Ocular safety of propiverine hydrochloride in elderly patients with primary open- and narrow-angle glaucoma
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BACKGROUND: Propiverine hydrochloride (P4) is an antimuscarinic drug used in overactive bladder syndrome. METHODS: Two studies were performed: one in 24 patients with open-angle glaucoma (OAG) treated with topical ß-blockers, one in 24 patients with narrow-angle glaucoma (NAG) treated with pilocarpine ± topical ß-blockers. Patients were treated in randomized, placebo-controlled, double-blind parallel-group fashion (15 : 9 attribution to P4 vs. placebo (PL)). TREATMENTS: Single-blind PL dose in the morning of day 1 for baseline; double-blind 15 mg P4 or matched placebo t.i.d. from the afternoon of day 1 until the morning of day 7. RESULTS: In the morning of day 7, trough mean serum P4 concentrations were 169.4 ng/mL (CV (coefficient of variation): 0.55) and 140.7 ng/mL (CV: 0.56) in OAG and NAG; at 3:15 hours after dosing: 237.4 ng/mL (CV: 0.47) and 212.4 ng/mL P4 (CV: 0.38), respectively. P4-treatment led to a prompt (OAG) or more gradient (NAG) increase in pupil diameter (PUD), with a maximum difference from PL of 0.97 mm (95% confidence interval (CI): 0.67 - 1.27) and 0.87 mm (95% CI: 0.36 - 1.39) in OAG and NAG, respectively. However, there was no average increase in intraocular pressure (IOP) or increase in noteworthy safety-relevant individual IOP values (or changes thereof). There was no effect on visual acuity or accommodation. CONCLUSIONS: 1-week treatment with P4 appeared to be safe 1) in OAG patients treated with topical ß-blockers and 2) in NAG patients treated with topical pilocarpine ± ß-blockers, irrespective of whether the eyes had previously been treated with glaucoma surgery or laser therapy.
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Effects of renal insufficiency on the elimination of fluorescein lisicol (NRL972), an investigational marker of hepatic transporter function.

BACKGROUND: NRL972 (Fluorescein Lisicol), a fluorescent-labelled bile salt, is an investigational marker of hepatic biliary transporter function. OBJECTIVE: To investigate the pharmacokinetics (PK) of NRL972 in patients with severe (SRI: creatinine clearance (CLCr)<30 mL/min per 1.73 m2 body surface area (BSA)) and mild-to-moderate renal insufficiency (MRI: 30≤CLCr<80 mL/min) relative to matched controls (CON: CLCr≥90 mL/min). METHODS: The plasma and urinary PK of NRL972 were determined after single 2-mg doses of NRL972 administered by 15-second intravenous (IV) injection. The PK were derived noncompartmentally using all data points up to 6 hours after dosing or only using the concentrations at 10 and 30 minutes after injection. RESULTS: 17, 22, and 16 subjects were enrolled in the SRI, MRI, and CON group, respectively. NRL972 was hardly quantifiable in urine in any of the subjects groups. The plasma concentrations of NRL972 declined rapidly after dosing in mostly monoexponential fashion. The decline tended to be faster in patients with renal insufficiency: in SRI patients, the point and 95% confidence interval (CI) estimates of the group ratios (SRI/CON) were 0.691 (CI: 0.517 to 0.925) for the C(30):C(10) concentration ratio, 0.785 (CI: 0.634 to 0.970) for t1/2, and 1.344 (CI: 1.028 to 1.757) for bodyweight normalized clearance (CL/BW); in MRI patients, the effect was slightly less. CONCLUSION: Renal insufficiency does not impair the elimination of NRL972; instead, there is a trend of enhanced NRL972 disposition in patients with compromised renal function. Concomitant renal impairment is unlikely to have confounding effects on the evaluation of hepatic function by NRL972 testing.

Effects of advanced age and renal dysfunction on the single- and repeated-dose pharmacokinetics of modified-release flupirtine.

BACKGROUND: Flupirtine is a nonopioid, central analgesic without antipyretic or antiphlogistic properties. Flupirtine-MR is an oral modified-release formulation with a 100 mg fast-input and a 300 mg portion with slow protracted release. METHODS: Single- (D01) and repeated-dose (D03-D09) pharmacokinetics of 400 mg flupirtine-MR were investigated in patients with severe renal dysfunction (REN: N: 12; 21 50 years of age; creatinine clearance (CLCr)≤30 mL/min per 1.73 m2 body surface area (BSA)) and healthy older subjects (EN1: N: 8; 60-69 years; CLCr≥80 mL/min and EN2: N: 8; ≥70 years, CLCr≥60 mL/min) vs. young healthy control subjects (YN: N: 12; 21-40 years; CLCr≥90 mL/min). RESULTS: Renal dysfunction led to a relatively small average increase in systemic exposure to flupirtine: on D09, the REN : YN-ratios were 1.37 (95% confidence interval (CI): 1.03-1.82), 1.21 (CI: 1.01-1.45), and 1.34 (CI: 1.09-1.64) for Css,0, Css,max, and Css,av, respectively. A similar increase in exposure was observed in older subjects: the respective EN1:YN-ratios were 1.30 (CI: 0.95-1.79), 1.23 (CI: 1.01-1.49), and 1.23 (CI: 0.98-1.54); the EN2:YN-ratios were 1.50 (CI: 1.10-2.04), 1.16 (CI: 0.85-1.41), and 1.41 (CI: 1.12-1.79), respectively. Neither age nor renal function was a predominant factor of pharmacokinetic variability. Single and repeated doses of flupirtine-MR were very well tolerated. CONCLUSIONS: The average renal and age effects were small, but the use of a lower starting dose (1/2 tablet) is recommended since some of these subjects might have relatively high exposure levels.

Pharmacodynamic equivalence study of two preparations of eye drops containing dorzolamide and timolol in healthy volunteers.

OBJECTIVE: The aim of the present study was to assess the pharmacodynamic equivalence (lowering of intraocular pressure) of two preparations of eye drops containing 20 mg dorzolamide (CAS 120279-96-1) and 5 mg timolol (CAS 26839-75-8). METHOD: The study was conducted as a monocentric, observer-blinded, randomized, single-dose, two-period crossover study in 38 healthy volunteers. Each volunteer received on day 1 in each period in a random way a single dose of 1 drop of the test or the reference formulation in the conjunctival sac of the right eye separated by a wash-out period of 7 days. Measurement of intraocular pressure (IOP) of the right eye (by a blinded observer) was performed on day 1 of each study period pre-dose and 2 h post dosing by means of Goldmann applanation tonometry. In order to investigate the pharmacodynamic equivalence of both products, the two-sided 95% confidence interval was calculated for the difference of the primary target parameter (absolute decrease in IOP 2 h post dose), by means of a parametric (ANOVA) statistical method. RESULTS: The results of the statistical evaluation of the primary target parameter "absolute decrease in IOP 2 h post dose" demonstrated a decrease in the IOP of 4.72 mmHg for the eye treated with the test formulation (dorzolamide 20 mg/ml + timolol 5 mg/ml eye drops) and 4.61 mmHg for the treated with the reference formulation. The mean difference was 0.11 mmHg. The 95% confidence interval was between -0.33 and 0.55 mmHg and thus entirely within the pre-defined equivalence range (+/- 1.5 mmHg). The results of the statistical evaluation of the secondary target parameter relative (as % of baseline) decrease in IOP 2 h post dose demonstrated essentially similar effectiveness in lowering the IOP by 27.63% (test formulation) and 27.12% (reference formulation), respectively. Both drug products were well tolerated. CONCLUSION: Both formulations showed comparable results obtained at a time probably equal to the maximum effect concerning the primary target parameter lowering of IOP 2 h post dose. The safety profile of both preparations showed no difference.

Bioequivalence of a novel oral metronidazole formulation.

The plasma pharmacokinetics of metronidazole (CAS 443-48-1) and its active OH-metabolite (CAS 4812-40-2) were investigated in 16 healthy volunteers after the oral administration of single oral doses of 500 mg metronidazole by means of a novel (test, T) and reference formulation (reference, R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design with two periods one week apart for wash-out. A single oral dose of 500 mg metronidazole by means of the test formulation T (Vagimid Dragees) resulted in a geometric mean C(max) of 10649 ng/ mL (CV: 0.21) for metronidazole after a median t(max) of 70 min (range: 40 to 120); the geometric mean of the AUC(0-t(z)) and AUC(0-infinity) were 107406 (CV: 0.25) and 109056 ng x h/mL (CV: 0.26); the arithmetic mean of the half-life (t1/2) and the mean residence time (MRT) were 7.28 h (CV: 0.12) and 11.62 h (CV: 0.10). For the OH-metabolite, the geometric mean C(max) was 1941 ng/mL (CV: 0.22) after a median t(max) of 480 min (range: 360 to 600) with a geometric mean AUC(0-tz) and AUC(0-infinity) of 48653 (CV: 0.21) and 52417 ng x h/mL (CV: 0.22), respectively; the arithmetic mean t1/2 and MRT were 10.60 h (CV: 0.21) and 21.14 h (CV: 0.13), respectively. The test formulation was bioequivalent with the reference formulation for both metronidazole (90% CI of the treatment ratio of 1.02 to 1.15 and 1.02 to 1.12 for C(max) and AUC) and its metabolite (90% CI of 0.92 to 1.05 and 0.98 to 1.06, respectively). The treatments were very well tolerated and there were no limiting safety-relevant findings.

Analysis of pooled plasma samples as a predictor for proving bioequivalence of drugs with a long elimination half-life. The example of phenprocoumon.

The results of pooled plasma analysis in a bioequivalence trial provide information comparable with that of the mean concentration vs. time curves for each formulation. Although it seems feasible that pool plasma analysis will have similar or even greater advantages in cases of bioequivalence trials with a parallel-group design, no such data has been published in the literature probably due to the limited number of such trials. The present study was designed with the aim to investigate the prediction value of pool plasma analysis in a bioequivalence trial with phenprocoumon (CAS 435-972). The study was performed as a monocentric, randomized, open clinical trial in two parallel groups of healthy male volunteers (31 per group), all of which received a single oral dose of 3 mg phenprocoumon. Serial blood samples were drawn for the pharmacokinetic analysis pre-dose, and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 12, 24, 48, 96, 144, 192, and 240 h after drug administration. Pool plasma was prepared for each sampling point and each formulation. Drug concentrations were measured by means of an HPLC method. A comparison between the pool plasma results and the results of individual analysis revealed a very good correspondence regarding the parameters AUC, Cmax and t(max). The present trial demonstrates that the method of time-wise pooling provides reliable information not only in cross-over trials but also in trials with parallel groups of volunteers.

Studies on the bioequivalence of second generation cephalosporins: cefaclor capsules and suspension.

The aim of the present studies, performed in two different groups of volunteers, was to prove the bioequivalence of 500 mg cefaclor (CAS 70356-03-5) test and reference capsules (Losefar 500 mg Capsules as test and an originator product as reference; study 1) and cefaclor 250 mg/5 mL test and reference suspensions (Losefar 250 mg/5 mL Granules oral suspension as test and an originator product as reference; study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 8 h post dosing, and concentrations of cefaclor were determined by HPLC method. In the first study, the 90% confidence intervals for intra-individual ratios of AUC0-t and Cmax of cefaclor were 0.99-1.08 for AUC0-t and 0.82-1.06 for Cmax, and thus within the acceptance ranges for bioequivalence trials. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of cefaclor administered as suspensions were 1.10-1.19 and 1.02-1.21, respectively. These values were also within the acceptance range. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences for cefaclor were between -0.13 - 0.13 in the first and between 0.00 - 0.13 in the second study, respectively. In the light of the results of the studies reported here it can be concluded that cefaclor test formulations, i.e. capsules and suspension are bioequivalent to the respective reference formulations.