JKSCPT Journal of Korean Society for Clinical Pharmacology and Therapeutics J Korean Soc Clin Pharmacol Ther 1225-5467 Korean Society for Clinical Pharmacology and Therapeutics 10.12793/jkscpt.2013.21.1.52 jkscpt-21-52 Original Article A Randomized, Placebo Controlled, Double Blind, Parallel Group, Multiple Dosing, Dose Escalation Clinical Study to Evaluate Pharmacokinetics/Pharmacodynamics and Tolerability of Zofenopril in Healthy Korean Subjects OhJaeseong LeeSeungHwan LimKyoung Soo ChungJae-Yong ShinSang-Goo JangIn-Jin YuKyung-Sang Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea E-mail: ksyu@snu.ac.kr 01 2013 11 01 2013 211 52 62 19062013 26062013 27062013 Copyright © 2013 Korean Society for Clinical Pharmacology and Therapeutics 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background:

Zofenopril is a new Angiotensin Converting Enzyme (ACE) inhibitor for the treatment of the patients with hypertension and congestive heart failure. This study aimed to evaluate the pharmacokinetics (PKs)/pharmacodynamics (PDs) and tolerability of zofenopril in healthy Korean subjects.

 Methods:

A randomized, double blind, placebo-controlled, multiple dosing parallel group study with two dosage groups (zofenopril 30 mg or 60 mg) was conducted in healthy Korean male subjects. Each dosage group consisted of 10 subjects and they were randomly assigned to receive zofenopril or placebo with a ratio of 4:1. PK characteristics of zofenopril and its active metabolite, zofenoprilat, were evaluated after single or multiple dosing. Serum ACE activities and blood pressures were measured for PD evaluation. Adverse events, clinical laboratory tests, electrocardiograms, vital signs and physical examinations were performed for tolerability evaluation.

 Results:

The PK characteristics of zofenopril and zofenoprilat after single dose and multiple doses were similar to one another. The metabolic ratio of zofenoprilat to zofenopril after single dose and multiple doses were 12.4 and 14.9, respectively, in the 30 mg dosage group, and were 6.8 and 6.6, respectively, in the 60 mg dosage group. Complete serum ACE activity inhibition was observed within 1 hour in both doses but it was maintained longer in the 60 mg dosage group compared to the 30 mg dosage group. There were no clinically significant abnormalities in tolerability evaluations.

 Conclusion:

The PK/PD characteristics of zofenopril and zofenoprilat after single or multiple administrations were explored. Zofenopril was well tolerated after multiple administrations in healthy Korean subjects.

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Plasma concentration-time curves of zofenopril and zofenoprilat after a single or multiple oral administration of zofenopril 30 mg or 60 mg (Semi-log scale).

Dose normalized Cmax and AUClast of zofenopril after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

Metabolic Ratio of zofenopril after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

Inhibition of ACE activity after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

Cmax and AUClast of zofenoprilat vs ACE activity 100 % inhibition time after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

Mean blood pressures vs time curve after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

Pharmacokinetic parameters of zofenopril and zofenoprilat after a single or multiple oral administration of zofenopril 30 mg or 60 mg

Zofenopril
Dose (mg) Day Tmax (h) Cmax (µg/L) t1/2 (h) AUClast (µg×h/L) Vd/F (L) CL/F (L/h) Accumulation index
30 1 175 (1.50~4.00) 27.2±29.9 (110 0) 0.67±0.22 (32 66) 58.8±53.4 (90.8) 862.8±771.9 (89.47) 837.6±575.6 (68.72) -
7 1.11 (0.82~4.02) 29.2±12.5 (42.9) 0.84±0.41 (48.38) 67.0±47.7 (71.2) 633.8±286.7 (45.24) 585.3±281.3 (48.06) 1.1
60 1 1.75 (0.33~3.98) 93.5±62.5 (66.9) 1.08±0.62 (57.59) 232.8±115.8 (49.8) 273.6±174.3 (63.7) 226.1±242.1 (107.07) -
7
 2.78 (0.69~6.02)
 96.0±48.9 (50.9)
 1.17±0.60 (50.9)
 237.7±53.2 (22.4)
 480.1±360.0 (74.98)
 266.3±75.5 (28.34)
 1.0
Zofenoprilat
Dose (mg) Day Tmax (h) Cmax (µg/L) t1/2 (h) AUClast (µg×h/L) Accumulation index Metabolic Ratio
30 1 2 (1.00~4.00) 348.6±241.8 (69.4) 4.03±0.55 (13.65) 729.0±304.2 (41.7) - 12.4
7 1.11 (0.82~4.02) 530.2±186.7 (35.2) 3.68±0.32 (8.59) 995.2±221.1 (22.2) 1.4 14.9
60 1 2 (0.33~3.98) 766.3±249.7 (32.6) 4.21±1.55 (36.76) 1572.1±310.4 (19.7) - 6.8
7 2.77 (0.69~4.27) 780.9±411.6 (52.7) 4.35±0.72 (16.48) 1560.5±425.2 (27.2) 1.0 6.6

Results are presented as mean ± standard deviation (CV(%)). Tmax: median & range are presented. CV: Coefficient of Variation. Dose: Dose of zofenopril. AUClast: Day 1: 0 - 16h. Day 7: 0 - 24h. Accumulation Index: AUClast,ss(Day 7)/AUClast(Day 1). Metabolic Ratio: AUCzofenoprilat/AUCzofenopril.

Adverse events after a single or multiple oral administration of zofenopril 30 mg or 60 mg or placebo

Placebo
 30 mg
 60 mg
 Total
Related Not-related Related Not-related Related Not-related
General 1 1
Body weakness
Fatigue
 1
 1
Digestive
 Abdominal pain
 2
 1
 3
Headache 2 1 3
Neurology Dizziness 1 2 1 4
Drowsiness
 1
 2
 3
Nasal stuffiness 1 1
Respiratory Rhinorrhea 1 1
Sore throat
 1
 1
Total 2 4 5 1 4 2 18