Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis.

BACKGROUND: The recombinant human epoetin-a HX575 (Sandoz Pharmaceuticals GmbH/Hexal AG, Holzkirchen, Germany) is the first biosimilar erythropoiesis-stimulating agent (ESA) with marketing authorization in Europe. The primary objective of the study was the evaluation of therapeutic equivalence in terms of hemoglobin (Hb) response of HX575 compared with the comparator product (EPREX/ ERYPO, Janssen-Cilag/Ortho Biotech, Neuss, Germany) in the long-term intravenous (i.v.) treatment of anemia in chronic renal failure patients on hemodialysis following a 1 : 1 dose conversion from the comparator product to HX575. METHODS: Hemodialysis patients with Hb levels of 10.0 - 13.0 g/dl were randomized to either continue their current i.v. epoetin-a treatment or switch to HX575. During treatment, epoetin dosages were titrated to maintain Hb values. The primary endpoint was the difference between treatment groups in the mean absolute change of Hb levels between baseline and evaluation period (Weeks 25 - 28). RESULTS: Therapeutic equivalence of HX575 and the comparator epoetin-alpha, assessed during the evaluation period, was statistically confirmed: mean changes in Hb levels were 0.15 +/- 0.09 g/dl in the HX575 and 0.06 +/- 0.12 g/dl in the comparator epoetin-a group, with a difference between groups of 0.08 g/dl (95% confidence interval: -0.17; 0.34). Hb levels and epoetin dosages remained stable throughout the entire study period of 56 weeks. The long-term safety profile of HX575 was similar to that of the comparator epoetin-alpha. No antibody formation was detected. CONCLUSIONS: The study demonstrated therapeutic equivalence of biosimilar HX575 to the comparator epoetin-a, together with a comparable safety profile.

A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis.

OBJECTIVE: We conducted a single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of NAC. METHODS: Twenty-one patients (DeltaF508 homo/heterozygous, FEV1>40% pred.) were included in the study. After a 3-weeks placebo run-in phase, 11 patients received low-dose NAC, and 10 patients received high-dose NAC. Outcomes included safety and clinical parameters, inflammatory (total leukocyte numbers, cell differentials, TNF-alpha, IL-8) measures in induced sputum, and concentrations of extracellular glutathione in induced sputum and blood. RESULTS: High-dose NAC was a well-tolerated and safe medication. High-dose NAC did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC. CONCLUSIONS: High-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways.

Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration.

OBJECTIVE: To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon, Roche Ltd., Welwyn Garden City, UK). METHODS: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or epoetin beta three-times-weekly for 4 weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratios of hematological characteristics were used as surrogate parameters for efficacy evaluation. RESULTS: The pharmacokinetic profiles after multiple doses were similar for both treatments. HX575 was bioequivalent to epoetin beta with respect to the rate and extent of exposure of exogenous epoetin, as indicated by the ratios (90% confidence intervals) of AUC(tau) (96.1 (86.4 - 106.9)) and C(max,ss) (98.5 (85.2 - 113.9)). The hematological profiles of both treatments were similar as determined from the population mean curves and the AUEC(Hb) ratio (90% confidence interval] (99.2 (97.7 - 100.7)), the primary endpoint of this study. Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected at any time. CONCLUSIONS: HX575 and epoetin beta were bioequivalent with respect to their steady-state pharmacokinetic profile and pharmacodynamic action. These results support the conclusion that HX575 and epoetin beta will be equally efficacious and may be interchangeable as therapy.

Bioequivalence studies with metformin: comparability of reference tablets from different origins.

BACKGROUND: The choice of an appropriate reference product is still a problem within the European Union. When no direct comparisons between originator products in different countries are available, registration authorities are sometimes only prepared to grant registration for a generic product on the basis of a comparison with the originator product in the respective country. The aim of the investigation was therefore to evaluate the bioequivalence of reference products from different origins in two different bioequivalence trials with the same test drug. METHODS: Two separate bioequivalence trials were performed involving the oral administration of one test and two reference products containing 500 mg metformin. Both studies had a randomized, open, single-dose, three-period crossover design and were carried out in 24 healthy volunteers. The reference products in the first trial were Glucophage mite (Germany) and Diabex (Australia). In the second trial the reference drugs were Glucophage mite (France) and Glucophage mite (Switzerland). The results of each trial were analyzed regarding the bioequivalence of the respective reference drugs. FINDINGS: The reference drugs in each of both trials were bioequivalent: the 90% confidence intervals for both AUC(0-tlast) and C(max) were entirely within the acceptance range for bio-equivalence trials (0.80 - 1.25 for both parameters). INTERPRETATION: In the case of metformin, the reference products available in the countries examined were very similar. This retrospective analysis involving two studies, therefore, confirmed bioequivalence between these reference products.

Comparison of peak and trough level monitoring of cyclosporine treatment using two modern cyclosporine preparations.

AIMS: Determination of the peak cyclosporine blood level instead of the trough level promises to represent an improvement in cyclosporine therapy monitoring due to better correlation with the AUC. In kidney transplant recipients we investigated whether this conclusion applies also to a new dispersion formulation of cyclosporine (Cicloral). PATIENTS: 42 stable kidney transplant recipients were converted from Sandimmun Neoral (NEO) to Cicloral (CIC) in a 1:1 dose relation. METHODS: On the last day of NEO administration and 14 days after conversion to CIC a full 12 h cyclosporine AUC was performed using blood samples obtained prior to and at serial times after dosing. The correlations between cyclosporine levels at these time points and the AUC were determined for NEO and CIC. For each measurement, a predicted AUC was calculated by regression analysis. The prediction error for each sampling time was calculated separately for NEO and CIC. RESULTS: The cyclosporine trough levels showed the poorest correlation with AUC for both preparations (NEO: r = 0.187 vs CIC: r = 0.554). The best correlation was observed for samples obtained at three hours after intake of either CIC (r = 0.807) or NEO (r = 0.611). The number of 2 hours measurements that lead to an unacceptable estimate from the real AUC was somewhat lower for CIC (8/40 vs 11/41 with NEO). CONCLUSIONS: Two- or three-hour cyclosporine level monitoring with the newer cyclosporine preparation Cicloral has at least the same precision as that of the original Neoral(R). In this study, the newer preparation even showed a tendency towards superior monitoring properties.

Penetration of cefaclor into the interstitial space fluid of skeletal muscle and lung tissue in rats.

PURPOSE: To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. METHODS: Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. RESULTS: The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC(tissue(unbound)))/AUC(plasma(unbound))) of approximately 0.26 independent of dose, tissue and mode of administration. CONCLUSIONS: Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.

Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol.

AIM: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. METHODS: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. RESULTS: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCtau), minium steady-state concentration (C(min)ss) and average steady-state concentration (C(av)ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for C(max)ss, t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.

Mefenamic acid bioequivalence assessment with a new statistical procedure.

The bioequivalence of three different formulations of mefenamic acid was tested using the index zeta 2 previously defined by Rescigno. This index is a measure of the distance in Hilbert space of two concentration vs time functions; unlike the approach of Westlake which assumes a multiplicative model for the AUC and Cmax characteristics, this approach does not imply any hypotheses on the structure of the data and no particular model of the absorption or of the elimination processes. The index zeta 2 is simply an indication of how similar two formulations are. Results for this new test were compared with those obtained with two other tests, namely 90 and 95% symmetrical confidence intervals of Westlake and two one-sided t-tests of Shuirmann through the 90% confidence intervals in the ranges 80-125% for AUC and 70-143% for Cmax. Results of the new test are fully comparable with those obtained using the other two tests.

Ibopamine as a valuable adjunct and substitute for dopamine in bridging therapy before heart transplantation.

Ibopamine is an active dopamine analogue leading to improved renal perfusion and afterload reduction in heart failure. This report describes casuistic experiences in patients with severe heart failure awaiting heart transplantation. All patients could be stabilized, intravenous catecholamines be discontinued, and diuretics be reduced. Six of seven patients could be successfully transplanted. No major side effects were noted. Thus ibopamine can be a suitable adjunct for patients with endstage heart failure.

Spectrum and susceptibility of pathogens causing acute uncomplicated lower UTI in females and its correlation to bacteriologic outcome after single dose therapy with fosfomycin trometamol versus ofloxacin/co-trimoxazole.

In a multicentric study comparing oral single-dose therapy of fosfomycin trometamol (3 g as fosfomycin) versus co-trimoxazole (1.92 g) or ofloxacin (200 mg) as many as possible of the pathogens were sent to and analysed in a central laboratory. The pathogens were identified and minimal inhibitory concentrations (MIC) of fosfomycin, trimethoprim alone and in combination with sulfamethoxazole, ofloxacin, ampicillin, amoxicillin combined with clavulanic acid, and cephadroxil were determined. The eradication of pathogens (cfu < 10(3)/ml at one week after single-dose therapy) was analysed according to species and MIC of the antibiotic used. Urine cultures of 349 patients were analysed. Escherichia coli was the predominating species followed by staphylococci and Proteus mirabilis. Enterococci were mostly found in mixed culture. Baseline pathogens of monoinfections were eradicated in 87.1%, in 88.9% and in 86.4% of 284 patients treated with fosfomycin trometamol, co-trimoxazole and ofloxacin, respectively. The MICs of the five antibacterial agents and the two antibiotic combinations for 253 baseline pathogens showed that of the E. coli strains none was resistant to ofloxacin, three (MIC = 128 mg/l) were resistant to fosfomycin, 3.6% to co-trimoxazole, 6.2% to trimethoprim, 8.8% to ampicillin, and 5.7% to amoxicillin/clavulanic acid. The eradication rates according to the MICs of the corresponding drugs showed equally good eradication rates for fosfomycin up to an MIC of 64 mg/l. Above this level two out of three strains were also eradicated by fosfomycin trometamol. For co-trimoxazole and ofloxacin no intermediately sensitive or resistant strains were found. Within the range of MICs found there were equally good eradication rates for both antibacterial agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of mild chronic congestive heart failure with ibopamine, hydrochlorothiazide, ibopamine plus hydrochlorothiazide or placebo. A double-blind comparative study.

This multicentre, double-blind, double-dummy, randomised parallel group study in 247 patients with mild chronic congestive heart failure compared the efficacy and tolerability of ibopamine, hydrochlorothiazide (HCTZ), ibopamine plus HCTZ and placebo during an 8-week treatment period. The combination of ibopamine and HCTZ resulted in a significantly greater reduction in body weight (p less than 0.05) than HCTZ alone. Trends in favour of the combination as compared to ibopamine or HCTZ alone and in favour of ibopamine as compared to HCTZ were observed. All active treatments were superior to placebo. All active treatments were well tolerated. There was a trend towards a higher incidence of hypokalemia in patients treated with HCTZ, alone or in combination, compared to those receiving ibopamine alone or placebo.

Ibopamine versus digoxin in the treatment of mild congestive heart failure. A double-blind, randomized, placebo-controlled trial.

We describe a randomized double-blind 4-week study on the efficacy of monotherapy with ibopamine 200 mg b.i.d. in comparison to placebo and open titrated digoxin in patients with mild congestive heart failure NYHA class I and II. A total of 60 patients (22 males and 38 females) were evaluated for body weight, signs and symptoms score and the need for additional diuretic treatment for adequate symptom control. Mean decreases in body weight in the ibopamine group exceeded mean decreases in body weight in the placebo group (3.03 kg). The signs and symptoms score was improved in 7 out of 20 patients in the placebo group, in all patients treated with ibopamine and in 21 of 22 patients of the digoxin subgroup while the patient-questionnaire score improved in 23.5% (placebo), 100% (ibopamine) and 81.2% (digoxin) of the cases, respectively. There were no treatment failures in the ibopamine and digoxin group. However, 8 of 20 patients receiving placebo had need of additional diuretic therapy. No adverse drug reactions were reported in the ibopamine-treated patients. We conclude that ibopamine monotherapy over 4 weeks has favourable effects on body weight and signs and symptoms of mild congestive heart failure without exerting major side effects. The efficacy is comparable to digoxin therapy.

Fosfomycin trometamol versus ofloxacin/co-trimoxazole as single dose therapy of acute uncomplicated urinary tract infection in females: a multicentre study.

20 urologists took part in a single blind, randomized study. Female patients with acute uncomplicated UTI were recruited. The patients received either a single dose of 3 g fosfomycin trometamol versus 200 mg ofloxacin or 1.92 g co-trimoxazole. Follow-up examinations were carried out after one and four weeks. Of 562 patients 446 could be evaluated for efficacy and 496 for tolerance. Patients were analysed according to the amount of bacteriuria: "significant" (greater than or equal to 10(5)/ml), "low count" (10(2) - 10(4) ml) and "no bacteriuria" (less than or equal to 10(1)/ml), as well as according to the sensitivity of the infecting organisms: sensitive (resistant): fosfomycin trometamol less than or equal to 16 mg/l (greater than or equal to 128 mg/l), ofloxacin less than or equal to 1 mg/l (greater than or equal to 8 mg/l), co-trimoxazole less than or equal to 2/38 mg/l (greater than or equal to 16/304 mg/l). Up to one week the following results could be achieved: clinical improvement was attained in patients with "significant" bacteriuria (fosfomycin trometamol-150, ofloxacin-89, co-trimoxazole-69) in 94.7% for fosfomycin trometamol, in 95.4% for ofloxacin, and in 94% for co-trimoxazole; in patients with "low count" bacteriuria (fosfomycin trometamol-44, ofloxacin-18, co-trimoxazole-30) in 95.2% for fosfomycin trometamol, in 93.7% for ofloxacin, and in 96.4% for co-trimoxazole; and in patients with no bacteriuria (fosfomycin trometamol-11, ofloxacin-6, co-trimoxazole-4) in 81.8% for fosfomycin trometamol, in 100% for ofloxacin and in 100% for co-trimoxazole.(ABSTRACT TRUNCATED AT 250 WORDS)