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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]

Pharmacokinetics

Absorption pattern of trospium chloride along the human gastrointestinal tract assessed using local enteral administration

S. Schröder, A. Jetter, M. Zaigler, R. Weyhenmeyer, G. Krumbiegel, W. Wächter and U. Fuhr

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Volume 42 p. 543 - 549

Abstract

S. Schröder¹, A. Jetter¹, M. Zaigler¹, R. Weyhenmeyer², G. Krumbiegel², W. Wächter² and U. Fuhr¹

¹Department of Pharmacology, Clinical Pharmacology, University of Cologne, Cologne, and ²Madaus AG, Cologne, Germany
Background and objectives: The antimuscarinic drug trospium chloride is hydrophilic and therefore does not enter the CNS when used for the treatment of overactive bladder disturbances. However, the same property is the main reason for low and variable oral bioavailability. The present study was performed to assess the influence of intestinal site on absorption of the drug as the basis for the development of modified release preparations. Methods: In a change-over pilot study, 8 healthy male volunteers received single 20 mg doses of trospium chloride orally as a tablet (reference), as Eudragit-coated tablets dissolving at pH 6.0 (local administration into the small intestine), and rectally via a mini enema (corresponding to local administration into the large intestine). Plasma concentrations of trospium chloride were determined up to 36 hours after administration using GC/MS. Results: Extent and rate of trospium chloride absorption declined rapidly upon administration into more distal regions of the gastrointestinal tract. Cmax (median: 6.42 ng/ml) and AUC(0-tlast) (42.28 ng/ml × h) were highest and tmax (3.5 h) was shortest after administration of the reference tablet. AUC(0-tlast) reached 78% (90% CI 43 – 139%) after small intestine administration and 2% (90% CI 1 – 9%) following rectal administration, respectively, relative to the values for the oral tablet. Conclusion: Trospium chloride is absorbed primarily in the upper gastrointestinal tract. Development of modified release preparations must balance prolonged apparent absorption rates of the drug against a decrease in bioavailability.
Correspondence to:
Prof. Dr. U. Fuhr
Department of Pharmacology
University of Cologne, Clinical Pharmacology
Gleueler Straße 24
D-50931 Köln, Germany
Email: [email protected]

Extended Abstract

Population pharmacokinetics of etoposide*

S. Reif, A. Jetter, U. Fuhr, H. McLeod, D. Kingreen, W. Siegert and U. Jaehde

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Volume 40 p. 578 - 579

Extended Abstract

Population pharmacokinetics of cyclo- phosphamide, doxorubicin and etoposide in 30 patients with BEACOPP chemotherapy

S. Wilde, A. Jetter, M. Zaigler, S. Rietbrock, H. Menzel, M. Sieber, H. Tesch, G. Hempel, D. Busse, M. Schwab, S. Reif, U. Jaehde, V. Diehl and U. Fuhr

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Volume 40 p. 586 - 588

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