Multiple-dose Oral Administration Research Articles

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration.

To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. 7 sexually intact, female, mixed-breed dogs. A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.

Sex Differences in the Pharmacokinetics of Dehydroepiandrosterone (DHEA) after Single‐ and Multiple‐Dose Administration in Healthy Older Adults

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.

A pharmacokinetic simulation model for ivabradine in healthy volunteers

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of this study is to develop a pharmacokinetic simulation model. Pharmacokinetic data from two studies were pooled and included data from a total of 66 healthy male volunteers. The data were collected following single dose intravenous and multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h and there were seven active dosing levels. The modelling was performed using the NONMEM software. The model was assessed in terms of its ability to describe the original data set used in its construction and also data arising from a different clinical pharmacology study involving 12 additional subjects. The pharmacokinetics of ivabradine and S-18982 were best described by two linked two compartment intravenous bolus and first-order input, with first-pass loss, and first-order output model. When the model was used for simulation it produced an adequate description of both the original data and data arising from a different clinical pharmacology study.

Development of a sequential linked pharmacokinetic and pharmacodynamic simulation model for ivabradine in healthy volunteers

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of the study was to develop a linked pharmacokinetic–pharmacodynamic simulation model for the description of exercise-induced heart rate. The pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. The data consisted of multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h. There were eight active dosing levels and placebo, and a no-dose run in the period before each study. The modelling was performed using the NONMEM software. Both ivabradine and S-18982 possess bradycardic activity, although the extent of the activity of both could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data. The model was assessed in terms of its posterior predictive performance and was able to describe the original data adequately when used for simulation purposes.

The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency.

Carvedilol, a chiral compound possessing nonselective beta- and alpha1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar alpha1-blocking activity; only S-carvedilol possesses beta-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug. The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR < or = 30 ml x min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2 9) dosing. Mean with (SD) AUC(0-24h) (ng x h x ml(-1)) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng x ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0-24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree. Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.

Risedronate pharmacokinetics upon multiple dose oral administration to postmenopausal women for six months

Risedronate pharmacokinetics upon multiple dose oral administration to postmenopausal women for six months

Pharmacokinetics of Intravenous and Oral Losartan in Patients with Heart Failure

The pharmacokinetics of a selective AT1-subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady-state was 34 L, and terminal plasma half-life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple-dose oral administration for 7 to 8 days. Terminal plasma half-life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Disposition of cyproheptadine in cats after intravenous or oral administration of a single dose

SUMMARY Objective To determine disposition of cyproheptadine hydrochloride in cats after intravenous or oral administration of a single dose. Animals 6 healthy cats. Procedure A randomized crossover design was used, and each cat was studied after intravenous (2 mg) and oral (8 mg) administration of cyproheptadine. Blood samples were collected at fixed time intervals after drug administration, and serum cyproheptadine concentration was determined by means of polarized immunofluorescence. Results Mean (± SD) residence time was significantly longer after oral (823 ± 191 minutes) than after intravenous (339 ±217 minutes) administration, but no significant differences were detected between other pharmacokinetic parameters after oral and intravenous administration. Mean ± SD oral bioavailability was 1.01 ± 0.36. Mean elimination half-life after oral administration was 12.8 ± 9.9 hours. Peak extrapolated cyproheptadine concentration was 669 ± 206 ng/ml. Only 1 cat developed adverse effects (transient vocalization). Conclusions Cyproheptadine appeared to be well tolerated in cats and had high bioavailability after oral administration. The mean elimination half-life of 12 hours indicated that approximately 2.5 days must elapse to achieve steady-state concentrations of cyproheptadine after oral administration of multiple doses. A 12-hour dosing interval is acceptable, but an 8-hour interval may be indicated for some cats. Clinical Relevance On the basis of pharmacokinetic parameters determined in this study, the oral form of cyproheptadine appears to be suitable for use in clinical trials to treat anorexia in cats. Its half-life is compatible with once or twice daily dosing. (Am J Vet Res 1998;59:79–81)

Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites.

The object of this study is to evaluate the effects of age, gender, age-by-gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady-state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple-dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC0-24 (area under plasma concentration-time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age-by-gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log-probit plots. Age, gender, age-by-gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC0-24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady-state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC0-24 and Cl/F, the explanatory power of the overall model was weak (R2 < 0.2). Log-probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady-state pharmacokinetics of troglitazone and its metabolites.

Pharmacokinetics of Tropatepine in Healthy Volunteers

Tropatepine is a compound with central anticholinergic properties that has been used in the treatment of neuroleptic-induced extrapyramidal syndrome. In this study, we report the plasma pharmacokinetics of tropatepine after intravenous and oral administration (20mg) in 8 healthy volunteers, after oral administration of different doses (10, 15 and 20mg) in 12 healthy volunteers, and following administration of multiple dosages of the drug (20mg/day) in 2 healthy volunteers. Pharmacokinetic parameters of tropatepine and the desmethylated active metabolite nortropatepine were estimated. Clearance following intravenous administration (19 \+- 4 L/h) and after multiple-dose oral administration (27 to 28 L/h) were stable given a bioavailability of 76.1 \+- 24%. A good correlation was found between dose (10, 15 and 20mg) and maximum plasma concentration (Cmax) [6.5 \+-4.5 \gmg/L, 8.5 \+- 6.2 \gmg/Land 18.2 \+- 8.2 \gmg/L, respectively] and total quantity of tropatepine excreted in urine over a period of 120 hours (200 \+- 67\gmg, 254 \+- 93\gmg and 351 \+- 139\gmg, respectively). Such a correlation and the stable clearance confirmed a good linearity in plasma concentrations. Time to reach Cmax (tmax) was 6 to 7 hours for tropatepine and nortropatepine. This delay and the half-life of tropatepine (around 40 hours) were long enough to allow daily administration. However, plasma concentrations varied from a Cmax of 29 \+- 1.4 \gmg/L to a Cmin of 13.8 \+- 1.1 \gmg/L. This doubling in concentration led to the fractionation of the daily dose. Divisible tablets of 5mg have been prepared by Diamant Laboratories. Since the half-life of nortropatepine is long (65.5 \+- 7.95 hours), the range of variations in plasma concentration was smaller than that of tropatepine, i.e. between a Cinmin of 6.5 \+-1.5 |J.g/L and a Cinmax of 9.5 \+- 3.2 \gmg/L. Tropatepine undergoes important metabolism, but nortropatepine is not the main metabolite. After multiple-dose administration, the ratio of urinary excretion of nortropatepine to tropatepine was higher (152%) than that after single-dose administration (62%).

Concentrations of trovafloxacin in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum after administration of single or multiple oral doses to patients undergoing fibre-optic bronchoscopy.

Concentrations of trovafloxacin were measured in serum, alveolar macrophages, epithelial lining fluid and bronchial mucosa following single and multiple oral doses. Concentrations were determined using a microbiological assay method. There were 18 subjects in the single dose and nine subjects in the multiple dose groups. After single dosing, mean concentrations in serum, alveolar macrophages, epithelial lining fluid and bronchial mucosa at 6, 12 and 24 h were as follows: 6 h, 1.41 mg/L, 19.06 mg/L, 3.01 mg/L and 1.52 mg/kg; 12 h, 0.85 mg/L, 16.22 mg/L, 4.8 mg/L and 1.01 mg/kg; 24 h, 0.37 mg/L, 10.23 mg/L, 0.93 mg/L, and no measurable concentration, respectively. After multiple dosing (approximately 6 h post-dose) the corresponding concentrations were 1.47 mg/L, 34.3 mg/L, 10.21 mg/L and 1.67 mg/kg, respectively. These concentrations exceed the MIC90s for the common respiratory pathogens, Haemophilus influenzae 0.06 mg/L, Moraxella catarrhalis 0.008 mg/L and Streptococcus pneumoniae 0.12 mg/L and suggest that trovafloxacin should be efficacious in the treatment of community- and hospital-acquired respiratory infections.

Lansoprazole pharmacokinetics in subjects with various degrees of kidney function.

The pharmacokinetics of lansoprazole, a new benzimidazole proton pump inhibitor, was evaluated after multiple-dose oral administration to 20 subjects with various degrees of kidney function. Multiple blood samples were obtained after doses 1 and 7 of the once-daily seven-dose regimen, and plasma concentrations of lansoprazole and five metabolites were quantitated with use of HPLC. The free fraction of lansoprazole increased as kidney function declined. A significant, although weak, relationship existed between creatinine clearance (CLCR) and area under the plasma concentration versus time curve (AUC) and terminal disposition half-life (t1/2), calculated with total concentration data. Those individuals with lower CLCR values also had lower total AUC and t1/2 values. However, there was no statistically significant relationship between CLCR and peak plasma concentration or AUC, calculated with unbound concentration data. No adjustment of lansoprazole dose is recommended on the basis of impaired kidney function.

Assessment of Doxylamine Influence on Mixed Function Oxidase Activity upon Multiple Dose Oral Administration to Normal Volunteers

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmaco-kinetics and 6β-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5mg of doxylamine succinate, placebo, or 30mg of phenobarbital administered orally every 6h for 17days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45mL/h/kg) and nonrenal (35 versus 44mL/h/kg) clearances and 6β-hydroxycortisol excretion (338 versus 529 µg) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Safety, Tolerance, and Preliminary Pharmacokinetics of Nefazodone After Administration of Single and Multiple Oral Doses to Healthy Adult Male Volunteers: A Double‐Blind, Phase I Study

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double-blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5-500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-escalation period, the subjects in the multiple daily dose segment underwent a 3-day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0-8 that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well-tolerated by patients receiving expected therapeutic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.

Absorption Pharmacokinetics of Atenolol in Patients with the Marfan Syndrome

The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral administration of multiple doses to patients with the Marfan syndrome. We studied the pharmacokinetics of atenolol in 13 such patients aged 18.7 +/- 2.9 years who were receiving 1.78 +/- 0.58 mg/kg/day (70.1 +/- 20.3 mg/m2/day) of atenolol for 6 weeks or longer. Mean +/- SD percentage change in baseline heart rate after the administration of atenolol was -18.03 +/- 16.59% and mean +/- SD percentage change in exercise heart rate after atenolol was -33.22 +/- 14.75% (P < .01). Six to 8 atenolol serum concentrations were collected in each patient during a 12-hour dosing interval and were determined by high-performance liquid chromatography with ultraviolet detection. Serum atenolol concentrations at 0 (123 +/- 70 micrograms/L) and 12 (116 +/- 66 micrograms/L) hours were within 20% of each other and were thus assumed to be at steady-state. A one-compartment, steady-state pharmacokinetic model with first-order absorption and elimination was fitted to the concentration-time data for each patient using nonlinear regression. Maximal concentration was 343 +/- 120 micrograms/L, and the mean half-life was 4.72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of Pharmacokinetic Interaction between Zileuton and Phenytoin in Humans

A randomised double-blind crossover study was undertaken in 20 healthy adult male volunteers to assess the effects of multiple oral dose administration of zileuton (600mg every 6 hours for 8 days) on the single dose pharmacokinetics of phenytoin 300mg. Serial blood samples were collected up to 72 hours after phenytoin administration and plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic data were analysed utilising noncompartmental and Michaelis-Menten-based population pharmacokinetic analysis. Zileuton did not significantly alter the peak plasma concentration, time to peak plasma concentration, and area under the plasma concentration-time curve of phenytoin. Moreover, population analysis revealed no significant effect of zileuton on the Michaelis-Menten parameters of phenytoin. Thus, coadministration of multiple doses of zileuton (2.4 g/day) did not significantly affect the single dose pharmacokinetics of phenytoin.

Bioavailability of single and multiple doses of a new oral formulation of 5‐ASA in patients with inflammatory bowel disease and healthy volunteers

An oral multiparticulate coated formulation of 5-aminosalicylic acid (5-ASA: mesalazine) has been developed to provide a controlled release of the drug, in a pH-dependent fashion, in the distal ileum and colon. The purpose of the present study was to assess the systemic availability of the drug and its metabolite, acetyl-5-ASA, following single (800 mg) and multiple (2400 mg for 56 days) oral dose administration. Three groups were investigated: six healthy volunteers, six patients with ulcerative colitis, and nine patients with Crohn's disease in remission. In the single oral dose study (800 mg) all three groups participated, whereas in the multiple oral dose study (2400 mg/day for 56 days) only the patients with inflammatory bowel disease took part. Plasma and urine 5-ASA and Ac-5-ASA were measured for 48 h. In the single oral dose regimen, systemic absorption of 5-ASA and Ac-5-ASA were low and did not differ between the three groups. Only about 20% of the 5-ASA given was absorbed, with more than 80% of the drug being available in the terminal ileum and colon for therapeutic activity. The multiple oral dose regimen in patients with inflammatory bowel disease produced a significantly higher plasma concentration and urine excretion of both 5-ASA and Ac-5-ASA by the end of the treatment, in comparison to the first dose. There was a statistically higher systemic absorption of 5-ASA in patients with ulcerative colitis than in patients with Crohn's disease. After 56 days of dosing, no adverse event was reported and laboratory screening tests remained within normal ranges. The new oral 5-ASA formulation is gradually released throughout the small and large intestine, reflected by a low plasma concentration of the drug and its metabolite, with about 80% of the drug being available for ileum-colon therapeutic activity.

Single and Multiple Dose Pharmacokinetics of a Sustained-Release Formulation of Bunazosin (E1015) in Healthy Young and Elderly Volunteers

The results of 1 multiple dose and 2 single dose pharmacokinetic studies of sustained-release bunazosin (Bunazosin Retard®) 6mg in healthy elderly (n = 47) and healthy young (n = 12) volunteers are suggestive of an age-related difference in the drug’s disposition. Area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) values were significantly higher [AUC: x 1.9 (male) and x 1.9 (female); Cmax x 2.0 (male) and x 1.9 (female)] in the elderly than in their younger counterparts. This difference in AUC0-48h and Cmax values appeared to be due to reduced bunazosin clearance in the elderly. Steady-state plasma bunazosin concentrations in elderly volunteers (n = 12) were achieved 9 days after initiating multiple oral dose administration of Bunazosin Retard® 6mg once daily. There was no evidence of further bunazosin accumulation after 8 days of oral dose administration.

Multiple Oral Dose Pharmacokinetic and Pharmacodynamic Study of a Sustained-Release Formulation of Bunazosin (E1015) in Healthy Volunteers

The results of short term (8-day) and longer term (28-day) pharmacokinetic studies in healthy male volunteers (n = 27) indicate that steady-state plasma bunazosin concentrations are achieved within 8 to 14 days on initiating multiple oral dose administration of a sustained-release formulation of bunazosin (Bunazosin Retard®) 6mg once daily. There is no evidence of bunazosin accumulation with multiple oral dose administration.