Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants.

OBJECTIVE: To compare the pharmacokinetics of milnacipran in extensive metabolisers (EMs) and poor metabolisers (PMs) of sparteine and mephenytoin, and to assess the influence of multiple administrations of milnacipran on the activity of cytochrome P450 (CYP) isoenzymes through its own metabolism and through various probes, namely CYP2D6 (sparteine/dextromethorphan), CYP2C19 (mephenytoin), CYP1A2 (caffeine) and CYP3A4 (endogenous 6-beta-hydroxy-cortisol excretion). METHODS: Twenty-five healthy subjects, 12 EMs for both sparteine/dextromethorphan and mephenytoin, nine EMs for mephenytoin and PMs for sparteine/dextromethorphan (PM(2D6)) and four PMs for mephenytoin and EMs for sparteine/dextromethorphan (PM(2C19)) were administered milnacipran as a single 50 mg capsule on day 1 followed by a 50 mg capsule twice daily for 7 days. The pharmacokinetics of milnacipran and its oxidative metabolites were assessed after the first dose (day 1) and after multiple administration (day 8), and were compared for differences between CYP2D6 and CYP2C19 PMs and EMs. Metabolic tests were performed before (day -2), during (days 1 and 8) and after (day 20) milnacipran administration. RESULTS: Milnacipran steady state was rapidly achieved. Metabolism was limited: approximately 50% unchanged drug, 30% as glucuronide and 20% as oxidative metabolite (mainly F2800 the N-dealkyl metabolite). Milnacipran administration to PM2D6 and PM2C19 subjects did not increase parent drug exposure or decrease metabolite exposure. Milnacipran oxidative metabolism is not mediated through CYP2D6 or CYP2C19 polymorphic pathways nor does it significantly interact with CYP1A2, CYP2C19, CYP2D6 or CYP3A4 activities. CONCLUSION: Limited reciprocal pharmacokinetic interaction between milnacipran and CYP isoenzymes would confer flexibility in the therapeutic use of the drug when combined with antidepressants. Drug-drug interaction risk would be low, even if the combined treatments were likely to inhibit CYP2D6 and CYP2C19 isoenzyme activities.

Single oral dose pharmacokinetic interaction study of manidipine and delapril in healthy volunteers.

OBJECTIVE: The objective of the study was to assess potential pharmacokinetic interactions between delapril, an angiotensin conversion enzyme inhibitor, and manidipine, a calcium channel antagonist, prior to the development of a fixed combination drug product. METHODS: Eighteen healthy male volunteers received a single oral dose of 10 mg manidipine dihydrochloride (CAS 89226-75-5), or 30 mg delapril hydrochloride (CAS 83435-67-0), or both simultaneously, according to a fully balanced three-way cross-over design. The three treatments were separated by a one-week washout period. Blood samples were collected during 24 h for plasma determination of manidipine and metabolite M-XIII and/or of delapril and metabolites M1, M2 and M3, using specific LCMS/MS methods. RESULTS: The bioavailability of manidipine and M-XIII was slightly decreased by concomitant administration of delapril (manidipine: Cmax-19% and AUC infinity-11% M-XIII: Cmax-17% and AUCt-18%). The bioavailability of delapril was not influenced by co-administration with manidipine (Cmax-7% and AUC infinity +4%). The effect on delapril pharmacologically active metabolites M1 and M3 was negligible. The inactive metabolite M2 underwent a 13% reduction of Cmax and AUC infinity. The 90% confidence intervals were confined within limits of acceptance (70-143% for Cmax and 80-125% for AUC). Mean residence times and apparent elimination half-lives were unaltered. Blood pressure and heart rate versus time profiles were similar during the three treatments. CONCLUSIONS: Simultaneous oral administration of 10 mg manidipine and 30 mg delapril does not significantly alter the pharmacokinetics of either drug or that of their principal metabolites.

Pharmacokinetics and tolerability of a new manidipine and delapril fixed oral combination in young and elderly subjects.

OBJECTIVES: The aim of the present study was to compare the pharmacokinetic and pharmacodynamic properties of a fixed combination tablet containing 10 mg of manidipine dihydrochloride (CAS 89226-75-5), a calcium channel antagonist, and 30 mg of delapril hydrochloride (CAS 83435-67-0), an angiotensin converting enzyme (ACE) inhibitor, during once daily repeated dosing in young and elderly subjects and to assess the bioequivalence of the fixed combination tablet and the single ingredient tablets taken simultaneously in young healthy subjects after a single dose administration. METHODS: Eighteen young healthy male volunteers received a single oral dose of 10 mg manidipine and 30 mg delapril as two separate tablets or a fixed combination tablet, followed by a week of once daily dosing with the fixed combination. Eight male and eight female elderly volunteers also received a week of once daily dosing with the fixed combination. Blood samples were collected during 24 h on the first and last treatment day for plasma determination of manidipine, delapril and their main metabolites, using specific LC-MS/MS methods. Blood pressure and heart rate were also recorded during 24 h. RESULTS: Bioequivalence was strictly demonstrated between the extemporaneous and the fixed combination tablet after single dose administration. At steady-state in young subjects, manidipine AUC and Cmax were lower (-8 and -12%) and t1/2 was longer (+45%), while delapril and metabolites were little affected as compared to single dose. In elderly subjects, manidipine Cmax was 4% lower than after single dose, AUC was 13% higher, and t1/2 was increased 2.4-fold. For delapril and active metabolites, Cmax and AUC increased modestly. Blood pressure and heart rate versus time profiles after single dose and at steady-state were almost superimposable. In elderly compared to young subjects at steady-state, peak concentrations of manidipine and delapril changed by +35% and -15% while AUCs increased by +70% and +9.7%. CONCLUSION: The fixed combination tablet of 10 mg manidipine and 30 mg delapril is bioequivalent to mono-ingredient tablets. At steady-state, the pharmacokinetic and pharmacodynamic profiles in young and elderly subjects undergo minor changes and indicate negligible accumulation. Drug exposure is higher in elderly subjects.