title: A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations.
abstract: 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), 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 (cmin), the maximum plasma concentration (cmax), the time to reach that concentration (tmax), the time interval during which the plasma concentration exceeds 50% of cmax (t50), the area under the plasma concentration-time curve (AUC72-96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC72-96 (AUCNDM and AUCDAD) 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 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.
authors.affiliation: Pharma Bio-Research International BV, AE Zuidlaren, The Netherlands.
authors.forename: M G
authors.initials: MG
authors.lastname: Hendriks
authors.forename: P
authors.initials: P
authors.lastname: Dogterom
authors.forename: J T
authors.initials: JT
authors.lastname: Ebels
authors.forename: B
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: L R
authors.initials: LR
authors.lastname: Geertsema
authors.forename: T
authors.initials: T
authors.lastname: Hulot
authors.forename: G
authors.initials: G
authors.lastname: Bianchetti
authors.forename: J H
authors.initials: JH
authors.lastname: Jonkman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004110:Diltiazem / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male
chemical_list: D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004110:Diltiazem