Pharmacokinetic diversity of two modified-release diltiazem formulations

M Bogiel1, J Duda1, M Pawlowska1, E Sieradzki2. 1Institute of Biotechnology and Antibiotics, 02-516, Poland, 2Medical University of Warsaw, 02-091, Poland

Introduction: Diltiazem is a calcium antagonist used for the management of angina pectoris and hypertension.

Modified-release formulations of diltiazem reduce drug fluctuations in plasma over the course of time, reduce the risk of adverse events and allow to improve patients’ compliance.

Due to the technological diversities not all modified-release oral formulations of the same drug can be used as therapeutic equivalents. Differences in the pharmaceutical technology may cause significant differences in pharmacokinetics parameters and the bioavailability that may lead to dissimilarities in pharmacological action.

Objectives: The purpose of the study was to compare the pharmacokinetic characteristics of diltiazem in two different modified-release formulations - capsules with micropellets (multiple unit formulation) and film-coated tablets (single-unit formulation), containing the same amount of active substance – 120 mg. Parameters describing drug release process, diltiazem’s absorption kinetics and bioavailability were of particular importance.

Methods: The study was performed in two independent groups of 24 healthy volunteers in accordance with GCP and legal requirements.

Both formulation were administered as a single-dose or a multiple-dose regimen in a cross-over manner. Pharmacokinetic profiles were plotted up to 36 hours after dosing in the single-dose arm and up to 24 hours in steady state.

Diltiazem concentration in plasma was assayed by fully validated HPLC-UV method after liquid-liquid extraction. LLOQ was assessed at 2.9 ng/mL whereas LLOD at 1.0 ng/mL.

Standard pharmacokinetic and bioavailability parameters were calculated by noncompartmental methods in both study groups. Parameters characterising the absorption kinetics and prolonged release of the drug (e.g. HVD, Cmax/AUC, MIT, AUCTmax, Cav, %PTF) were calculated based on non-compartmental method for single dose as well as for steady-state arm of the study.

Additionally, data were fitted to the compartmental pharmacokinetic models and the absorption rate constants were calculated.

Differences between two formulations were statistically tested by t-test at the level of significance 0.05. Assessment of bioequivalence was based upon the 90% CI for the ratio of geometric means.

Results: Mean AUCinf/AUCss does not significantly differ between two formulations and indicate very similar bioavailability. But the bioequivalence can not be concluded because of the differences in Cmax .

Statistical differences were observed between capsules and tables in many of significant pharmacokinetic parameters, including ones describing absorption and prolonged release of the formulations (for results: see Table 1). Differences in model pharmacokinetics were also observed.

Table 1. Comparison of selected pharmacokinetics parameters

Conclusions: The absorption kinetics and characteristics of drug release are different for capsules and tablets. Two tested formulation can not be considered equivalent in respect of pharmacokinetics. It is crucial to consider their therapeutic equivalence.