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Pharmacokinetics

Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation

F. Sörgel, U. Fuhr, M. Minic, M. Siegmund, J. Maares, A. Jetter, M. Kinzig- Schippers, D. Tomalik-Scharte, J. Szymanski, T. Goeser, U. Toex, B. Scheidel and W. Lehmacher

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Volume 43 p. 140 - 149

Abstract

F. Sörgel¹, U. Fuhr², M. Minic³, M. Siegmund⁴, J. Maares⁴, A. Jetter², M. Kinzig- Schippers², D. Tomalik-Scharte², J. Szymanski², T. Goeser⁵, U. Toex⁵, B. Scheidel¹ and W. Lehmacher⁶

¹Institute for Biomedical and Pharmaceutical Research, Nuremberg-Heroldsberg, ²University of Cologne, Department of Pharmacology, Clinical Pharmacology, Cologne, Germany, ³F. Hoffmann-La Roche Ltd., Basel, ⁴Roche Consumer Health Ltd., Kaiseraugst, Switzerland, ⁵University of Cologne, Department of Gastroenterology and ⁶University of Cologne, Department of Medical Statistics, Cologne, Germany
Objective: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. Material and Method: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 × 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 × 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. Results: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C_max to ibuprofen lysinate and ibuprofen liquagels and significantly higher C_max than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t_max for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. Conclusions: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.Correspondence to:
Prof. Dr. F. Sörgel; Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Straße 19,
90562 Nürnberg-Heroldsberg, Germany
Email: [email protected]

Editorial

Biosimilars / Follow-on proteins – a case for Clinical Pharmacology

F. Sörgel

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Volume 47 p. 365 - 365

Biosimilars

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

F. Sörgel, U. Thyroff-Friesinger, A. Vetter, B. Vens-Cappell and M. Kinzig

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Volume 47 p. 391 - 401

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]

Original

Liver and gut mucosa acetylation of mesalazine in healthy volunteers

T.B. Vree, E. Dammers, P.S. Exler, F. Sörgel, S. Bondesen and R.A.A. Maes

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Volume 38 p. 514 - 522

Abstract

T.B. Vree¹, E. Dammers², P.S. Exler³, F. Sörgel⁴, S. Bondesen⁵ and R.A.A. Maes⁶

¹Institute for Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, ²DADA Consultancy, Nijmegen, ³Disphar International, Hengelo (Gld), The Netherlands, ⁴Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany, ⁵Frederiksberg Hospital, Copenhagen, Denmark, and ⁶Department of Human Toxicology, University of Utrecht, Utrecht, The Netherlands
Aim: The aim of this investigation was to identify which part of a dose mesalazine is acetylated by enzymes in the gut wall during the absorption process, and which part by the liver enzymes after absorption. Method: This study was based on data from four bioequivalence studies of different formulations of tablets (gastro-resistant single dose 500 mg (n = 24) and prolonged-release tablets (single dose 1000 mg, n = 18; multiple dose 1000 mg t.i.d. six days n = 28), suppositories (single 500 mg dose, n = 24) and a study with two i.v. administrations of 100 and 250 mg mesalazine (n = 6). In total, 200 administrations were carried out and plasma concentration-time curves obtained and analyzed. There was a large variability in the absorption of mesalazine for all formulations. The plasma concentration-time curves of parent drug and metabolite acetylmesalazine run nearly parallel, independent of the formulation and the dose. Plasma and urine mesalazine and acetylmesalazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass-spectrometric detection. Results: As a result of the large variations in release and absorption of mesalazine in the pharmaceutical formulations and administrations, it was possible to demonstrate that acetylation occurs in the gut wall and in the liver. By comparing oral and rectal data to intravenous data, it was possible to indicate where (and to what extent) acetylation occurs in the gut wall, in the liver, or both. Rectal administration of a mesalazine suppository and intravenous administration results in hepatic acetylation. Oral administrations of mesalazine results in both gut wall and hepatic acetylation. Acetylation by the gut wall amounts to 30% of the dose for gastro-resistant tablets and to 40% of the dose for prolonged-release tablets.Correspondence to:
Dr. T.B. Vree; Institute for Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands

Extended Abstracts

Biomarker response on exposure to sunitinib and its primary metabolite (SU12662) in metastatic colorectal cancer patients

F. Kanefendt, A. Lindauer, M. Kinzig, D. Strumberg, M.E. Scheulen, K. Mross, R. Fischer, B. Moritz, F. Sörgel and U. Jaehde

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Volume 49 p. 88 - 90

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