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The Effect of Food on the Pharmacokinetics of a Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240
Author(s) -
Cirillo Iolanda,
Martin Nancy E.,
Brennan Barbara,
Barrett Jeffrey S.
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004269557
Subject(s) - pharmacokinetics , pharmacology , crossover study , chemistry , angiotensin converting enzyme , neprilysin , ace inhibitor , captopril , renin–angiotensin system , medicine , blood pressure , enzyme , biochemistry , alternative medicine , pathology , placebo
M100240 is a thioester of MDL 100,173, a dual angiotensin‐converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor. Clinical studies have shown that M100240 is capable of decreasing ACE activity and angiotensin II concentrations while increasing plasma renin activity and potentiating the effects of atrial natriuretic peptide. This may result in a unique treatment benefit in disease states characterized by intravascular volume or sodium overload or increased venous pressure. The pharmacokinetics of MDL 100,173 were evaluated in 30 healthy subjects in an open‐label, randomized, 2‐period crossover design. Subjects received a single oral dose of 50 mg of M100240 administered with a high‐fat meal and separately under fasted conditions. Serial plasma concentrations of M100240 and MDL 100,173 were analyzed, and pharmacokinetic parameters were calculated with noncompartmental methods. The intrasubject percent coefficient of variation for MDL 100,173 C max and AUC 0–24h were less than 20%, indicating that this agent is a moderately variable drug. Although AUC 0–24h was within the protocol‐defined range of 80% to 125%, the lower limit of the 90% confidence interval for C max fell outside of the 70% to 143% range. Absence of a food effect on the pharmacokinetic profile of 50 mg of M100240 could therefore not be demonstrated. This finding is not surprising based on the documented food effect with the sulfhydryl‐containing ACE inhibitor, captopril. Clinical significance of this pharmacokinetic food effect is unlikely, as the magnitude of pharmacodynamic response is probably better correlated with AUC than a single‐point determination of C max . Single oral doses of 50 mg of M100240 were safe and well tolerated under fed and fasted conditions.