Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects

Abstract

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers

“…The BP-lowering effect of trandolapril was greater in noncarriers than carriers, although the difference did not reach a statistically significant level. Consistent with previous studies, 35,37 the maximum BP reduction in noncarriers occurred at 6-8 h after dosing, which corresponds to the T max of trandolaprilat. The CES1 G143E variant was originally identified in a study subject who displayed a markedly abnormal PK profile in a methylphenidate PK study.…”

Orthostatic Hypotension and Therapy with an Ace Inhibitor in Hypertensive Patients

“…Finally, it is important to note that in both short-and long-term use, Trandolapril is characterized by a low incidence of orthostatic hypotension, unlike other ACE inhibitors. Several other studies have also shown the absence of orthostatic hypotension with the use of Trandolapril (19,20).…”

Correlation of body mass index and orthostatic hypotension in patients with hypertension on ACE inhibitor monotherapy

“…The absence of OH when using trandolapril was also shown in several other studies. 27,28 treatment (p < 0.05), within only 6.2 % of subjects with OH.…”