Conference report: the 3rd Global CRO Council for Bioanalysis at the International Reid Bioanalytical Forum.

The 3rd Global CRO Council Closed Forum was held on the 3rd and 4th July 2011 in Guildford, United Kingdom, in conjunction with the 19th International Reid Bioanalytical Forum. In attendance were 21 senior-level representatives from 19 CROs on behalf of nine European countries and, for many of the attendees, this occasion was the first time that they had participated in a GCC meeting. Therefore, this closed forum was an opportunity to increase awareness of the aim of the GCC and how it works, share information about bioanalytical regulations and audit findings from different agencies, their policies and procedures and also to discuss some topics of interest and aim to develop ideas and provide recommendations for bioanalytical practices at future GCC meetings in Europe.

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.

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).