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Abstract

F. Sörgel¹, U. Thyroff-Friesinger², A. Vetter², B. Vens-Cappell³ and M. Kinzig¹

¹IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, ²Clinical Research, Hexal AG, Holzkirchen, and ³Scope International, Hamburg, Germany
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.Correspondence to:
Prof. F. Sörgel
Department of Research
IBMP-Institute for Biomedical and Pharmaceutical Research
Paul-Ehrlich-Straße 19
90562 Nürnberg-Heroldsberg, Germany
Email: [email protected]

Abstract

M. Wangemann¹, A. Retzow¹, D. Mazur² and B. Vens-Cappell²

¹Desitin Arzneimittel GmbH Hamburg, and ²Phoenix International Mc Knight Hamburg, Germany
Objective: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. Subjects and methods: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. Results: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 mg/ml, 6.8 mg/ml and 12.8 mg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-¥ as well as Cmax related to each other approximately according to the expected ratios of 0.33 : 0.5 : 1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-¥, Cmax) were included by the acceptance range of 80 – 125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. Conclusion: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.Correspondence to:
Dr. M. Wangemann; Desitin Arzneimittel GmbH, Weg beim Jäger 214, D-22335 Hamburg, Germany

Abstract

B. Terhaag¹, A. Hoffmann¹, M. Barkworth² and B. Vens-Cappell²

¹Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Radebeul, and ²Phoenix International McKnight, Hamburg,Germany
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-¥ 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-¥ (arithm. mean ± SD) amounts to 1097 ± 210 ng/ml´h for DIC-effervesc and 1262 ± 220 ng/ml´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 dragée. A rapid onset of therapeutic effect is postulated in acute pain disorders.Correspondence to:
Prof. Dr. B. Terhaag; Arzneimittelwerk Dresden GmbH, Department of Medical Research, Meißner Straße 35, D-01445 Radebeul, Germany

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