0.7 ± 0.2 | 0.8 ± 0.2 |
Glucose, mg/dL | 87.2 ± 5.7 | 86.9 ± 9.8 | 88.0 ± 2.2 | 83.0 ± 6.4 | 91.1 ± 14.3 | 83.9 ± 6.7 |
Potassium, mmol/L | 4.0 ± 0.3 | 4.0 ± 0.3 | 4.4 ± 0.3 | 4.1 ± 0.2 | 4.1 ± 0.4 | 4.1 ± 0.3 |
Sodium, mmol/L | 138.5 ± 1.3 | 138.6 ± 1.8 | 138.2 ± 2.1 | 138.5 ± 1.3 | 138.7 ± 1.4 | 138.4 ± 1.6 |
Uric acid, mg/dL | 6.0 ± 0.8 | 4.6 ± 1.5 | 4.8 ± 0.7 | 5.4 ± 1.4 | 5.2 ± 1.2 | 4.9 ± 1.3 |
3.2 Safety, Tolerability, and Immunogenicity
Treatment | Eflapegrastim, μg/kg | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Dose | 1.1 | 3.3 | 10 | 45 | 135 | 270 | ||||
Subjects | Caucasian | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | |
All TEAEs | 2 (33.3) | 2 (33.3) | 1 (16.7) | 4 (66.7) | 2 (33.3) | 5 (83.3) | 4 (66.7) | 6 (100.0) | 6 (100.0) | 6 (100.0) |
Drug‐related TEAEs | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 2 (33.3) | 4 (66.7) | 4 (66.7) | 6 (100.0) | 6 (100.0) | 6 (100.0) |
TEAEs related to study medication* | ||||||||||
Musculoskeletal and connective tissue disorders | ||||||||||
Bone pain | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (33.3) | 1 (16.7) | 1 (16.7) | 1 (16.7) | 3 (50.0) | 5 (83.3) |
Back pain | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 3 (50.0) | 3 (50.0) | 1 (16.7) |
Arthralgia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 3 (50.0) | 0 (0.0) | 0 (0.0) |
Myalgia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) | 0 (0.0) |
Pain in extremity | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 1 (16.7) | 0 (0.0) | 0 (0.0) |
Musculoskeletal chest pain | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) |
Nervous system disorders | ||||||||||
Headache | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 2 (33.3) | 3 (50.0) | 1 (16.7) | 2 (33.3) | 3 (50.0) | 1 (16.7) |
Dizziness | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Gastrointestinal disorders | ||||||||||
Nausea | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 0 (0.0) |
Diarrhea | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Vomiting | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
General disorders and administration site conditions | ||||||||||
Chest pain | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) |
Injection site pain | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 0 (0.0) |
Chest discomfort | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Fatigue | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) |
Cardiac disorders | ||||||||||
Tachycardia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) |
Palpitations | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) |
Skin and subcutaneous tissue disorders | ||||||||||
Ecchymosis | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Ear and labyrinth disorders | ||||||||||
Tinnitus | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) | 0 (0.0) |
Reproductive system and breast disorders | ||||||||||
Testicular disorder | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (16.7) |
Vascular disorders | ||||||||||
Hot flush | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Treatment | Eflapegrastim, μg/kg | Pegfilgrastim, mg | Placebo | |||
---|---|---|---|---|---|---|
Dose | Total | 6 | ||||
Subjects | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 24] | [n = 36] | [n = 4] | [n = 8] | [n = 4] | [n = 8] | |
All TEAEs | 13 (54.2) | 25 (69.4) | 4 (100.0) | 7 (87.5) | 4 (100.0) | 3 (37.5) |
Drug‐related TEAEs | 13 (54.2) | 17 (47.2) | 4 (100.0) | 7 (87.5) | 2 (50.0) | 1 (12.5) |
TEAEs related to study medication* | ||||||
Musculoskeletal and connective tissue disorders | ||||||
Bone pain | 6 (25.0) | 7 (19.4) | 1 (25.0) | 3 (37.5) | 0 (0.0) | 0 (0.0) |
Back pain | 4 (16.7) | 4 (11.1) | 3 (75.0) | 1 (12.5) | 0 (0.0) | 1 (12.5) |
Arthralgia | 1 (4.2) | 5 (13.9) | 0 (0.0) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
Myalgia | 0 (0.0) | 2 (5.6) | 0 (0.0) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
Pain in extremity | 1 (4.2) | 2 (5.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Musculoskeletal chest pain | 1 (4.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Nervous system disorders | ||||||
Headache | 6 (25.0) | 7 (19.4) | 0 (0.0) | 4 (50.0) | 1 (25.0) | 0 (0.0) |
Dizziness | 0 (0.0) | 1 (2.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Gastrointestinal disorders | ||||||
Nausea | 2 (8.3) | 2 (5.6) | 0 (0.0) | 2 (25.0) | 1 (25.0) | 0 (0.0) |
Diarrhea | 1 (4.2) | 0 (0.0) | 0 (0.0) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
Vomiting | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) | 1 (25.0) | 0 (0.0) |
General disorders and administration site conditions | ||||||
Chest pain | 1 (4.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Injection site pain | 1 (4.2) | 1 (2.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Chest discomfort | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
Fatigue | 0 (0.0) | 1 (2.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Cardiac disorders | ||||||
Tachycardia | 1 (4.2) | 1 (2.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Palpitations | 1 (4.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Skin and subcutaneous tissue disorders | ||||||
Ecchymosis | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (25.0) | 0 (0.0) |
Ear and labyrinth disorders | ||||||
Tinnitus | 1 (4.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Reproductive system and breast disorders | ||||||
Testicular disorder | 0 (0.0) | 1 (2.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Vascular disorders | ||||||
Hot flush | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
3.3 Pharmacokinetics
Treatment | Eflapegrastim, μg/kg | Pegfilgrastim, mg | ||||||
---|---|---|---|---|---|---|---|---|
Dose | 45 | 135 | 270 | 6 | ||||
Subjects | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 4] | [n = 8] | |
Cmax (μg/L) | 23.4 ± 30.0a | 55.7 ± 33.8a | 181.4 ± 139.6 | 152.5 ± 47.8 | 763.0 ± 429.9 | 989.8 ± 280.6 | 137.5 ± 65.5 | 84.2 ± 70.6 |
Tmax (h) | 6.0 [4.0–8.0]a | 6.0 [4.0–12.0]a | 8.0 [4.0–16.0] | 12.0 [12.0–24.0] | 26.0 [12.0–48.0] | 30.0 [6.0–36.0] | 30.0 [16.0–36.0] | 30.0 [12.0–48.0] |
AUClast (μg∙h/L) | 266.8 ± 350.2a | 873.4 ± 954.8a | 3415.5 ± 2452.2 | 3318.3 ± 924.0 | 25,822.5 ± 16,785.5 | 36,275.7 ± 18908.6 | 6185.8 ± 1953.8 | 4282.3 ± 3172.0 |
AUC48 (μg∙h/L) | 893.9c | 1196.2 ± 885.9b | 3930.0 ± 1642.7a | 3502.7 ± 881.5a | 21,168.8 ± 13,567.5 | 31,466.2 ± 15455.0 | 4315.5 ± 1960.7 | 2873.2 ± 2681.5 |
AUC∞ (μg∙h/L) | 895.8c | 1227.7 ± 939.3b | 4429.1 ± 2236.3a | 3831.3 ± 527.5a | 27,128.6 ± 18,411.1a | 39,974.6 ± 20378.7a | 6643.5 ± 2014.4 | 4527.6 ± 3221.9 |
t½ (h) | 5.25c | 6.7 ± 1.6b | 20.4 ± 22.3a | 12.9 ± 8.7a | 19.1 ± 14.6a | 16.6 ± 11.0a | 33.6 ± 7.9 | 27.1 ± 9.2 |
CL (L/h/kg) | 0.050c | 0.050 ± 0.024b | 0.037 ± 0.018a | 0.036 ± 0.005a | 0.023 ± 0.031a | 0.012 ± 0.015a | 0.014 ± 0.006d | 0.028 ± 0.020d |
3.4 Pharmacodynamics
Treatment | Eflapegrastim, μg/kg | Pegfilgrastim, mg | Placebo | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Dose | 1.1 | 3.3 | 10 | 45 | 135 | 270 | 6 | |||||||
Subjects | Caucasian | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian | Japanese | Caucasian |
[n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 6] | [n = 4] | [n = 8] | [n = 4] | [n = 8] | |
ANC | ||||||||||||||
AUEClast observed (K·h/µL) | 1808.7 ± 462.3 | 2455.1 ± 576.2 | 2927.3 ± 390.2 | 3885.6 ± 2149.8 | 4569.3 ± 1079.0 | 4174.1 ± 771.3 | 6920.5 ± 2098.8 | 6547.9 ± 873.3 | 9178.7 ± 1835.6 | 10112.3 ± 2656.8 | 7014.7 ± 2532.9 | 6539.2 ± 1344.0 | 1483.0 ± 436.4 | 1901.6 ± 928.1 |
AUEClast change (K·h/µL) | NA | 710.2 ± 489.5 | 1291.8 ± 340.7 | 1481.0 ± 585.4 | 2589.1 ± 652.3 | 2742.8 ± 542.3 | 4992.2 ± 1339.1 | 4729.5 ± 582.9 | 7220.1 ± 1405.3 | 8088.4 ± 2344.4 | 5526.6 ± 2029.6 | 4170.5 ± 923.2a | 49.3 ± 148.0 | 72.3 ± 91.7b |
ANCmax (K/µL) | 5.0 ± 1.43 | 8.73 ± 1.44 | 14.4 ± 4.3 | 13.8 ± 3.4 | 21.3 ± 2.8 | 22.2 ± 3.5 | 33.1 ± 4.0 | 27.6 ± 4.1 | 37.2 ± 7.6 | 49.5 ± 11.4 | 44.2 ± 3.2 | 34.3 ± 8.6 | 5.6 ± 1.8 | 5.5 ± 2.4 |
Tmax_ANC (h) | 61.8 [24.0–506.9] | 12.0 [8.0–243.5] | 12.0 [8.0–16.0] | 12.0 [8.0–36.0] | 20.0 [12.0–36.0] | 36.0 [16.0–36.0] | 48.0 [24.0–150.5] | 42.1 [24.0–73.7] | 74.2 [72.5–146.0] | 74.0 [73.5–75.5] | 73.5 [48.2–99.1] | 48.0 [36.0–73.7] | 48.8 [12.0–122.5] | 7.0 [0.0–507.9] |
CD34+ | ||||||||||||||
AUEClast (cells·h/µL) | 2679.4 ± 1016.2 | 1941.7 ± 754.9 | 2653.7 ± 1774.7 | 1875.5 ± 563.1 | 2054.9 ± 396.5 | 3392.7 ± 1600.6 | 4127.8 ± 2279.6 | 3894.1 ± 1205.2 | 7964.0 ± 1515.7 | 11109.0 ± 2808.7 | 3465.9 ± 2072.8 | 8304.0 ± 6536.3 | 958.5 ± 154.3 | 2720.4 ± 1085.7 |
CD34+max (cells/µL) | 15.8 ± 14.5 | 8.5 ± 6.2 | 9.3 ± 6.4 | 7.6 ± 3.6 | 9.1 ± 3.9 | 17.6 ± 8.8 | 31.2 ± 17.1 | 30.5 ± 9.2 | 65.7 ± 12.5 | 90.1 ± 17.4 | 33.8 ± 17.2 | 74.3 ± 57.5 | 3.7 ± 1.6 | 12.3 ± 9.7 |
Tmax_CD34+ (h) | 84.6 [0.0–506.4] | 48.0 [24.0–338.6] | 48.0 [0.0–241.4] | 73.6 [24.0–122.0] | 97.2 [73.0–338.2] | 98.1 [48.0–146.5] | 74.7 [71.9–122.1] | 97.7 [96.8–121.2] | 97.6 [97.0–101.4] | 97.4 [74.0–99.3] | 98.2 [75.8–121.6] | 97.8 [73.7–124.0] | 108.6 [0.0–338.2] | 48.0 [0.0–504.3] |