Why carry out this study?
|
Amenamevir (ASP2151), a herpesvirus helicase-primase inhibitor currently used for the treatment of herpes zoster in Japan, is mainly metabolized in the liver and urinary excretion of amenamevir was approximately 10% of the total dose in healthy adults. |
The increase of systemic exposure in non-dialysis patients with severe renal impairment was much less than that associated with nucleoside antiviral agents. |
The aim of this study was to evaluate the pharmacokinetics and dialyzability of a single oral dose (400 mg) of amenamevir in hemodialysis patients. |
What was learned from the study?
|
The area under the plasma concentration–time curve (AUC) in hemodialysis patients was approximately double that in healthy adults, but the increase was much less than that reported in nucleoside antiviral agents. |
The amount of amenamevir removed by hemodialysis was minimal. |
There were no clinically relevant safety concerns when 400 mg of amenamevir was administered as a single dose to hemodialysis patients without dose adjustment and/or modification of the dosing schedule. |
Introduction
Methods
Study Design
Patients and Treatment
Study Assessments
Statistical Analyses
Results
Patient Characteristics
Subject | Sex | Age (years) | Dry weight (kg) | Duration of dialysis (months) | Creatinine clearance (mL/min) | Albumin (g/dL) |
---|---|---|---|---|---|---|
1 | Male | 69 | 56.3 | 13.3 | 5.3 | 3.40 |
2 | Female | 57 | 76.4 | 41.9 | 9.2 | 3.90 |
3 | Male | 61 | 71.9 | 61.3 | 7.1 | 3.90 |
4 | Male | 73 | 47.4 | 147.6 | 4.6 | 3.60 |
5 | Male | 77 | 64.5 | 141.6 | 6.1 | 3.20 |
6 | Male | 50 | 79.7 | 140.5 | 6.0 | 3.87 |
7 | Male | 63 | 50.7 | 93.1 | 3.7 | 3.80 |
8 | Male | 72 | 58.2 | 10.2 | 5.9 | 3.70 |
9 | Male | 65 | 61.6 | 45.1 | 5.6 | 3.70 |
Mean (SD) | – | 65.0 (9.0) | 63.0 (11.2) | 77.2 (55.3) | 5.9 (1.6) | 3.7 (0.2) |
Subject | Time from dosing to start of HD (h) | Duration of HD session (h) | Blood flow rate (mL/min) | Ultrafiltration rate (L/h) | Dialyzer membrane | Dialyzer surface area (m2) | Kt/V |
---|---|---|---|---|---|---|---|
1 | 24–28 | 3.9 | 250 | 0.66 | Polysulfone | 2.6 | 1.56 |
2 | 24–28 | 4.2 | 220 | 0.42–0.63 | Polysulfone | 1.5 | 1.53 |
3 | 24–28 | 4.0 | 190–220 | 0.55 | Polysulfone | 2.1 | 1.16 |
4 | 24–28 | 4.0 | 200 | 0.33 | Polysulfone | 1.5 | 1.65 |
5 | 24–28 | 4.0 | 200 | 0.45 | Polysulfone | 1.8 | 1.42 |
6 | 24–28 | 4.0 | 230 | 0.5 | Polysulfone | 2.5 | 1.29 |
7 | 24–28 | 4.0 | 200 | 0.3–0.5 | Polysulfone | 1.1 | 1.50 |
8 | 24–28 | 4.2 | 150 | 0.43 | Polysulfone | 1.5 | 1.04 |
9 | 24–28 | 4.0 | 200 | 0.58 | Polysulfone | 1.3 | 1.52 |
Mean (SD) | – | 4.0 (0.1) | 206.9 (27.4) | 0.50 (0.10) | – | 1.8 (0.5) | 1.41 (0.20) |
Pharmacokinetics
Amenamevir | R5 | |||||
---|---|---|---|---|---|---|
n | Mean (SD) | Median (Min–Max) | n | Mean (SD) | Median (Min–Max) | |
Cmax (ng/mL) | 9 | 1585 (442) | 1658 (888–2407) | 9 | 337.6 (104.7) | 347.0 (215.8–486.9) |
tmax (h) | 9 | 6.2 (2.5) | 6 (4–12) | 9 | 12.9 (4.4) | 12 (8–24) |
AUC24h (ng h/mL) | 9 | 23,890 (8400) | 22,310 (12,370–40,280) | 9 | 6054 (2125) | 5830 (3855–9765) |
AUCinf (ng h/mL) | 7 | 38,120 (17,180) | 34,100 (16,210–65,970) | 0 | − | − |
t1/2pre (h) | 7 | 13.9 (2.6) | 14.7 (9.9–17.0) | 0 | − | − |
t1/2HD (h) | 9 | 32.7 (47.7) | 15.2 (7.5–158.3) | 9 | 15.2 (13.5) | 11.9 (7.0–49.8) |
t1/2post (h) | 9 | 12.0 (2.5) | 12.4 (8.4–15.7) | 9 | 14.0 (2.8) | 15.0 (9.3–17.2) |
AUCD (ng h/mL) | 9 | 2301 (926) | 2041 (808.7–3626) | 9 | 903.8 (392.6) | 1025 (370.9–1561) |
AUCA24–28h (ng h/mL) | 9 | 2145 (905) | 2004 (724.8–3555) | 9 | 882.2 (401.6) | 1021 (351.2–1571) |
AUCV24–28h (ng h/mL) | 9 | 1509 (672) | 1252 (435.7–2451) | 9 | 565.7 (262.4) | 672.9 (193.5–964.2) |
Ae24h (mg) | 5 | 1.6 (0.8) | 1.8 (0.7–2.7) | 5 | 0.9 (0.9) | 0.8 (0.2–2.4) |
Ae24–48h (mg) | 5 | 0.4 (0.3) | 0.2 (0.1–0.8) | 5 | 0.4 (0.3) | 0.5 (0.1–0.8) |
fb4h (%) | 8 | 64.2 (3.3) | 63.6 (61.3–72.0) | − | − | − |
fb24h (%) | 9 | 62.7 (4.0) | 62.2 (58.5–72.5) | − | − | − |
Amenamevir | R5 | |||||
---|---|---|---|---|---|---|
Mean (SD) | Median | Min–Max | Mean (SD) | Median | Min–Max | |
Hemodialysis clearance (mL/min) | 37.8 (5.3) | 37.5 | 30.9–48.0 | 46.5 (4.4) | 45.0 | 41.4–56.2 |
Hemodialysis clearance normalized with dialyzer surface area (mL/min/m2) | 22.7 (5.4) | 22.8 | 15.1–32.3 | 28.2 (7.4) | 27.6 | 18.2–40.8 |
Elimination fraction percentage (%) | 28.1 (5.1) | 27.4 | 22.2–36.6 | 34.5 (4.7) | 32.5 | 29.6–42.9 |
Removed amount (μg) | 132.0 (54.2) | 131.6 | 43.4–236.8 | 65.1 (28.7) | 69.6 | 23.7–121.4 |