J Korean Soc Clin Pharmacol Ther.  2013 Jun;21(1):52-62.

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

• Oh J
• Lee S
• Lim KS
• Chung JY
• Shin SG
• Jang IJ
• Yu KS

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.

Keyword

Zofenopril; Zofenoprilat; ACE inhibitor; Pharmacokinetics; Pharmacodynamics

MeSH Terms

Captopril
Electrocardiography
Heart Failure
Humans
Hypertension
Male
Peptidyl-Dipeptidase A
Physical Examination
Vital Signs
Captopril
Peptidyl-Dipeptidase A

Figure

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  Figure 1. 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).

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  Figure 2. Dose normalized Cmax and AUClast of zofenopril after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

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  Figure 3. Metabolic Ratio of zofenopril after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

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  Figure 4. Inhibition of ACE activity after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

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  Figure 5. 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.

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  Figure 6. Mean blood pressures vs time curve after a single or multiple oral administration of zofenopril 30 mg or 60 mg.

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