A STUDY COMPARING BIOPHARMACEUTIC CHARACTERISTICS OF 4 ONCE-DAILY CONTROLLED-RELEASE DILTIAZEM PREPARATIONS

In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsu les: Mono-Tildiem LP 300(R) (300 mg), Adizem(R) XL (300 mg)(1), Cardiz em(R) (300 mg) and Dilacor(R) (240 mg). Sixteen healthy male volunteer s (aged 22.9 +/- 3.3 years, range 19-31 years) completed an open label , multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem fo rmulation once daily for four days. Trough diltiazem and metabolites p lasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of e ach period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c(min)), the maximum plasma concentration (c(max)), the time to reach that conc entration (t(max)), the time interval during which the plasma concentr ation exceeds 50% of c(max) (t(50)), the area under the plasma concent ration-time curve (AUC(72-96)) and the peak-to-trough fluctuation (PTF ). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC(72-96) (AUC(NDM) and AUC(DAD)) and t he ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations hav e satisfactory controlled release properties allowing once daily admin istration. However, significant (P < 0.05) differences were found betw een the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng.mL(-1) in t he morning hours were observed for Dilacor(R) (240 mg) and Adizem(R) X L (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, th e major circulating metabolites, parallel the plasma concentration pro files for the parent compound. From a clinical point of view, all trea tments were well tolerated. (C) Elsevier, Paris.