Studies of the Clinical Pharmacology of Perindopril: A New Inhibitor of Angiotensin Converting Enzyme

Lees, Kennedy Richardson (1986) Studies of the Clinical Pharmacology of Perindopril: A New Inhibitor of Angiotensin Converting Enzyme. MD thesis, University of Glasgow.

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Abstract

Over the last thirty years, effective and relatively safe control of hypertension has become possible. As a result, less severe forms of high blood pressure now warrant treatment. Such treatment needs to be acceptable to the patient and free from long-term toxicity. The angiotensin converting enzyme (ACE) inhibitors offer the possibility of improved tolerability and a novel mechanism of action. After review of the renin-angiotensin system, the clinical pharmacology of the two currently available ACE inhibitors is discussed. Captopril and enalapril have been demonstrated to be effective treatments in hypertension and cardiac failure. Both drugs may cause significant side effects and so there is justification for investigation of a similar compound which has an excellent safety profile in laboratory studies. The steps involved in the transfer of drugs from the animal laboratory to early clinical studies in man are then discussed. Perindopril is the esterified form of a potent and long-acting ACE inhibitor, S-9780: it is a prodrug which relies on bioactivation in vivo. The studies described in this thesis include some of the earliest administrations of perindopril to man and the first clinical trial involving S-9780. In the earliest dose-ranging study, 36 normotensive volunteers, in parallel groups of 6 subjects, were given perindopril (1 to 16 mg) orally for 7 consecutive days. The drug was well tolerated and no sign of toxicity was detected. Blood pressure was lowered by active treatment (14/11 mmHg 6 hours after 16 mg) with only a slight rise in heart rate (15 beats. min-1) after chronic treatment with 16 mg. Plasma ACE was inhibited and plasma renin activity was elevated in a dose-related pattern. Plasma aldosterone levels fell. The maximum effect occurred after 4-6 hours and 60% inhibition of plasma ACE persisted 24 hours after dosing with 8 and 16 mg. Plasma catecholamines were unchanged. A double blind crossover study in 8 normotensive volunteers demonstrated that intravenous administration of the active metabolite of perindopril, S-9780, was well tolerated and apparently safe. Maximal inhibition of plasma ACE occurred after only 1 mg. A dose-related rise in plasma renin activity occurred but no effect on plasma aldosterone was detected. Blood pressure was lowered by 8/14 mmHg 3 hours after 4 mg of S-9780 intravenously with no change in heart rate or plasma catecholamines. The effect of perindopril on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligrammes given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally mediated heart rate variation with deep breathing. There was no impairment of the response to either bicycle exercise at 175 W for 5 minutes or isometric handgrip. The pressor response to cold and the response to the Valsalva manoeuvre were unaltered. These results suggested that the absence of tachycardia after perindopril might be in part related to enhanced parasympathetic tone. In a single blind, placebo controlled study in seven hypertensive patients treated for one month, tolerability was excellent. Blood pressure was lowered from 164/93 mmHg to 145/84 mmHg by 4 mg of perindopril and after one month remained 142/82 mmHg. Neither postural hypotension nor tachycardia occurred. The biochemical effects were comparable to those in the volunteers. Plasma S-9780 levels were determined by an enzyme inhibition assay following treatment with oral perindopril and intravenous S-9780. The kinetics were linear and were not altered by repeated dosing. The intravenous data showed triphasic decay with a terminal half-life of over 30 hours; despite this, the accumulation half-life after repeated dosing was under 9 hours. The controversy over the pharmacokinetics of ACE inhibitors is acknowledged. Bioavailability of S-9780 after perindopril given orally was 15%. The kinetics of S-9780 in man corresponded to the kinetics in the laboratory animals which were used for the preclinical studies. Plasma ACE inhibition was related to plasma drug concentrations following intravenously administered S-9780: a close correlation was obtained using the Hill equation to describe the relationship. The plasma concentration of S-9780 which produced 50% inhibition of plasma ACE was 1.8 + 0.9 ng. ml-1 After oral dosing, the peak effect on ACE lagged behind peak plasma S-9780 concentration by several hours. A concentration-effeet model allowed description of this relationship. Using the parameters of the model, it was shown that the sensitivity of plasma ACE to S-9780 diminished slightly with repeated dosing. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Pharmacology
Date of Award: 1986
Depositing User: Enlighten Team
Unique ID: glathesis:1986-77399
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:09
Last Modified: 14 Jan 2020 09:09
URI: http://theses.gla.ac.uk/id/eprint/77399

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