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Drug Safety

Multiple drug prescribing by general practitioners in a German region: implications for drug interactions and patient safety

R. Fux, D. Greiner, M. Geldmacher, K. Mörike and C.H. Gleiter

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Volume 44 p. 539 - 547

Abstract

R. Fux¹, D. Greiner¹, M. Geldmacher², K. Mörike¹ and C.H. Gleiter¹

¹Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, and ²Health Insurance Medical Service (MDK) Baden-Württemberg, Lahr/Schwarzwald, Germany
Objective: An increased number of drugs used by patients enhances the risk of potentially hazardous drug interactions. So far, no representative data are available about how common this problem is in German general practices. Methods: We performed a retrospective analysis using a prescription database for a German region. The 50 general practitioners (out of 1,457) who wrote the most prescriptions during January to March 2003 were included. Data on 4,153 patients who were prescribed at least 10 drugs were analyzed for 92 predefined Drug Combinations Prone to Interact (DCPI) to a clinically relevant extent and possible contraindications. Results: From 92 DCPIs, 71 occurred in the analyzed population between 1 and 275 times. The total number of DCPI cases was 1,295, which included 10% (n = 129) of contraindicated combinations. Among 4,153 analyzed patients, 822 patients (19.8%) were affected by at least 1 DCPI. In 268 patients (6.5%), multiple DCPIs occurred. The most frequently found drug pairs were digitalis/diuretics, digitalis/calcium channel blockers, and theophylline/quinolones. Among contraindicated combinations, tricyclic antidepressants, St. John’s wort and antiarrhythmic drugs were most frequently involved. In about 1/3 of patients treated for chronic heart failure, pharmacotherapy appeared not to be guideline-adherent. Conclusion: Drug interactions, especially in polypharmacotherapy, represent a potential hazard which must be taken into account by the prescribing physician. Our study is the first to use a prescription database for the evaluation of drug prescriptions within a German region.Correspondence to:
C.H. Gleiter, MD
Department of Clinical Pharmacology
Institute of Pharmacology and Toxicology
University Hospital Tübingen
Otfried-Müller-Straße 45
72076 Tübingen, Germany
Email: [email protected]

Drug Utilization

What do primary care patients think about generic drugs?

W. Himmel, A. Simmenroth-Nayda, W. Niebling, T. Ledig, R.-D. Jansen, M.M. Kochen, C.H. Gleiter and E. Hummers-Pradier

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Volume 43 p. 472 - 479

Abstract

W. Himmel, A. Simmenroth-Nayda, W. Niebling, T. Ledig, R.-D. Jansen, M.M. Kochen, C.H. Gleiter and E. Hummers-Pradier

¹Department of General Practice, University of G
Objective: To examine the attitude of patients towards generic drugs and prescriptions containing generic drugs as an alternative to brand-name products, with a special focus on information on patients attitude to generic drugs provided by their general practitioners (GPs). Methods: A total of 804 patients in 31 general practices were surveyed using a self-questionnaire. The influence of age, sex, education, disease, knowledge of generic drugs, experience with generic substitution and information provided by the GP on patient attitudes towards generic drugs and substitutions were examined. Results: Nearly two thirds of the patients (509/804) stated that they knew of the difference between brand-name drugs and generics; of these, one third were not satisfied with the information given by their GPs and 37% of patients expressed general skepticism towards generic drugs because of their lower price. This attitude was more frequent among those who felt that generic prescribing was ?invented? to solve the financial crisis in the German health insurance system at their expense (odds ratio (OR): 6.2; 95% confidence interval: 4.0 ? 9.8) and those who had not been confronted personally with a generic substitution (OR: 1.8; 1.3 ? 3.0). Patients who had been skeptical when first confronted with a generic substitution were more frequently among those who considered inexpensive drugs to be inferior (OR: 4.5; 2.0 ? 10.4) and they were frequently not satisfied with the information on substitution provided by their GP (OR: 2.7; 1.2 ? 5.9). Conclusion: GPs are in an ideal position to inform their patients adequately about the equivalence of brand-name and generic drugs. However, the patient view that inexpensive drugs must be inferior may be difficult to rectify in the short term.Correspondence to:
PD Dr. W. Himmel Department of General Practice University of G
Email: [email protected]

Therapeutics

The role of active metabolites in dihydrocodeine effects

H. Schmidt, S.V. Vormfelde, M. Walchner-Bonjean, K. Klinder, S. Freudenthaler, C.H. Gleiter, U. Gundert-Remy, G. Skopp, R. Aderjan and U. Fuhr

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Volume 41 p. 95 - 106

Abstract

H. Schmidt, S.V. Vormfelde, M. Walchner-Bonjean, K. Klinder, S. Freudenthaler, C.H. Gleiter, U. Gundert-Remy, G. Skopp, R. Aderjan and U. Fuhr

¹pharmazentrum frankfurt, Clinical Pharmacology, University of Frankfurt, ²Institute of Clinical Pharmacology, University of Göttingen, ³Institute of Pharmacology, Clinical Pharmacology, University of Köln, ⁴Institute of Forensic Medicine, University of Heidelberg, ⁵Department of Clinical Pharmacology, University of Tübingen, and ⁶BgVV, Berlin, Germany
Objective: The metabolism of dihydrocodeine to dihydromorphine, a high affinity m-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. Methods: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. Results: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. Conclusion: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.

Letter to the Editor

Psoriasis aggravation and metoprolol treatment – a prospective observational case study

R. Fux, K. Mörike, A.M.T. Pröhmer, U. Delabar, E. Schaeffeler, C.H. Gleiter and M. Schwab

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Volume 45 p. 659 - 661

Original Research

Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults

G. Böhmer, C.H. Gleiter, A. Hünnemeyer, G. Lahu and T.D. Bethke

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Volume 49 p. 451 - 460

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (451-460)

Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults

G. Böhmer¹, C.H. Gleiter¹, A. Hünnemeyer², G. Lahu² and T.D. Bethke²

¹Department of Clinical Pharmacology, University of Tübingen, Tübingen, and ²Nycomed GmbH, Konstanz, Germany
Objective: To investigate whether a pharmacokinetic drug-drug interaction exists between theophylline (THEO), a CYP1A2 substrate with a narrow therapeutic index, and the concomitant substrate roflumilast (ROF), a novel selective PDE4 inhibitor partially metabolized by CYP1A2. Materials and methods: In an open-label, 2-period, crossover study, Treatment A (oral ROF 500 μg q.d. on Days 6 – 10 in addition to oral THEO 375 mg b.i.d. on Days 1 – 10) and treatment B (oral ROF 500 μg q.d. on Days 1 – 5) were administered consecutively in random order to each of 24 healthy adult subjects. Both periods were separated by a wash-out phase of at least 10 days. Plasma samples for pharmacokinetic evaluation (AUC, C_max, t_1/2, t_max) including percent peak-trough fluctuation (%PTF) of THEO were taken. Point estimates and the 90% confidence interval of the geometric mean ratios were calculated for AUC and C_max and descriptive statistics for other pharmacokinetic parameters. Results: Concomitant administration of ROF did not alter pharmacokinetics of THEO. With coadministered THEO, only steady-state total exposure to ROF (AUC) was increased by 28% whereas other pharmacokinetic parameters (t_1/2, C_max, t_max) of ROF and of the active metabolite roflumilast-N-oxide (R-NO), its main contributor to the pharmacodynamic effects, remained unchanged. Conclusions: Neither ROF nor its main metabolite had any impact on the metabolism of the concomitant CYP1A2 substrate THEO in humans. Though co-administration of THEO resulted in a minor increase (28%) in total ROF exposure, no safety or tolerability concerns and no altered total PDE4 inhibition of both ROF and R-NO, were observed.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: [email protected]

Original Research

Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study

T.D. Bethke, M. Hartmann, A. Hünnemeyer, G. Lahu and C.H. Gleiter

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Volume 49 p. 491 - 499

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (491-499)

Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study

T.D. Bethke¹, M. Hartmann¹, A. Hünnemeyer¹, G. Lahu¹ and C.H. Gleiter²

¹Nycomed GmbH, Konstanz, and ²Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany
Objective: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized. Materials and methods: Patients (n = 12) with severe renal impairment (creatinine clearance CL_CR < 30 ml/ min/1.73 m²; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CL_CR > 80 ml/min/1.73 m²) were enrolled into an open-label, parallelgroup study. Single dose (500 μg, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups. Results: A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC_0–∞), maximum plasma concentration (C_max)) and a small increase in elimination half-life (t_1/2) of roflumilast (–1%; –6%; +19%, respectively) and roflumilast N-oxide (–%; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups. Conclusions: The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: [email protected]

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