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 Cmax and AUC0–24h were less than 20%, indicating that this agent is a moderately variable drug. Although AUC0–24h was within the protocol‐defined range of 80% to 125%, the lower limit of the 90% confidence interval for Cmax 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 Cmax. Single oral doses of 50 mg of M100240 were safe and well tolerated under fed and fasted conditions.

2004-08-01·The Journal of Clinical Pharmacology3区 · 医学

Pharmacokinetics of M100240 and MDL 100,173, a Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, in Healthy Young and Elderly Volunteers

3区 · 医学

Article

作者: Gary T. Emmons ; Louis L. Martin ; Bradford K. Jensen ; Rick Argenti ; Nancy E. Martin

M100240 is an acetate thioester of MDL 100,173—a dual angiotensin‐converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor—in phase II development. The pharmacokinetics of M100240 and MDL 100,173 were compared in young and elderly subjects. Pharmacokinetic data were obtained from 12 young (ages 18–45 years, 10 male, 2 female) and 12 elderly (ages 65–85 years, 7 male, 5 female) healthy subjects in a parallel‐group, open‐label study. Following an overnight fast, subjects received a single 25‐mg oral dose of M100240. Serial plasma concentrations of M100240 and MDL 100,173 were determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, and pharmacokinetic parameters were calculated with noncompartmental methods. Single‐dose treatment with M100240 was well tolerated in both groups of subjects, with no clinically significant changes in vital signs, ECG recordings, or laboratory safety parameters. M100240 was rapidly absorbed and converted to MDL 100,173, with M100240 concentrations no longer detectable at 3 to 4 hours postdose in both groups. The pharmacokinetics of the pharmacologically active MDL 100,173 were similar for both groups. Although maximum concentrations of M100240 were generally higher in elderly versus young subjects (Cmax 0.48 ng/mL vs. 0.17 ng/mL), systemic availability of M100240 was quite low and variable with plasma, and this apparent difference in parent drug exposure is unlikely to have important clinical implications. No age‐related differences in the pharmacokinetic parameters of MDL 100,173 (Cmax 8.16 vs. 9.62 ng/mL, tmax 1.25 vs. 1.5 h, AUC(0‐last) 81.6 vs. 72.2 ng•h/mL) were observed between young and elderly subjects, respectively. In conclusion, there are no age‐related differences in the pharmacokinetics of MDL 100,173 between young and elderly subjects.

2004-04-01·The Journal of Clinical Pharmacology3区 · 医学

No Clinically Relevant CYP3A Induction with the Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240

3区 · 医学

Article

作者: Jeffrey S. Barrett ; Iolanda Cirillo ; Louis L. Martin ; Nancy E. Martin ; Stanley R. Howell

M100240, an acetate thioester of MDL 100,173, is a dual angiotensin‐converting enzyme/neutral endopeptidase inhibitor currently in Phase II development. M100240 and MDL 100,173 were evaluated in an in vitro cytochrome P450 human hepatocyte model for enzyme induction. Although a dose‐dependent CYP3A induction was observed between 10 and 100 μM, at 1 μM—which approaches clinically relevant plasma concentrations in humans—there was no evidence of CYP3A induction. An in vitro reporter gene assay also demonstrated the CYP3A isozyme induction potential of M100240 and MDL 100,173 with an EC50 ∼ 1.5 μM. The present study evaluated the potential for CYP3A enzyme induction in healthy volunteers. In an open‐label, single‐sequence, replicate‐design study using midazolam as a CYP3A probe in 13 healthy volunteers, we found no evidence of clinically relevant CYP3A induction after multiple‐dose administration of 50 mg M100240 orally once daily for 15 days. Single and multiple doses of M100240 increased the midazolam AUC0–24 h about 1.6‐fold compared to baseline, suggesting weak CYP3A inhibition. Concomitant administration of midazolam and M100240 was generally safe and well tolerated. Although in vitro CYP3A induction at exposures in excess of clinically relevant human plasma concentrations has been demonstrated, there is no clinical evidence of CYP3A induction with M100240 administration at proposed therapeutic doses.

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适应症	最高研发状态	国家/地区	公司	日期
心脏衰竭	临床2期	欧洲	Hoechst Pakistan Ltd.	-
心脏衰竭	临床2期	-	Sanofi	-
心脏衰竭	临床2期	美国	Hoechst Pakistan Ltd.	-
高血压	临床2期	-	Sanofi	-
高血压	临床1期	美国	Hoechst Pakistan Ltd.	-
高血压	临床1期	欧洲	Hoechst Pakistan Ltd.	-