Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation

AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment. METHODS: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females. CONCLUSIONS: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects.     

硝苯地平缓释片与硝苯地平控释片治疗高血压的疗效比较

目的比较硝苯地平缓释片与硝苯地平控释片治疗高血压病的临床疗效。方法 112例高血压患者随机分为控释片组和缓释片组,各61例。缓释片组服用硝苯地平缓释片10mg,每天2次;控释片组服用硝苯地平控释片30mg,每天1次。2组均治疗8周。观察2组血压变化情况、谷/峰（T/P）比值和不良反应发生情况。结果控释片组总有效率为91.8%高于缓释片组的80.3%（P〈0.05）;2组治疗后血压均降低,控释片组HR降低,缓释片组HR升高,与治疗后比较差异有统计学意义（P〈0.05）;控释片组治疗后血压、心率均低于缓释片组（P〈0.05）;控释片组SBP与DBP降压T/P值分别为92.1%与85.9%,缓释片组分别为29.7%与25.6%;控释片组不良反应发生率低于缓释片组（P〈0.05）。结论硝苯地平控释片具有良好的抗高血压作用,不良反应少,效果优于硝苯地平缓释片。     

Pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin and immediate-release oxybutynin

Oxybutynin is used to treat patients with urinary urgency, frequency, and urge incontinence. In this 2-way, multiple-dose, crossover study, the pharmacokinetics and pharmacodynamics of once-daily controlled-release oxybutynin were compared with immediate-release oxybutynin. Eighteen healthy male volunteers received one 15-mg controlled-release oxybutynin tablet once daily for 5 days or one 5-mg immediate-release oxybutynin tablet every 8 hours for 5 days. The washout period between treatments was > or =7 days. The mean steady-state AUC for oxybutynin following controlled-release oxybutynin treatment was higher (73.0 ng.h/mL) than following immediate-release oxybutynin treatment (53.6 ng.h/mL) (P = .0001). The mean C(max) was lower for controlled-release oxybutynin (5.7 ng/mL) than for immediate-release oxybutynin (7.5 ng/mL) (P = .0051), with a smaller fluctuation in oxybutynin plasma concentration for controlled-release oxybutynin (135.6%) than for immediate-release oxybutynin (319.3%) (P = .0001). Mean stimulated saliva output was greater for controlled-release oxybutynin, and mean dry mouth severity was less than immediate-release oxybutynin.     

Multiple-dose pharmacokinetics of naproxen from a controlled-release tablet in healthy volunteers

The pharmacokinetics of a new controlled-release tablet of naproxen (750 mg) given once daily has been studied in healthy volunteers, in comparison with two doses of the conventional naproxen tablets (375 and 500 mg) administered twice daily. Steady-state plasma concentrations of naproxen were achieved after two days of repeated administration of both the controlled-release and the conventional tablets. On day seven, peak concentration, cowest concentration and the steady-state average plasma concentration values of the controlled-release tablet were significantly higher than those of 375 mg conventional tablet and comparable to those of 500 mg conventional tablet. Areas under the plasma concentration-time curve indicated an equal extent of absorption between the new and the conventional formulation. Overall the controlled-release tablet administered once daily mimicked a twice daily regimen so suggesting that the new formulation could be suitable for once daily dosing.     

Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers

Objective: To study the influence of the lipase inhibitor orlistat on the pharmacokinetics of the antihypertensive drugs atenolol, furosemide, captopril and nifedipine. Methods: Four open-label, crossover studies were performed on six to eight healthy male volunteers. Orlistat was given in doses of 50 mg 3 times daily mid-meal for 7 (nifedipine and captopril) or 8 days (atenolol and furosemide). The four antihypertensive drugs (atenolol 100-mg tablet, furosemide 40-mg tablet, captopril 50-mg tablet and nifedipine 20-mg slow-release tablet) were administered in single doses twice, once before and once together, with orlistat at the end of the orlistat treatment period. Results: The plasma concentration time profiles and the pharmacokinetic parameters estimated for these drugs were in the expected range, except for furosemide, whose bioavailability was lower than reported in the literature. This was probably due to the fact that furosemide was given during a meal. There were minor, but statistically significant, differences in one of the pharmacokinetic parameters of furosemide and nifedipine (no difference for captopril and atenolol) when these drugs were given alone and in combination with orlistat: the half-life of furosemide was slightly longer, the time to peak plasma concentrations of nifedipine was slightly longer. None of these are considered to be clinically significant changes. Conclusions: The lipase inhibitor orlistat given 50 mg 3 times daily does not alter the pharmacokinetics of atenolol, furosemide, nifedipine and captopril to a clinically significant extent. Received: 15 November 1995/Accepted in revised form: 22 February 1996     

Doxazosin gastrointestinal therapeutic system: a review of its use in benign prostatic hyperplasia

Doxazosin, a well established treatment in patients with bothersome lower urinary tract symptoms from benign prostatic hyperplasia (BPH), is available in a new controlled-release formulation, doxazosin gastrointestinal therapeutic system (GITS). Doxazosin GITS (Cardura XL, Cardular PP Uro, Diblocin PP Uro) has an altered pharmacokinetic profile, which allows a higher initial dosage to be used than with the standard formulation and less titration steps to reach a clinically effective dosage. In two large, double-blind, randomised studies (one was placebo-controlled) in patients with BPH, doxazosin GITS (4-8 mg once daily) was as effective as the standard formulation (2-8 mg once daily), and both were more effective than placebo, after 13 weeks' treatment in improving symptom scores, health-related quality of life (HR-QOL), and maximum urinary flow rate (Qmax). Doxazosin GITS was at least as well tolerated as the standard formulation of doxazosin in clinical studies in patients with BPH.     

A multiple-dose pharmacokinetic comparison of naproxen as a once-daily controlled-release tablet and a twice-daily conventional tablet

The bioequivalence and absorption kinetics of naproxen in a new controlled-release tablet (750 mg or 1,000 mg naproxen) administered once daily were determined relative to an equivalent dose of the conventional naproxen tablet (375 mg or 500 mg naproxen) administered q12h. Naproxen was well absorbed from the controlled-release tablet (about 90%) compared with the conventional tablet. Absorption was dependent on drug release from the tablet matrix. The mean absorption time of naproxen averaged 8.4 hours for the 750-mg controlled-release tablet and 9.2 hours for the 1,000-mg controlled-release tablet. Once-daily administration of the controlled-release tablet resulted in equivalent trough concentrations of naproxen, and steady-state plasma concentrations were maintained within narrower limits than with twice-daily naproxen.     

Relative bioavailability of a controlled-release albuterol formulation for twice-daily use

A two-way-crossover bioavailability study was completed with 15 healthy male volunteers to evaluate the relative bioavailability of an orally administered controlled-release (CR) formulation of albuterol as compared to the immediate-release (IR) formulation of albuterol. The CR formulation of albuterol used in this study was based mechanistically on the elementary osmotic pump. Each subject received one 8 mg CR tablet every 12 h for 8 consecutive days and one 4 mg IR tablet every 6 h for 8 consecutive days, with 7 days separating each phase. During day 8 of dosing, hourly blood samples (0-12 h) were collected after the morning dose and three additional samples were obtained 16, 20 and 24 h following this dose. Plasma concentrations were measured using a gas chromatography-mass spectrometry procedure. No statistically significant differences were observed in mean steady-state values for Cmax, Cmin, AUC(0-12 h) and peak-to-trough fluctuations (PTF) in comparing the two dosage formulations. Mean steady state Tmax values were 2.6 and 6.0 h for the TR and CR formulations, respectively. It was concluded that twice daily administration of the controlled-release formulation of albuterol provides an alternative to four times daily administration of conventional (immediate-release) albuterol tablets.     

Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus

This study was designed to compare the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide GITS (Glucotrol XL) given in a dosage of 20 mg once daily with that of immediate-release glipizide (Glucotrol) 10mg twice daily in patients with type II diabetes mellitus. In an open-label, randomized, two-way crossover study, each glipizide formulation was administered for 5 days. Serial blood samples were drawn at baseline and on the 5th day of each treatment phase for measurement of glipizide, glucose, insulin, and C-peptide concentrations. At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Although the mean Cmin with glipizide GITS was about 80% higher than with immediate-release glipizide, the mean AUC0-24 was significantly lower. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects.     

Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days).     

Formulation dependent pharmacokinetics--does the dosage form matter for nifedipine?

This was an open-label, randomized, 3-way crossover study that compared in 25 healthy male subjects, the pharmacokinetics of a single 60-mg dose of nifedipine GITS tablet versus (1) 20-mg doses of nifedipine prolonged action tablets given q12h for a total of two doses and (2) 2 x 10 mg doses of nifedipine capsules given q8h for a total of three doses. Following capsule administration, there was a rapid rise in plasma concentration of drug achieving a peak concentration of 196(35) ng/mL (mean and coefficient of variation) within 0.7 (105) hours and an AUC(infinity) of 973(39) ng.hr/mL. After nifedipine PA there was also a rapid rise in plasma concentration of drug achieving a Cmax of 85.5 (36) ng/mL with a tmax of 1.7(58) hours and an AUC(infinity) of 879(46) ng.hr/mL. For the nifedipine GITS formulation, there was a lag in the plasma concentration time profile for approximately 2 to 3 hours, then it rose gradually achieving a Cmax of of 686(54) 30.5(63) ng/mL with a tmax of 15.0(50) hours and an AUC(infinity) ng.hr/mL. The AUC(infinity) and Cmax were significantly (P = 0.0001) greater in the capsule and PA formulations than for the GITS; however, the tmax for the GITS formulation was significantly (P = 0.001) longer than for the other formulations.This study suggests marked formulation-dependent pharmacokinetics, which may have important clinical implications.     

Analysis of Nifedipine Absorption from Soft Gelatin Capsules Using PBPK Modeling and Biorelevant Dissolution Testing

Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat® 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat® 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach.     

Combination of lisinopril and nifedipine GITS increases blood pressure control compared with single drugs in essential hypertensive patients

The present study was designed to evaluate the effect of combination therapy using the angiotensin-converting enzyme-inhibitor lisinopril and the dihydropyridine calcium antagonist nifedipine GITS on the degree and homogeneity of 24-hour blood pressure reduction in essential hypertensive patients. After a 4-week placebo run-in period, 51 patients (mean age, 54.4 +/- 9.4 years) with essential hypertension and clinic diastolic blood pressure between 105 and 115 mm Hg were randomized to 4-week treatment with lisinopril (20 mg), nifedipine GITS (30 mg), or their combination according to a multicenter, randomized, double-blind, crossover study. Trough clinic blood pressure and 24-hour ambulatory blood pressure were measured at the end of the run-in period and after 4 weeks of treatment. In addition to clinic and 24-hour average blood pressure reduction, the trough-to-peak ratio and the smoothness index, a new measure for the homogeneity of blood pressure reduction, were also calculated. Although both lisinopril and nifedipine GITS produced a significant reduction in clinic and 24-hour average blood pressure values, the reduction obtained with the combination was significantly (P < 0.001) greater. Moreover, the combination therapy increased (P < 0.01) the smoothness index as compared with each single drug for both systolic (lisinopril, 1.02; nifedipine GITS, 1.1; combination, 1.76) and diastolic (lisinopril, 0.98; nifedipine GITS, 0.87; combination, 1.54) blood pressure values, whereas trough-to-peak ratio values (expressed as median) for systolic (lisinopril, 0.41; nifedipine GITS, 0.52; combination, 0.55) and diastolic (lisinopril, 0.35; nifedipine GITS, 0.40; combination, 0.49) blood pressure values were not significantly increased by the combination therapy. Thus, antihypertensive treatment with the combination of lisinopril and nifedipine GITS is more effective and balanced over the 24 hours than the combination components administered alone, confirming that the smoothness index is superior to the trough-to-peak ratio in assessing homogeneity of pharmacologic blood pressure reduction.     

A comparison of the anticholinergic effects of two formulations of disopyramide in healthy volunteers

Eight healthy male volunteers took a single oral dose of one of the following: Rythmodan (conventionally formulated disopyramide) 150 mg; Rythmodan 250 mg; Rythmodan Retard (controlled-release disopyramide) 250 mg; placebo. The subjects were allocated double-blind to sessions and treatments according to a Latin square design. In each session pupil diameter, heart rate, salivation, and QT interval were measured immediately before and at 1, 2, 3, 4, 6, 8, and 24 h after the drug. QT interval was corrected for heart rate (QT60). Plasma concentrations of total and unbound disopyramide were also determined at each time point. Both formulations of disopyramide reduced salivary output and increased QT60 interval, but there was not significant difference between the effects of the three active treatments. Neither formulation had any effect on pupil diameter or heart rate. The peak plasma concentration of unbound disopyramide was reached 2 h after Rythmodan and 4 h after Rythmodan Retard. The peak plasma concentration of disopyramide was significantly lower after Rythmodan Retard 250 mg than after Rythmodan 250 mg. The plasma concentration of unbound disopyramide was positively correlated with the reduction in salivation and prolongation of the QT60 interval. The reduction in salivation is likely to reflect blockade of muscarinic receptors by disopyramide, whereas the increase in QT60 interval is likely to be related to a direct effect of the drug on the heart. The results of this single-dose study do not indicate that disopyramide in the controlled-release formulation would be better tolerated by patients than conventionally formulated disopyramide.     

The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast

AIMS: The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH-dependent differences in the in vitro release properties of the two dosage forms. METHODS: This was a randomized, open, 4-way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat OROS or Slofedipine XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC-MS/MS method. Calculation of pharmacokinetic parameters was conducted model-independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat-bottomed glass vessels, with various buffer systems covering the entire physiological pH-range of the gastrointestinal tract. RESULTS: After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,infinity) was slightly lower for Slofedipine XL compared with Adalat OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine XL compared with Adalat OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine XL which resulted in lag-times of more than 15 h in 15 out of 24 subjects. Owing to this lag-time under fed conditions the relative bioavailability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 h. CONCLUSIONS: In this study a dosage form-dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine XL and Adalat OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine XL is administered after a high-fat breakfast may be explained by the formulation properties. Slofedipine XL is an erosive tablet with an acid resistant coating whereas Adalat OROS is designed with an osmotic push-pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push-pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.     

Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1- and 3-demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1- and 3-demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.     

硝苯地平控释片与缓释片治疗高血压疗效比较

目的 探讨硝苯地平缓释剂(SR)与硝苯地平控释剂(GITS)治疗原发性高血压的临床疗效.方法 将160例原发性高血压2级患者随机分为SR组和GITS组.SR组给予硝苯地平缓释片20 mg,2次/d;GITS组给予硝苯地平控释片30 ng,1次/d.两组均治疗8周,并对所有患者进行动态血压监测(ABPM),观察治疗前后两组患者的24 h平均血压、心率、谷/峰(T/P)值的变化及不良反应等情况.结果 治疗后GITS组收缩压(SBP)、舒张压(DBP)的T/P比值分别为68.5％、74.6％,均高于SR组的57.2％、61.1％(x2=6.32、7.05,均P＜0.05);GITS组心率低于SR组(t=4.17,P＜0.05);两组不良反应差异无统计学意义(x2=0.16,P＞0.05).结论 SR与GITS均能有效降压,但GITS更高效、平稳、安全,对心率的影响小.     

Reproducibility of nifedipine absorption from GITS tablets: comparison of single-dose pharmacokinetics using 10, 20, 40 and 60 mg nifedipine

OBJECTIVE: To examine the reproducibility of nifedipine absorption from gastrointestinal therapeutic system (GITS) tablets by comparing the single-dose pharmacokinetic profiles of 4 different dosages administered orally. METHODS: Twelve healthy male volunteers, aged between 22 and 29 years were enrolled in the open, 4-way, dose escalation study with single oral doses of 10, 20, 40 and 60 mg (two 30 mg) nifedipine GITS tablets. Each administration was separated by a 1-week washout period. Coefficients of variation (CV) of dose-corrected area under the concentration-time curve (AUC) and peak plasma drug concentrations (Cmax) were calculated from the pharmacokinetic profiles. RESULTS: Mean AUC and mean Cmax were dose-proportional from 10 to 60 mg. Although the CV of 4 mean dose-corrected AUC and Cmax were 5.5% and 17.5%, respectively, CV of dose-corrected AUC and Cmax in each subject varied from 5.1 to 37.4% (mean 11.0%) and from 14.1% to 46.4% (mean 25.8%), respectively. CONCLUSIONS: Whereas mean plasma nifedipine concentration remained markedly stable over a 16- to 24-hour interval and mean dose-corrected AUC showed good reproducibility with nifedipine GITS, the CV of dose-corrected AUC of the nifedipine GITS tablets in each subject showed large variability.     

Comparative bioavailability of two tablet preparations of diltiazem in healthy volunteers.

Comparative bioavailability of two formulations of diltiazem (Dilzene, CAS 42399-41-7), a calcium antagonist, was evaluated on 10 healthy volunteers (5 males and 5 females) in a cross-over study. A single dose of 120 mg of diltiazem was administered to the volunteers in the form of either two 60-mg tablets or a 120 mg controlled-release tablet. Plasma concentrations of diltiazem over a 24-h time interval were determined by HPLC analysis. Results of this investigation demonstrate that the controlled-release formulation of diltiazem has a lower Cmax value when compared to the 60 mg conventional tablet formulation, but a longer tmax and a superimposable AUC.     

Pharmacokinetic evaluation of conventional and controlled release dosage form of propranolol

A comparative pharmacokinetic study of a new controlled release multiple unit propranolol formulation and a conventional propranolol tablet was carried out in twelve healthy human volunteers in a randomized balanced crossover design. Under a single dosage regimen, subjects were administered either a single capsule containing controlled release propranolol equivalent to 160 mg of the drug or 80 mg of conventional propranolol tablet, twelve hourly. Peak plasma propranolol concentrations were low which occurred later after controlled release administration than after the administration of the conventional tablet. Analysis of the area under the plasma concentration-time curve (AUC) for the two formulations indicate no significant difference of bioavailability despite a prolonged absorption time and maintenance of effective plasma concentration for the controlled release preparation.