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A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations
Author(s) -
Hendriks MGC,
Dogterom P,
Ebels JT,
Oosterhuis B,
Geertsema LR,
Hulot T,
Bianchetti G,
Jonkman JHG
Publication year - 1998
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1998.tb00986.x
Subject(s) - diltiazem , pharmacokinetics , cmin , cmax , crossover study , chemistry , metabolite , morning , steady state (chemistry) , washout , active metabolite , pharmacology , zoology , medicine , calcium , placebo , biochemistry , biology , alternative medicine , organic chemistry , pathology
Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono‐Tildiem LP 300® (300 mg), Adizem® XL (300 mg) 1 , Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (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 formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24‐h plasma concentration‐time profiles were assessed after the dose on day 4 of each 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 concentration ( t max ), the time interval during which the plasma concentration exceeds 50% of c max ( t 50 ), the area under the plasma concentration‐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 the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant ( P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL ‐1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (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, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.