Efficacy and tolerability of flupirtine in subacute/ chronic musculoskeletal pain - results of a patient level, pooled re-analysis of randomized, double-blind, controlled trials.

INTRODUCTION: Flupirtine, a nonopioid analgesic without antipyretic or antiphlogistic properties, constitutes a unique class within the group of WHO-I analgesics. First approved in Germany on a national level in 1989, this selective neuronal potassium channel opener evolved rapidly into one of the most preferred analgesics for the treatment of musculoskeletal pain in some European countries. However, its use outside Europe was limited due to a discrepancy between the empirical application of the drug and supporting evidence. As a consequence, the German Pain Society commissioned an independent research institute to perform a pooled re-analysis of all available data from randomized controlled trials (including some trial not yet published). METHODS: A retrospective pooled analysis of the individual patient data from 8 randomized controlled Phase III - IV clinical trials was carried out which included patients with sub-acute and chronic musculoskeletal pain. The efficacy and tolerability of flupirtine at dosages of 100 - 400 mg/d were compared to placebo and/or active comparators. Data were pooled by treatment and by subject. The primary endpoint was the average change in pain intensity for the overall maintenance period. RESULTS: A total of 1,046 patients was evaluated for efficacy and 1,095 patients for safety. Based on 3,337 pain assessments, treatment with flupirtine and active comparators resulted in significant reductions in pain intensity compared to baseline beginning from Day 4 (flupirtine) and Day 5 (comparators) and continuing up to the end of the study period as well as during the overall maintenance period (all p < 0.001). Flupirtine prooved to be non-inferior to the active comparators (p < 0.001) but showed a superior tolerability profile with a significantly lower number of patients reporting treatment emergent adverse events (28.6 vs. 39.1%, p < 0.001) and a significantly lower percentage of patients who prematurely discontinued study medication due to these adverse events (7.1 vs. 11.7%, p = 0.013). LIMITATIONS: The limitations in the study were confined to those inherent in the retrospective and pooled analysis design. CONCLUSION: On the basis of this pooled analysis of individual data from 8 controlled clinical trials involving patients suffering from sub-acute/chronic musculoskeletal pain, the efficacy of flupirtine was superior to placebo across its effective and approved dosage range. Flupirtine was at least as active as the active comparators and showed a superior tolerability profile with a significantly lower treatment discontinuation rate.

Analgesic efficacy and tolerability of flupirtine vs. tramadol in patients with subacute low back pain: a double-blind multicentre trial*.

OBJECTIVE: To assess the efficacy and tolerability of flupirtine in comparison with tramadol for the treatment of moderate to severe subacute low back pain (LBP). DESIGN AND METHODS: In this randomised, double-blind, parallel-group trial, 209 LBP patients, aged 18-65 years, were orally treated with flupirtine 100 mg (n = 105) vs. tramadol 50 mg (n = 104), both three times daily for 5-7 days. MAIN OUTCOME MEASURES: Patient assessment of pain intensity after 5-7 days (primary); physicians' global assessment of improvement in pain and functional capacity; adverse events. RESULTS: Flupirtine showed an overall pain-relieving efficacy comparable to tramadol. Mean LBP intensity after end of treatment dropped from 6.8 (95% CI: 6.5-7.0) to 2.8 (95% CI: 2.3-3.1) for flupirtine and from 6.9 (95% CI: 6.6-7.1) to 3.0 (95% CI: 2.6-3.4) for tramadol, corresponding to pain relief rates of 57% (95% CI: 51-63%) and 56% (95% CI: 50-62%) respectively (p = 0.796), indicating non-inferiority of flupirtine. All other efficacy endpoints supported equivalent efficacy. Adverse events (AEs) occurred significantly less in patients after flupirtine (33%) vs. tramadol (49%) (p = 0.02) and both the respective severity grading and the AE-related dropout rates were significantly lower after flupirtine than after tramadol (1% vs. 15%, p < 0.001). CONCLUSION: Flupirtine 100 mg three times daily was associated with a reduction in pain and improvements in functional capacity equivalent to that observed with tramadol 50 mg three times daily, and was better tolerated, when administered to patients with subacute back pain for one week. The limitations of this study were the lack of a placebo control and the short (7-day) duration of the study.

Anti-anginal and anti-ischemic effects of the selective beta-blocker talinolol in patients with stable angina pectoris.

OBJECTIVE: To determine the dose dependency of the anti-anginal and antiischemic effects of the selective beta-blocker talinolol administered once-daily in a randomized, double-blind, placebo-controlled multicenter study in patients with stable angina pectoris. METHODS: Standardized bicycle ergometry at baseline and after 3 and 6 weeks of treatment was used to assess exercise capacity. The primary endpoint was the change in the maximum exercise time (MET) 24 +/- 1 h after the last intake of study medication compared to baseline. Secondary efficacy parameters were time to onset of angina, time to 1 mm ST segment depression, angina attacks, consumption of short-acting nitrates, blood pressure and pulse rate. Patients were randomly allocated to treatment with talinolol (100, 200 or 300 mg once daily) or placebo for a period of 6 weeks. RESULTS: A total of 241 outpatients (204 male and 37 female) aged between 34 and 83 years, were randomized in 31 centers in Germany, Poland and the Czech Republic. At the end of treatment, the primary endpoint (change in MET compared to baseline) showed no significant difference between the talinolol groups and placebo. The means of MET prolongation ranged from 27.4 sec under placebo to a maximum of 47.6 sec in the 200 mg group. However, the time to 1 mm ST segment depression during exercise increased markedly with talinolol, the difference to placebo reaching statistical significance with the 200 mg/d dose (80.1 +/- 32.7 sec, p = 0.0182) and 300 mg/d dose (82.0 +/- 31.6 sec, p = 0.0127). In the case of the other secondary variables, the most pronounced effects were recorded for talinolol doses of 200 and 300 mg/d. Talinolol significantly inhibited the exercise-induced increase in heart rate and blood pressure. The decrease in rate pressure product at 100 W workload was statistically significant with all administered talinolol doses (delta from baseline to final visit 3090, 4351 and 4291 for 100, 200 and 300 mg/d, respectively, p < 0.0001). Despite once-daily dosing, talinolol at doses up to 300 mg/d was very well tolerated. No unexpected adverse drug reactions were observed. CONCLUSION: The results show that talinolol administered once daily in a dosage of 200 - 300 mg/d is effective and safe in the management of chronic stable angina.

Pharmacokinetics of oral talinolol following a single dose and during steady state in patients with chronic renal failure and healthy volunteers.

OBJECTIVE: The objective of this study was to investigate the effect of renal impairment on the pharmacokinetics of the selective beta1-receptor antagonist talinolol. METHODS: Pharmacokinetic data were obtained in 12 healthy volunteers, 12 patients with renal impairment and 8 patients with terminal renal insufficiency after the oral administration of 100 mg talinolol and under steady state conditions (100 mg talinolol daily). Concentrations of talinolol in plasma, urine and dialysate during hemodialysis were measured with a validated HPLC-method. RESULTS: Talinolol is absorbed quite rapidly from the gastrointestinal tract (tmax 2.5-4 h). Steady state conditions were reached within 3-4 days depending on renal function. The calculated mean elimination half-life (t(1/2z)) in healthy volunteers (11 male, 1 female) was about 12 h. After an oral dose of 100 mg, about 55% of the bioavailable talinolol is eliminated unchanged in the urine. This fraction is reduced to 25% in patients with moderate to severe renal failure. A strong correlation was found between the renal elimination of talinolol and creatinine clearance. In patients with renal failure, the delayed elimination leads to an increase in t(1/2z) and to a decrease in the apparent total body clearance. Steady state trough levels (c(min)ss) in these patients are about 2.2-fold higher than in volunteers. The hemodialysability of talinolol was low. CONCLUSION: The disposition of talinolol shows a strong dependence on the renal function. On the basis of the kinetic data for talinolol, dose reductions of 30-50% are recommended in subjects with moderate to severe renal impairment.

Bioavailability of a new effervescent tablet of diclofenac.

OBJECTIVE: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). SUBJECTS AND METHOD: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-infinity and Cmax. RESULTS: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean +/- SD) for DIC-effervesc is 950+/-341 ng/ml (first Cmax) and for DIC-enteric 1364+/-335 ng/ml. The mean AUC0-infinity, (arithm. mean +/- SD) amounts to 1097+/-210 ng/ml x h for DIC-effervesc and 1262+/-220 ng/ml x h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 - 91.3%). DIC-effervesc was well tolerated. CONCLUSION: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragee. A rapid onset of therapeutic effect is postulated in acute pain disorders.

Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction.

BACKGROUND: P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a beta1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings. METHODS: Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1-messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years). RESULTS: During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001). CONCLUSIONS: Rifampin induces P-glycoprotein-mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism.

Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein.

OBJECTIVE: Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein. METHODS: Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively. RESULTS: Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration. CONCLUSION: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.

[Antihypertensive action of various talinolol dosages after four week's treatment in comparison with placebo]. / Antihypertensive Wirksamkeit verschiedener Talinolol-Dosierungen nach vierwöchiger Behandlung im Vergleich zu Plazebo.

The dose dependence of the antihypertensive effect of the beta 1 selective blocker talinolol (CAS 57460-41-0, Cordanum) was investigated in 97 essential hypertensive patients (mild to moderate) using the ambulatory blood pressure monitoring (ABPM) in a single-centre, double-blind, randomized parallel-group study. After 4 weeks of treatment a comparison was made between the once daily administered doses of 50, 100 and 200 mg as well as with placebo. The primary parameter was the mean diastolic blood pressure between 8.00 and 22.00 (dTMW). Furthermore, the duration of action of the once daily administration of 200 mg talinolol was compared with the twice daily application of 100 mg each. With regard to dTMW an increasing antihypertensive effect was determined for the dosage step from 50 mg to 100 mg talinolol/d. No further increase in the blood pressure lowering effect was observed with 200 mg talinolol/d. The highest frequency of therapy responders was found in the 100 mg group with 72.2%. Moreover it could be demonstrated, that within the dosage range of 1 x 100-200 mg Talinolol/d a significant and 24 h lasting reduction of blood pressure and pulse rate was achieved, including the early morning period. There were no differences between the blood pressure profile of the 200 mg group and the 2 x 100 mg group at the end of the 4 weeks treatment. All talinolol dosages investigated in this study were proved to be safe and well tolerated. The observed complaints classified as adverse drug reactions represented typical side effects of beta-blockers of mild to moderate intensity. It can be concluded from the results that the once daily intake of talinolol in the dosage range of 100-200 mg/d shows a reliable efficacy in the treatment of essential hypertension accompanied by a noncritical safety profile.

P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound.

Among the different application routes peroral administration remains the one most widely used. Hence, mechanisms affecting p.o. bioavailability are of particular interest, also in drug development. In recent years, intestinal drug secretion mediated by the multi-drug resistance gene product P-glycoprotein (Pgp) has been discovered as a possible mechanism of low and erratic bioavailability. Due to the saturability of this process, a dose-dependent apparent oral clearance may be observed which decreases upon increasing dose. However, in vivo intestinal secretion might be revealed only in the lower or subtherapeutic dose range. In permeability studies with Caco-2 cell monolayers, the MDR-reversing agent verapamil inhibits secretion of P-glycoprotein substrates and, hence, increases apical-to-basolateral permeability. The aim of the rat studies with talinolol presented here was to test the relevance of the intestinal secretion process as well as the extent of inhibition by verapamil in ex vivo, in situ, and in vivo talinolol/verapamil drug-drug interaction studies. Intestinal secretion of talinolol was detected indirectly in ex vivo studies via transport inhibition with verapamil and directly in in situ intestinal perfusions in rats following a talinolol i.v. bolus. Both i.v. and p.o. verapamil appear to affect the concentration-time profiles of talinolol. Relevant observations with respect to drug absorption are the decreased apparent oral clearance upon verapamil coadministration as well as the decreased tmax and mean absorption times at high verapamil doses. Talinolol may be regarded as a potential model compound for mechanistic studies on Pgp interactions, including permeability as well as binding studies and the involvement of transporters other than Pgp.

A single and multiple dose bioavailability study with carbamazepine 400 mg retard tablets with reference to enzyme autoinduction and circadian time differences.

UNLABELLED: Both single and multiple dose bioequivalence studies are required to assess the quality of modified release formulations of drugs. In bioequivalence studies of drugs with enzyme autoinducing properties such as carbamazepine (CBZ), the standard multiple dose study design must be modified to guarantee equivalence of drug elimination. This problem was considered with regard to carbamazepine 400 retard AWD (test) whose bioavailability relative to a listed reference (Tegretal 400 retard) was studied in 2 randomized, open, crossover studies both with 18 healthy volunteers of Caucasian origin (20-36 years, 61.5-92 kg, 172-195 cm). The single dose study was done with 400 mg CBZ. Serum concentration time profiles of CBZ and its active metabolite CBZ-10,11-epoxide were determined until 144 h after administration. The multiple dose study was performed with 400 mg CBZ b.i.d. for 15 days (first 2 days: 200 mg b.i.d.) followed by a 7-day study with the alternative investigational product. 24-hour serum concentration time profiles of CBZ and its metabolite were measured on days 15 and 22 of the study. The quantitative drug analysis was done with an HPLC method the quality of which fulfilled the requirements of bioequivalence studies. Test was considered bioequivalent to reference with regard to the extent of absorption, if the 90% confidence intervals of the AUC0-infinity ratio (single dose) and AUC0-24h ratio (multiple dose) were within the range of 0.80-1.25, and with regard to rate of absorption if the 90% confidence intervals of the Cmax/AUC ratio (single dose) or AUCF0-24h ratio were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratio (test/reference) of CBZ were 0.979 (0.94, 1.02) for the single and 1.01 (0.947, 1.076) for the multiple dose comparison. The point estimator (90% confidence limits) of the Cmax/AUC ratio was 0.989 (0.959, 1.020) and of the AUCF0-24h ratio 1.066 (0.937, 1.212). There were no circadian time differences in any pharmacokinetic parameter. IN CONCLUSION: Carbamazepine 400 retard AWD tablets were bioequivalent to reference with regard to extent and rate of absorption after both single and multiple dose administration.

Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans.

OBJECTIVE: To examine the relevance of site-dependent small intestinal absorption for incomplete intestinal absorption of the poorly metabolized beta 1-adrenergic receptor antagonist talinolol. METHODS: The intestinal steady-state perfusion technique (triple lumen tubing system with a 30 cm test segment) for intraluminal measurements was combined with simultaneous determination of talinolol serum concentrations. Dissolved talinolol was perfused over 160 minutes into different parts of the small intestine. The middle of the test segment was located between 25 and 235 cm beyond the teeth. Each of the six healthy subjects was studied twice with a proximal and a more distal site of perfusion to allow for comparisons within an individual subject. RESULTS: The area under the curve for serum concentrations from 0 to 480 minutes [AUC(0-480 min)] and the maximum serum concentration after distal perfusions corresponded to only 15% to 73% and 7% to 90% of the proximal values, respectively. AUC decreased with increasing distance from the teeth. The mean amount of talinolol absorbed from the test segment per unit time (intestinal transport rate) corresponds to only one-tenth of the amount of drug offered to the test segment (perfusion rate). There was a direct correlation between the perfusion rate of talinolol and its transport rate for both regions and in all subjects investigated. However, to achieve the same transport rate in the distal region a higher perfusion rate is required, compared to the proximal small intestine. At perfusion rates lower than 600 micrograms/min, net secretion of talinolol into the intestinal lumen occurred against a steep concentration gradient blood: lumen of about 1:4200. CONCLUSION: Talinolol oral bioavailability of 55% is due to a low absorption rate and a decrease of absorption capabilities along the small intestine. Net absorption of talinolol is reduced by the involvement of active intestinal secretion.

Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo.

PURPOSE: To evaluate carrier-mediated intestinal secretion of talinolol enantiomers in vivo and in vitro. METHODS: In clinical studies with i.v. and p.o. dosage of rac-talinolol (30 mg and 100 mg, resp.) performed in a small number of cholecystectomized patients total and partial clearances were determined on the basis of plasma, bile and urine concentrations. The dose-dependence of AUC was investigated in 12 healthy volunteers (25, 50, 100, and 400 mg rac-talinolol as single p.o. doses). Concentration-dependence of the permeability across Caco-2 cell monolayers included concentrations from 0.1 to 2.0 mM, inhibition by verapamil was tested at 0.5 mM. RESULTS: The total clearance as well as the apparent oral clearance (CL/F) were slightly higher for S-(-)- than for R-(+)-talinolol. Calculation of the partial clearances showed that also the residual clearance was higher for the S- than for the R-enantiomer. In the healthy volunteers, CL/F increased with increasing doses, while the S/R ratio decreased approaching unity for the highest dose. Also the results from Caco-2 cell permeation studies yielded a clear concentration-dependence with decreasing stereoselectivity for the higher concentration range. Permeability of both enantiomers was considerably higher for b-->a than a-->b transport, however, this difference disappeared when verapamil was added. CONCLUSIONS: Although not very expressed, the detected stereoselectivities indicate a preferential absorption of R-(+)-talinolol in a lower concentration and dose range, which is most probably due to a moderate stereoselectivity at the carrier system involved in intestinal secretion.

Study on the bioequivalence of an oral nifedipine formulation and a sustained release reference preparation after single dose and repeated doses.

Pharmacokinetic parameters of an oral formulation of nifedipine (CAS 21829-25-4, Corinfar, test preparation T a dragee with 10 mg nifedipine) were compared with a reference preparation (R, a sustained release tablet with 20 mg nifedipine) in 16 healthy volunteers in a open two-way crossover study under the influence of ingestion of food. A GC/MS method was used to analyse the serum samples. The estimation of bioequivalence was based on a nonparametric statistical procedure of analysis of variance. Both, the test preparation T and the reference preparation R are bioequivalent at steady state. The main pharmacokinetic parameters (mean +/- standard deviation) used for the bioequivalence decision at steady state were AUC0- tau ss (T: 351.4 +/- 161.0 ng.ml-1.h; R: 345.5 +/- 146.8 ng.ml-1.h), Cmaxss (T: 67.3 +/- 29.5 ng.ml-1; 66.9 +/- 33.0 ng.ml-1) and HVDss (T: 3.8 +/- 1.3 h; R: 4.2 +/- 1.8 h). The bioequivalence of rate and extent of absorption was proved for both preparations at steady state by assessing mean serum level curves as well as by statistics (90% confidence intervals) using the main pharmacokinetic parameters AUC0 - tau ss (range: 0.84-1.02 point estimator: 0.92), Cmaxss (0.95-1.33; 1.15) HVDss (0.72-0.98; 0.82). The large interindividual variability of pharmacokinetics is typical of the drug and does not depend on the formulation used. No case of severe disturbance of circulatory function or other adverse events with the duty to treat occurred during the study. No volunteer dropped out.

Dose-effect and kinetic-dynamic relationships of the beta-adrenoceptor blocking properties of various doses of talinolol in healthy humans.

Twelve healthy subjects were investigated on six separate occasions at least 1 week apart when they either received a single oral dose of 80 mg propranolol; 25, 50, 100, or 400 mg talinolol; or placebo (double-blinded, period-balanced six-way cross-over design). The subjects were investigated during supine rest and performed supine bicycle ergometry 0200, 0500, 0730, 1000, and 2400 h after dosing. Isoprenaline (ISO) and epinephrine (EPI) were infused intravenously (i.v.) at a constant infusion rate of 1 microgram/min for 10 min, at 0315 and 0400 h after dosing, respectively. At various timepoints, blood was drawn for the high-performance liquid chromatography (HPLC) determination of the plasma concentrations of talinolol's enantiomers and for the ex vivo in vitro determination of beta 1- and beta 2-adrenoceptor binding and related concentrations by radioreceptor assay (RRA). Talinolol was confirmed to bind to beta-adrenoceptors with moderate affinity but to act as a highly selective and efficient beta 1-adrenoceptor antagonist in terms of the relative degree and duration of its ergometric effects. At doses < or = 100 mg talinolol hardly altered the reduction of estimated vascular total peripheral resistance (TPR) in response to the intravenous infusion of ISO and EPI. Only at doses of 400 mg did talinolol more closely approximate the effects of propranolol, which lead to a loss of the vasodilatory actions of EPI ("EPI reversal"). On the average, there was a smoothly linear relationship between the ergometric treatment effects and log-transformed dose, the logtransformed concentrations of the S(-)-enantiomer measured by HPLC, and the RRA-derived estimated occupancies beta 1-adrenoceptors.

Pharmacokinetics of the antiarrhythmic agent tiracizine: steady state kinetics in comparison with single-dose kinetics.

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, Cmax,ss = 391.8 ng mL-1 against Cmax,sd = 132.8 ng mL-1; M2, Cmax,ss = 143.2 ng mL-1 against Cmax,sd = 25.8 ng mL-1). However, significant increases of AUC (AUC tau = 261.9 ng h mL-1 against AUC0-infinity,sd = 182.9 ng h mL-1), Cmax (Cmax,ss = 75.9 ng mL-1 against Cmax,sd = 56.9 ng mL-1) and t 1/2 beta (t 1/2 beta,ss = 4.0 h against t 1/2 beta,sd = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the tmax of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.

Day-night variations in the renal excretion of the antiarrhythmic agent tiracizine and its metabolites.

Daytime and nighttime urinary recovery as well as morning and evening trough serum levels of the antiarrhythmic agent tiracizine and three of its metabolites (M1, M2, and M3) were assessed during a 7-day multiple-dose study period (50 mg tiracizine twice daily) in eight healthy volunteers. A significantly lower mean steady-state urinary recovery was observed during the daytime as compared with during the nighttime (Ae (tot tau d)=42.0 +/- 15.7% vs. Ae (tot tau n)=51.2 +/- 19.6%). This difference is mainly due to a substantial increase of M1 and a smaller increase of M2 urinary recovery by night. Results of additional in vitro investigations showed the ratio of the nonionic/ionic forms of M1 and M2 to be highly dependent on pH in the range of pH 5-pH 7. Therefore, the observed day-night variations might be attributed to alterations of ionization, i.e., nonionic tubular reabsorption of the metabolites due to circadian differences in urinary pH. Trough serum levels of M1 and M2 tended to be higher at 7 P.M. as compared with 7 A.M. Due to the narrow therapeutic index of class I antiarrhythmics, the present results indicate the need for further investigations concerning the effect of urinary pH on the pharmacokinetics of tiracizine and its metabolites.

[Relative bioavailability of the antiarrhythmia agent, tiracizine and its metabolites]. / Relative Bioverfügbarkeit des Antiarrhythmikums Tiracizin und seiner drei Metabolite.

Relative bioavailability of a 100 mg tablet formulation of the antiarrhythmic agent tiracizine (CAS 78816-67-8) compared to a 50 mg formulation was assessed in a simple cross over study after single administration of a 100 mg dose to 12 healthy volunteers. Tiracizine and three of its metabolites (M1, M2 and M3) were measured in serum and urine by high pressure liquid chromatography. AUC (means after administration of the test preparation and 95% nonparametric confidence interval for the ratio test preparation/reference preparation) were 391.5 ng.h/ml and 0.87-1.11 for tiracizine, 5184.5 ng.h/ml and 0.94-1.26 for M1, and 1319.9 ng.h/ml and 0.88-1.16 for M2. Mean maximum serum concentrations after the test preparation and corresponding 95% confidence interval were 111.2 ng/ml and 0.86-1.20 for tiracizine, 301.2 ng/ml and 0.98-1.22 for M1, 54.6 ng/ml and 0.86-1.17 for M2, and 35.2 ng/ml and 0.82-1.17 for M3.tmax did not differ after the two preparations for tiracizine, M2 and M3, but was significant lower for M1 after administration of the test preparation (2.2 +/- 0.7 vs 3.0 +/- 1.2 h). Total urinary recovery (sum of parent compound and metabolite recovery) up to 32 h after intake of the test preparation was 31.2% of the administered dose. The corresponding 95% confidence interval was 0.84-1.08. Statistical evaluation of all parameters revealed bioequivalence between the two preparations if a single dose of 100 mg is administered.

[The bioequivalence of metoclopramide in two tablet formulations]. / Untersuchung zur Bioäquivalenz von Metoclopramid in zwei Tablettenformulierungen.

An investigation on the bioavailability of a tablet with 10 mg metoclopramide-HCl (CAS 363-62-5) Cerucal was performed in a two-way cross-over study with 12 volunteers. Metoclopramide was determined in serum by HPLC. The relative bioavailability (mean and nonparametric 95% confidence interval) with respect to a reference preparation was 0.95 (95% CI 0.88-1.02) for AUC and 0.92 (95% CI 0.79-1.07) for Cmax. A positive decision for bioequivalence was derived from the usual confidence intervals for both parameters. The tmax-values did not differ significantly. Statistical evaluation of all parameters revealed bioequivalence between the two preparations.

Dose dependent tiracizine disposition in healthy volunteers: serum and urine kinetics and dose related ECG-changes.

The pharmacokinetics of tiracizine, a new class I antiarrhythmic agent, and 3 of its metabolites were assessed in serum and urine of 8 healthy extensive metabolisers after single oral administration of 50, 100, and 200 mg tiracizine hydrochloride. Additionally, tiracizine induced ECG-changes were compared between the different doses. With increasing doses enhancement of AUC and Cmax of tiracizine and its metabolites revealed a slight deviation from linearity indicated by exceeding the upper limits of the 95% nonparametric confidence interval set by 0.8-1.2 for the ratio (dose corrected parameters after the 100 and 200 mg dose, respectively)/(parameters after 50 mg). The increase of the dose corrected parameters after the 200 mg dose was about 1.3-fold compared with the 50 mg parameters for the parent compound as well as its metabolites. The significant decrease of the renal clearance of all 4 substances with increasing doses indicates that saturable tubular secretion mainly accounts for non-linearity. Due to the occurrence of non-linear (tubular secretion) as well as linear (glomerular filtration, hepatic metabolism) elimination in parallel, however, it is concluded that saturable tubular secretion is of minor importance at higher doses and should not be overestimated. However, there was some evidence for saturable hepatic tiracizine metabolism in 4 of the 8 participants. Therefore, a fall of apparent intrinsic clearance has also to be taken into consideration, especially at higher doses. PQ- and QRS-intervals were prolonged in a dose dependent manner and culminated at 1 h after drug intake. QTc-time, however, remained unchanged. A log-linear relationship between serum concentrations of the parent compound and PQ- as well as QRS-time is suspected for serum levels about 80 ng/ml, but has to be confirmed by individual pharmacokinetic-pharmacodynamic modelling. PQ- and QRS-intervals might be suitable for tiracizine therapeutic monitoring.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 in volunteers with T-tube after cholecystectomy.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 were investigated in 6 female volunteers (age: 26-69 years) 9-14 days after cholecystectomy and T-tube construction. After a single oral dose of 50 mg AWD 26-06 as an aqueous solution the amount of the unchanged substance was determined in serum, T-tube bile and urine with a special HPLC-method. The concentration maximum was reached earlier and higher in bile (60 +/- 22 min; 10.8 +/- 5.7 micrograms/ml) than in serum (73 +/- 28 min; 0.98 +/- 0.53 micrograms/ml). During the whole observation time of 24 h the AWD 26-06 concentration in bile was 2-21-fold higher than in serum. In mean 2.3 +/- 1.5% of the administered dose were eliminated unchanged by bile and 12.2 +/- 5.9% by urine. More than 70% of the dose were metabolized. The results gave a hint at active liver transport processes and an enterohepatic recirculation. A drug interaction was observed with valproic acid on the metabolic level. The great interindividual variability of pharmacokinetic data can be caused by the heterogeneity of the subject group and a genetic polymorphism in the metabolism of AWD 26-06. The bile sampling by means of a T-tube is a simple but effective method under consideration of special conditions.