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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[Relative bioavailability of various quinidine preparations in man after a single oral dose]. / Untersuchungen zur relativen Bioverfügbarkeit verschiedener Chinidin-präparationen beim Menschen nach einmaliger oraler Gabe.

The bioavailability of quinidine sulfate in different preparations (quinidine in capsules as reference; Quinidine longo; Qunidine longo with either quinidine in the cover or in the nucleus, Quinidine Duriles) was investigated in 8 healthy volunteers in plasma and urine in a crossover design. There are no differences in the AUCo infinitey and in the eliminated amount in urine after infinit time. Quinidine longo possesses two maxima at 0.8 +/- 0.1 h and at 3.1 +/- 0.2 h. These maxima are caused by the liberation from the cover and the nucleus. The quotients of retardation (RD = ratio of the duration at 1/2 Cpmax, RC = ratio of 1/2 Cpmax, quinidine sulfate as reference) is calculated for Quinidine longo: RD = 1.42 +/- 0.14, RC = 0.75 +/- 0,05 and for Quinidine Duriles: RD = 1.79 +/- 0.21, RC = 0.52 +/- 0.07. The effect of retardation of Quinidine longo is not so much as that of Quinidine Duriles. However there are no statistic differences for RD in contrast to RC between these two retard-preparations.

[The pharmacokinetic behavior of AWD 26-06 in humans following single and multiple administration]. / Untersuchungen zum pharmakokinetischen Verhalten von AWD 26-06 am Menschen nach ein- und mehrmaliger Gabe.

The pharmacokinetics of the muscarinolytic drug AWD 26-06 was investigated in two subjects after a single dose of 50 and 100 mg, respectively, and with six subjects after repeated dosage. The half time (t1/2) is 2.4 and 2.6 h, respectively, the height of the concentration maximum (Cmax) 500 and 1400 ng.ml-1, respectively, and the area under the curve (AUC) 2155 and 4334 ng.ml-1.h, respectively. The repeated dosage (25 mg every 8 h for 7 d) showed a small increase of the serum level. The t1/2 and the mean residence time (MRT) at the 1st and the 8th d are 2.6 h (range: 1.8-2.9 h) and 4 h (range: 2.7-5.8 h), respectively. The point (tmax) and the Cmax were not different at the 1st and 8th d: mean tmax (1st d) 1.1 h (range: 1.0-1.5 h), mean tmax (8th d) 0.9 h (range: 0.75-1.0 h); Cmax (1st d) 227 ng.ml-1 (range: 160-320 ng.ml-1), Cmax (8th d) 282 ng.ml-1 (range: 168-320 ng.ml-1). There were also no differences for the AUC0-t at the 1st and 8th d (1st d) 815 ng.ml-1.h (range: 610-1134 ng.ml-1.h). The simulation of the serum level by means of the data from the single dose were established by this investigation. Typical subjective muscarinolytic symptoms (e.g. dryness of the mouth, diminution of accommodation) were observed after the 2nd/3rd dosage. These signs diminished 24-36 h after discontinuation of the dosage. The parameter ALAT, proteins of plasma, and blood cell count were not changed at the end of therapy in comparison to the beginning.

[In vitro and in vivo studies of diclofenac suppositories in humans]. / Zur Beziehung von in-vitro- und in-vivo-Untersuchungen beim Menschen am Beispiel von Diclofenac-Suppositorien.

Five different preparations of diclofenac-suppositories (A, B, C, D, E) are investigated for in vitro liberation (modified paddle method) and for in vivo bioavailability in man (8-12 subjects) in a crossover design. In vitro, the time at which 63.2% of the drug are liberated (tL) is 14, 20, 25, 14 and 3.5 min for the preparations A, B, C, D and E, respectively. The steady state concentrations from the preparations B and C are 51 and 11%, respectively, and lower than for the others. In vivo, the time of the concentration maximum (tmax) in min is (mean +/- S mean): A = 68 +/- 18, B = 72 +/- 9, C = 120 +/- 22, D = 42 +/- 3, E = 24 +/- 0.5. The concentration maximum (cmax) in mumol . l-1 at tmax is (mean +/- S mean): A = 5.9 +/- 0.8, B = 3.9 +/- 0.3, C = 3.1 +/- 0.4, D = 5.7 +/- 0.6, and E = 5.5 +/- 0.8. The area under the curve (AUC) for all the preparations has found to be between 8.7 and 10,6 mumol . h . l-1. There is a significant correlation between the in vitro parameter tL and the in vivo data of tmax and cmax, respectively. In consequence, the invasion behaviour in vivo can be derived from in vitro data for drugs with similar good physicochemical properties as diclofenac-Na.

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.