Pharmacokinetic analysis of two new sustained-release products of diltiazem designed for twice-and once-daily treatment

The pharmacokinetics of two new sustained-release (SR) products of diltiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was analysed and characterized in three different studies, in comparison to the following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice-daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (±SD) relative bioavailability values of 99 ± 27% and 113 ± 38%, respectively. Dilapress 240, designed for once-a-day treatment, was found to have a slower absorption rate than Cardizem SR and its extent of absorption was 56 ± 19% relative to that of Cardizem SR. However, the bioavailability of Dilapress 240 relative to that of Cardizem CD was 118±46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54±29%. Diltiazem is partially available due to a saturable liver first-pass effect. A high dose of Cardizem SR may partially escape this first-pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once-daily treatment may not reach the saturation stage in the liver first-pass effect process that diltiazem is susceptible to. Consequently, a twice-daily SR product of diltiazem cannot serve as a reference for extent of absorption assessments of a once-daily SR product.     

Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers

Cardizem®SR and Bi-Tildiem® were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatographic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p <0.01) differences in AUC_0–12 with means (±SD) of 519.2(±172.8) and 429.6(±147.2)ng h ml^?1, AUC_0–36 of 835.6(±281.6) and 730.9 (±271.5)ng h ml^?1 and C_max of 89.1(±30.3) and 61.1(±21.2) ng ml^?1 for Cardizem®SR and Bi-Tildiem®, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (±SD) change in AUC_0–12 of ?13.6(±20.8) and +8.4(±31.7) mm Hg h (p = 0.0135) and in AUC_0–24 of ?33.0(±43.7) and ?0.3(±59.2) mm Hg h (p = 0.0463) for Cardizem®SR and Bi-Tildiem®, respectively. These findings suggest that assessment of efficacy of sustainedrelease formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.     

Bioequivalence assessment of diltiazem preparations by means of discriminant analysis of data from solid-phase extraction and liquid chromatography

A solid-phase extraction technique for sample clean-up coupled with a new LC procedure is reported for the assay of diltiazem in plasma. The use of disposable cartridges provides selective extraction and easy automation. A new LC system based on LiChrospher RP 60 Select B columns is described. For routine analysis, the procedure provides a rapid simultaneous clean-up of several samples prior to chromatography and reproducible recoveries over a concentration range of 10-800 ng. The procedure was used to analyse the plasma samples from a bioequivalence study of three commercial diltiazem preparations. The pharmacokinetic parameters in 12 healthy male volunteers were determined and the assessment of bioequivalence was conducted by discriminant analysis.     

Stability of diltiazem in different biological fluids

The hydrolysis of diltiazem in biological fluids: whole blood, plasma, and gastric fluid was investigated under conditions considered close to the physiological situation. The most significant rate of hydrolytic degradation was found in whole blood (half-life of 27 h), followed by plasma (half-life of 88 h), while the least significant degradation rate was observed in gastric fluid (half-life 153 h). The kinetic profiles of diltiazem hydrolysis indicate that hydrolytic degradation in the biological fluids makes a minimal contribution to the clearance and disposition of the drug.     

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

地尔硫辅治变异性心绞痛疗效观察

目的观察地尔硫辅治变异型心绞痛的疗效。方法将50例变异型心绞痛患者随机分为地尔卓组和对照组各25例。在常规治疗基础上,对照组给予单硝酸异山梨酯泵注,地尔硫组给予地尔卓泵注。治疗后观察2组临床疗效、心绞痛发作次数及持续时间。结果 2组总有效率均为100.0%,差异无统计学意义(P>0.05)。2组治疗后心绞痛发作次数减少,持续时间缩短(P<0.05)。结论地尔硫辅治变异型心绞痛安全、有效。     

曲美他嗪联合地尔硫卓治疗心绞痛的疗效

目的观察曲美他嗪联合地尔硫卓治疗心绞痛的疗效。方法选取笔者所在医院心绞痛患者50例,随机分为治疗组和对照组。对照组给予休息、吸氧、镇静、抗凝和抗血小板聚集等常规抗心绞痛处理,治疗组在此基础上,给予口服曲美他嗪片和地尔硫卓片,治疗2周后观察疗效和心电图情况。结果治疗组总有效率88%,对照组总有效率64%,治疗组疗效明显高于对照组,差异有统计学意义(P<0.01)。两组心电图改变情况比较,治疗组总有效率72%,对照组总有效率52%,治疗组心电图改变情况明显优于对照组,差异有统计学意义(P<0.01)。治疗后,治疗组使用硝酸甘油情况明显较对照组少,差异有统计学意义(P<0.01)。两组均未发现皮疹等过敏反应,也未发现肝肾功能损害。结论在常规治疗心绞痛的基础上,使用曲美他嗪联合地尔硫卓片治疗心绞痛,能够取得满意效果,值得临床推广。     

Prolongation of the PQ interval as a measure of therapeutic inequivalence between two formulations of diltiazem

We studied the use of atrioventricular (AV) conduction time to assess the therapeutic equivalence of two diltiazem formulations in 20 volunteers in a double-blind, cross-over trial. ECG recording was carried out before and at several intervals after drug administration, and prolongation of the PQ interval (PQ) was taken as a pharmacodynamic response. In addition, diltiazem plasma concentrations were determined in 8 subjects.The effect of diltiazem increased proportionally with the plasma concentration and could be detected up to 10 h after administration. The area under the effect-time curve (AUEC_0–10), the peak effect (E_max), and the effect mean residence time (MRT_E) showed significant differences. In contrast to the pharmacodynamics, the pharmacokinetic profiles of diltiazem do not vary to the same extent.We conclude that the formulations are therapeutically different. Furthermore, at the administered dose, PQ appears to be a sensitive measure for assessing the electrophysiological properties of diltiazem.     

Bioequivalence of two subcutaneous pharmaceutical products of interferon beta la

Blastoferon, in the following referred to as the test product, is a pharmaceutical product of interferon beta la (CAS 220581-49-7) currently marketed as a biosimilar to the innovator Interferon beta la product (referred to as the reference product). Pharmacokinetics and pharmacodynamIcs assays are critically relevant to demonstrate similarity between biopharmaceuticals. The aims of the present study were to investigate the bioavailability (BA) of the test product (either absolute or relative to the innovator product) and to compare the extent of increase of neopterin concentration following administration of either product. Two studies were performed: initially, an absolute BA assay with i.v. and s.c. injection of test product to 12 healthy subjects. Second, a formal relative BA study with s.c. injections of 88 microg of both products to 24 healthy volunteers. Blood samples for pharmacokinetic and pharmacodynamic profiling were drawn at different intervals after injection. Interferon beta (IFNB) concentrations were determined by ELISA. In the absolute BA study, a single s.c. dose of 44 microg of the test product resulted in a median bioavailable fraction of 29%, a median T(max) of 4 h (4-6) and a C(max) of 3.69 (3.27-4.41) IU x ml(-1). In the relative BA study, values for the test product were: median T(max) of 3 h (2-18), C(max) of 5.39 (4.99-6.31) IU x ml(-1), AUC (0-72) of 142.86 (134.16-190.15) IU x h x ml(-1) and AUC(0-infinity) of 190.95 (174.23-303.13) IU x h x ml(-1). The corresponding values for the innovator product were: T(max) of 3 h (1-24), C(max) of 4.44 (4.12-5.40) IU x ml(-1), AUC(0-72) of 128.77 (121.18-170.92) IU x h x ml(-1) and AUC(0-affinity) of 192.61 (183.04-286.46) IU x h x ml(-1). The AUC(0-72) ratio was 111% (CI 90%: 106-116), the AUC(0-affinity) was 99% (CI 90%: 92-107) and the C(max) ratio was 121% (CI 90%: 112-131). IFNB1a increased neopterin levels in both studies. Both products induced side-effects commonly reported for IFN with no serious adverse events. This study presents pharmacokinetics parameters of the test product and demonstrates similar bioavailability of IFNB1a for both pharmaceutical products.     

硫氮卓酮治疗室上性心动过速疗效分析

目的观察硫氮卓酮与其他药物治疗室上性心动过速疗效并进行比较。方法 246例次经心电图证实的阵发性室上性心动过速(PSVT)发作,随机单盲分为硫氮卓酮、普罗帕酮、西地兰、维拉帕米、乙胺碘呋酮5个治疗组,观察各组疗效及不良反应,部分药物转复无效者采用同步直流电复律。结果转复成功率:硫氮卓酮组94.1%,普罗帕酮组75.0%,西地兰组64.1%,维拉帕米组89.3%,乙胺碘呋酮组72.7%。硫氮卓酮、维拉帕米组转复成功率较普罗帕酮、西地兰、乙胺碘呋酮组高,差异有显著性(P<0.01),硫氮卓酮组比维拉帕米组稍高,差异无显著性(P>0.05)。组间不良反应差异无显著性(P>0.05)。结论硫氮卓酮是治疗PSVT安全、有效的药物,病情合适者可作为首选药物之一。     

Pharmacokinetic interaction between diltiazem and amiodarone in the dog

The pharmacokinetic interaction between diltiazem and amiodarone was investigated in dogs. In the presence of amiodarone, diltiazem's AUC values were significantly increased and its total body clearance and volume of distribution at steady-state significantly decreased. This study indicates that cardiac patients on combined diltiazem-amiodarone therapy may indeed be in a high risk situation in regards to the unexpectedly high blood levels of diltiazem induced: with the ultimate introduction of such side-effects as (1) the lowering of blood pressure, (2) A/V block, and (3) sinus node depression. Such cases would require immediate dosage adjustment. Assuming that the data obtained in this study can be extrapolated to humans, a patient's physiological parameters should be monitored at periodic intervals and, more importantly, the patient should report the first sign of any untoward effect.     

Bioinequivalence of marketed diltiazem preparations

Summary A bioequivalence study of three brands of regular diltiazem — Angizem (A), Dilzem (B) and Herbesser (C) has been carried out in 5 healthy, male volunteers.After a single oral dose of 60 mg of each preparation, the mean AUC(0–8 h) and C_max of preparation B was significantly higher than of brands A and C. The t_max of A and B was significantly lower than of C. B had a higher dissolution rate in vitro (98.8% dissolved in 45 min) than A and C.Thus, there was bioinequivalence of the three brands of diltiazem, due partly to differences in dissolution and perhaps in part to a first pass effect.     

地尔硫(艹卓)治疗窦性心动过缓并阵发性心房颤动

目的　探讨地尔硫 卓艹 对窦性心动过缓并阵发性心房颤动疗效及安全性。方法　经临床诊断为窦性心动过缓并阵发性心房颤动的病人 2 8例。口服地尔硫 卓艹 ,观察 12周 ,经动态心电图复查。判定标准 :转复窦律或房颤减少 90 %以上 ,为有效。结果　 2 8例病人中 16例有效 ,无药物不良反应 ,心率无明显改变。结论　口服地尔硫 卓艹治疗窦性心动过缓并阵发性心房颤动安全有效。     

Comparison of bioavailability and pharmacodynamics of diltiazem from two pharmaceutical preparations.

Diltiazem, a calcium channel blocker, is used in multiple divided doses daily, due to its short elimination half-life. Hence, administration as a modified release (MR) formulation is suggested. In this double blind cross-over trial, the pharmacokinetics and pharmacodynamics of diltiazem was studied in eight healthy Indian adults. Diltiazem was administered as single dose (60 mg) of the two formulations viz immediate release (IR) and MR. Venous blood samples, for estimation of diltiazem by HPLC, were collected at frequent intervals and BP, HR and ECG were monitored during the 12h study period. With MR formulation, plasma half-life was significantly (P < 0.05) prolonged (6.25 +/- 1.2 h vs. 2.69 +/- 0.2 h), the extent of alterations in BP, HR and PR interval was significantly less, while the duration of prolongation of PR interval was significantly more as compared to IR formulation. Therefore, MR formulation of diltiazem has better pharmacokinetic and pharmacodynamic profile as compared to IR formulation.     

Bioavailability of diltiazem as a function of the administered dose

Diltiazem undergoes extensive first-pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first-pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter-subject variability was highest at the lowest dose at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11.8 +/- 2.5 per cent after 10 mg to 28.2 per cent after 120 mg; (d) the elimination half-life was dose-related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 +/- 0.3 per cent after 10 mg to 3.0 +/- 0.5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first-pass effect for diltiazem.     

Influence of food on the bioavailability of diltiazem and two of its metabolites following the administration of conventional tablets and slow-release capsules

The influence of food on the bioavailability of a conventional tablet and of a slow-release capsule of diltiazem was investigated in two separate groups of 24 healthy volunteers in two open crossover studies. Diltiazem, as a conventional tablet (2 x 30 mg, first group) or as a slow-release capsule (120 mg SR, second group), was administered in a fasting condition and 30 min after a breakfast of 784 kcal (23 per cent proteins, 55 per cent lipids, and 22 per cent of carbohydrates). Multiple blood samples were withdrawn during the next 24 h and diltiazem, desmethyldiltiazem, and deacetyldiltiazem were assayed by HPLC. Neither the rate of absorption, assessed by the rate constant of absorption, the peak plasma concentration, and the time required to reach the peak, nor the amount of drug reaching the systemic circulation, assessed by the area under the plasma concentration time curve (AUC infinity) were influenced by food, and that independently of the formulation. Compared to the fasting experiment, food did not affect either the rate of formation or the AUC infinity of desmethyldiltiazem or deacetyldiltiazem. The results of the present study show that the relative bioavailability of the single dose of diltiazem administered as a slow-release capsule is significantly higher (69 per cent) than that estimated after the administration of diltiazem in a conventional tablet. It was concluded that food does not influence the bioavailability of diltiazem administered as a conventional tablet or as a slow-release formulation.     

静脉注射地尔硫和毛花甙C控制快速心房纤颤心室率的疗效比较

目的 比较静脉注射地尔硫、毛花甙C控制快速心房纤颤心室率的疗效。方法 将58例快速心室率心房纤颤(房颤)病人随机分为地尔硫组(Ⅰ组)30例、毛花甙C组(Ⅱ组)28例,分别给予地尔硫0.3mg/kg、毛花甙C 0.4mg稀释后静脉推注。结果 平均起效时间:Ⅰ组为4.2±1.8min,Ⅱ组为30.1±9.8min;最大效应时间:Ⅰ组10.2±3.4min,Ⅱ组80.6±10.6min;用药后心室率平均下降幅度:Ⅰ组46±18次/min,Ⅱ组30±12次/min(P值均<0.05)。结论 两种药物对控制快速心房纤颤心室率均有效,但地尔硫起效快,心室率下降幅度大。     

Pharmacokinetics of diltiazem and its major metabolite, deacetyidiltiazem after oral administration of diltiazem in mild and medium folate-induced renal failure rabbits

The pharmacokinetic changes of diltiazem (DTZ) and its main metabolite, deacetyldiltiazem (DAD) were studied after oral administration of DTZ to normal rabbits and mild and medium folate-induced renal failure rabbits. DTZ 10 mg/kg was given to the rabbits either orally (n=6). Plasma concentrations of DTZ and DAD were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration (Cmax) of DTZ were significantly increased in mild and medium folate-induced renal failure rabbits. The metabolite ratio of the DTZ to DAD were significantly decreased in mild and medium folate-induced renal failure rabbits. The volume of distribution (Vd) and total body clearance (CLt) of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits. The elimination rate constant (beta) of DTZ was significantly decreased in folate-induced renal failure rabbits, but that of DAD was significantly increased. These findings suggest that the hepatic metabolism of DTZ was inhibited and the Vd, CLt and beta of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits.     

Esmolol versus diltiazem in atrial fibrillation following coronary artery bypass graft surgery

SUMMARY

Purpose: Atrial fibrillation (AF) is the most common arrhythmic complication following coronary artery bypass graft surgery (CABG). The efficacy and safety of esmolol and diltiazem were compared in patients with post-CABG AF.

Methods: This study was a retrospective medical record review of consecutive patients with post-CABG AF >15?min in duration with a ventricular rate >110?b.p.m. who received either i.v. esmolol (n?=?59) or i.v. diltiazem (n?=?48) with or without concomitant digoxin therapy at a single university-affiliated teaching hospital. Treatment success was defined as either cardioversion to sinus rhythm or a reduction in the ventricular rate to <90?b.p.m. at 24?h after the start of therapy. Time to treatment success and the occurrence of adverse effects were considered secondary outcomes.

Results: A total of 107 patients with post-CABG AF were treated with i.v. esmolol (n?=?59) or i.v. diltiazem (n?=?48). The mean maximum dose of esmolol and diltiazem were 115?±?38?μg/kg/min and 11.2?±?3.5?mg/h, respectively. The average duration of the esmolol and diltiazem infusions were 19.3?±?8.5?h and 20.1?±?11.3?h, respectively. Based on the combined efficacy endpoint of cardioversion or ventricular rate control, esmolol was significantly more effective than diltiazem (90% vs 77%; p?=?0.038). Time to treatment success was significantly better for esmolol than diltiazem at all time points (1, 2,4,6,12, and 24?h post-treatment). The overall incidence of adverse effects was 44% with esmolol and 60% with diltiazem (p?=?0.04). Rates of drug discontinuance for adverse effects were significantly less for esmolol (20%) compared with diltiazem (38%) (p?=?0.04).

Conclusions: Esmolol is significantly more effective than diltiazem in the management of post-CABG AF. More patients converted to sinus rhythm with esmolol as compared to diltiazem. Esmolol was associated with fewer adverse effects than diltiazem, including adverse effects leading to drug discontinuance. Due to study design limitations (retrospective data collection), an adequately powered randomised, controlled trial is needed to confirm these preliminary findings.