A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Hendriks, M. G. C.; Dogterom, Peter; Ebels, J. T.; Oosterhuis, B.; Geertsema, L. R.; Hulot, T.; Bianchetti, G.; Jonkman, J. H. G.

doi:10.1111/j.1472-8206.1998.tb00986.x

Cited by 4 publications

(5 citation statements)

References 10 publications

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“…Several extended‐release (ER) formulations of diltiazem HCl have been introduced into the market over the past two decades, and pharmacokinetic characteristics of these products have been widely published 23 – 27 . To date, no diltiazem formulation has been developed for nighttime use.…”

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confidence: 99%

“…22 Several extended-release (ER) formulations of diltiazem HCl have been introduced into the market over the past two decades, and pharmacokinetic characteristics of these products have been widely published. [23][24][25][26][27] To date, no diltiazem formulation has been developed for nighttime use. Recently, an innovative, extended-release formulation of diltiazem HCl that exhibits a unique dissolution profile, with a built-in lag time, was developed for nighttime dosing.…”

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confidence: 99%

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Pharmacokinetics of a Novel Diltiazem HCl Extended‐Release Tablet Formulation for Evening Administration

Sista¹,

Lai²,

Eradiri³

et al. 2003

The Journal of Clinical Pharma

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A novel diltiazem HCl extended-release (ER) tablet formulation was developed for evening administration in the management of angina and hypertension. Pharmacokinetics of the formulation were evaluated to identify variations in morning (7 a.m. or 8 a.m.) versus evening (10 p.m.) drug administration. Single-dose (360 mg) and multiple-dose (360 mg once daily for 7 days), open-label, randomized, two-way crossover studies of the new diltiazem HCl ER tablets were completed in 48 healthy volunteers. Serial plasma samples were collected via direct venipuncture up to 48 hours postdose and analyzed for diltiazem and its two major metabolites by high-performance liquid chromatography (HPLC). The primary parameters used to assess the data were AUC0- infinity, AUC0-tau, AUC6 a.m.-12 p.m., Cmax, and tmax. Statistical comparisons using ANOVA were evaluated after logarithmic transformation of dose-dependent parameters. Diltiazem HCl ER tablets administered in the evening exhibited 17% and 22% greater bioavailability compared to morning administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. The evening schedule also provided more than twofold higher plasma diltiazem levels in the critical morning hours, when both blood pressure and the incidence of cardiovascular events are the highest.

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confidence: 99%

Pharmacokinetics of a Novel Diltiazem HCl Extended‐Release Tablet Formulation for Evening Administration

Sista¹,

Lai²,

Eradiri³

et al. 2003

The Journal of Clinical Pharma

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“…These days diltiazem is readily measured in blood and so there are a number of published studies reporting on the concentration-response relationship for diltiazem [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. However, the literature on diltiazem is full of conflicting evidence because the limited original data correlating serum concentration with therapeutic effect have proved difficult to interpret.…”

Section: Minimum Effective Concentration and Minimum Effective Dosementioning

confidence: 99%

“…In a study comparing four different formulations of diltiazem, Hendriks et al [9] used a minimum effective concentration of 50 ng/ml as their cut-off point for the treatment of angina. They cited literature by Low et al [10] and Opie [11] to support this value.…”

Section: Minimum Effective Concentration and Minimum Effective Dosementioning

confidence: 99%

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Mould

2002

Int J Pharm Med

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Diltiazem is a calcium antagonist effective in the treatment of stable and unstable angina and mild to moderate systemic hypertension with a generally favourable side-effect profile. A number of published studies have attempted to formulate a therapeutic target range, but there appears to be little consensus of opinion. A minimum effective concentration of 40 ng/ ml has been proposed by some authors whilst others have chosen 50 ng/ml and others upwards to 100 ng/ml. A review of the reports suggests that a trough concentration of above 50 ng/ml confers a better therapeutic outcome than does the lower concentrations. A number of modified release preparations enabling once a day dosing are available, all purporting to give adequate therapeutic concentrations. However, based on the above assumptions it would appear that those giving sustained concentrations above 50 ng/ml would be those of choice. Furthermore the benefits of once daily preparations lead to improved compliance and therefore improved therapeutic outcome and thus confirm that the modified preparations are the delivery of choice. Once chosen, it is advisable to maintain the same preparation in order to derive maximum clinical benefit.

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“…Propranolol is also approved for the prophylactic treatment of migraine although study data for chronic migraine has shown that there is no benefit from adding propranolol to patients insufficiently treated with topiramate . With the extended release once‐daily formulation, peak concentrations of diltiazem occur at 4–6 hours with elimination half‐life of 5–8 hours . Diltiazem undergoes extensive hepatic metabolism via CYP3A4 and CYP2D6 resulting in two major active metabolites, desacetyldiltiazem (DEA) and N‐desmethyldiltiazem (DEM), which are excreted primarily in the urine .…”

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Pharmacokinetic interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol

Manitpisitkul

Curtin

Shalayda

et al. 2014

Clinical Pharm in Drug Dev

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Drug-drug interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol were evaluated along with safety/tolerability in three open-label studies. Healthy participants (aged 18-45 years) received topiramate 75 mg every 12 hours (q12h) and diltiazem 240 mg/day (study 1); topiramate 96 mg q12h and hydrochlorothiazide 25 mg/day (study 2); topiramate 100 mg q12h and propranolol 40-80 mg q12h (study 3). The pharmacokinetic parameters for topiramate, diltiazem (and active metabolites, desacetyldiltiazem [DEA], N-demethyl diltiazem [DEM]), hydrochlorothiazide, and propranolol (and its active metabolite) were assessed at steady state. Results showed no effect of diltiazem on topiramate pharmacokinetics. However, a modest reduction in systemic exposures of diltiazem and DEA (10-27%) occurred during coadministration with topiramate. Systemic exposure of DEM was unaffected. Furthermore, oral and renal clearance of topiramate decreased (22-30%) significantly (P < 0.05) during coadministration with hydrochlorothiazide, while systemic exposure increased by 27-29%. Topiramate had no effect on hydrochlorothiazide pharmacokinetics. The results demonstrated lack of pharmacokinetic interaction between topiramate and propranolol. Overall, no new safety concerns emerged when topiramate was coadministered with diltiazem, hydrochlorothiazide, or propranolol.

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A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Cited by 4 publications

References 10 publications

Pharmacokinetics of a Novel Diltiazem HCl Extended‐Release Tablet Formulation for Evening Administration

Pharmacokinetics of a Novel Diltiazem HCl Extended‐Release Tablet Formulation for Evening Administration

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Pharmacokinetic interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol

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