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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]

Original

Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women

M. Zaigler, S. Rietbrock, J. Szymanski, J.S.E. Dericks-Tan, A.H. Staib and U. Fuhr

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Volume 38 p. 235 - 244

Abstract

M. Zaigler¹,², S. Rietbrock¹,², J. Szymanski², J.S.E. Dericks-Tan³, A.H. Staib² and U. Fuhr¹,²

¹Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, ²Institute for Clinical Pharmacology, and ³Department of Gynaecological Endocrinology, Centre for Gynaecology and Obstetrics, University Hospital, Frankfurt am Main, Germany
Background and objectives: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP1A2 activity is not clear. Methods: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean ± SD) 27.8 ± 3.8 years, body mass index 23.8 ± 3.8 kg × m–2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 ± 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. Results: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day –9 to –4 prior to onset of the next menses) to the follicular phase (days 5 – 10) was (n = 13, point estimate) 1.03 (90% CI 0.95 – 1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. Conclusions: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.Correspondence to:
Prof. Dr. med. U. Fuhr; Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, Gleueler Straße 24, D-50931 Köln, Germany

Original Research

Adverse drug reactions (ADRs) associated with hospital admissions – elderly female patients are at highest risk

C. Hofer-Dueckelmann, E. Prinz, W. Beindl, J. Szymanski, G. Fellhofer, M. Pichler and J. Schuler

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Volume 49 p. 577 - 586

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (577-586)

Adverse drug reactions (ADRs) associated with hospital admissions – elderly female patients are at highest risk

C. Hofer-Dueckelmann¹, E. Prinz², W. Beindl¹, J. Szymanski³, G. Fellhofer¹, M. Pichler² and J. Schuler²

¹Pharmacy Department, Landesapotheke Salzburg, ²Department of Cardiology, Landeskrankenhaus Salzburg, Private Paracelsus Medical University, Salzburg, Austria, and ³Helios Klinikum Wuppertal, Universität Witten/Herdecke, Department of Clinical Pharmacology, Wuppertal, Germany
Background: ADRs represent a significant problem in drug utilisation. The prevalence of admissions caused by ADRs varies depending on the observational site, studied population, data collection method and the used definitions. Women seem to be more frequently affected than men. Objective: To assess the incidence and quality of ADRs related to hospital admissions, to identify the drugs most commonly involved and to define risk factors and preventive strategies for those ADRs. Material and methods: 3,190 medical records of all newly admitted internal ward patients were assessed in a prospective observational study in an internal hospital over 6 months. Potential ADRs at hospital admission were identified following a list of suspicious symptoms and laboratory results. Cases were evaluated by means of a computer tool and data-base specialized on detecting causality and severity of ADRs. Results: 304 ADRs were identified in 242 patients (7.6%), with 60% directly leading to admission. More women than men encountered an ADR (10 vs. 6%, p < 0.005). Analyzed separately by age groups, this gender difference became significant at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances and over-anticoagulation. Diuretics and vitamin K antagonists were significantly correlated with ADRs. 62% of all ADRs were severe or life-threatening. Conclusion: ADRs leading or related to hospital admission are highly prevalent. Older age and female gender are significantly associated with ADR related hospital admissons. Causative drugs are the ones prescribed most frequently. Multidisciplinary preventive strategies and surveillance methods are necessary to ensure better care and patient safety especially for elderly women.Correspondence to:
C. Hofer-Dueckelmann
Pharmacy Department
Landesapotheke Salzburg
Müllner Hauptstr. 50
5020 Salzburg, Austria
Email: [email protected]

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