Volume 44, No. 4/2006(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Helicobacter pylori eradication prior to initiation of long-term non-steroidal anti-inflammatory drug therapy in Chinese patients – a cost-effectiveness analysis
J.H.S. You, W. Lau, I.Y.C. Lee, M. Yung, J.Y.L. Ching, F.K.L. Chan and K.K.C. Lee
Abstract
J.H.S. You1, W. Lau1, I.Y.C. Lee1, M. Yung3, J.Y.L. Ching2, F.K.L. Chan2 and K.K.C. Lee1
1Faculty of Medicine, School of Pharmacy, 2Department of Medicine and Therapeutics, Division of Gastroenterology and Hepatology, Faculty of Medicine, 3Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, China
Background: Recent randomized clinical trials suggested that eradication of Helicobacter pylori prior to initiation of non-steroidal anti-inflammatory drug (NSAID) therapy would reduce the rate of peptic ulcer disease (PUD). Objective: To analyze the cost-effectiveness of H. pylori eradication prior to initiation of long-term NSAID therapy for prevention of NSAID-induced PUD in a cohort of Chinese patients at high risk for PUD. Methods: Clinical and economic data of 100 participants from a previously reported clinical trial conducted in Hong Kong were analyzed. Patients with a history of peptic ulcers were randomized to 1-week omeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg twice daily (eradication group; n = 51) or 1-week omeprazole 20 mg twice daily (omeprazole group; n = 49) before initiation of diclofenac 100 mg daily for 6 months. The rates of PUD and healthcare utilization for routine follow-up as well as for management of symptomatic PUD of the 2 groups were retrieved from medical records. Results: The rate of symptomatic ulcers in eradication group and omeprazole group were 3.9% and 18%, respectively. The mean direct medical cost of the eradication group was significantly lower than that of the omeprazole group by 30% (US$ 797 (95% CI = 685 – 909) versus US$ 1,128 (95% CI = 879 – 1,377)) (p = 0.018). The results were robust to variation of all the cost items. Conclusions: H. pylori eradication prior to initiation of NSAID therapy appeared to reduce the ulcer rate and mean direct medical cost when compared to no eradication for Chinese H. pylori-infected NSAID users at high risk for PUD.Correspondence to:
K.K.C. Lee, BSC (Pharm), MPhil, PhD
School of Pharmacy, Faculty of Medicine
The Chinese University of Hong Kong
Shatin, N.T., Hong Kong, China
Email: kclee@cuhk.edu.hk
Adverse Drug Reactions
Modification of pepsinogen I levels and their correlation with gastrointestinal injury after administration of dexibuprofen, ibuprofen or diclofenac: a randomized, open-label, controlled clinical trial
B.J. Gómez, Á. Caunedo, L. Redondo, J. Esteban, M. Sáenz-Dana, M. Blasco, P. Hergueta, M. Rodríguez-Téllez, R. Romero, F.J. Pellicer and J.M. Herrerías
Abstract
B.J. Gómez1, Á. Caunedo1, L. Redondo2, J. Esteban3, M. Sáenz-Dana1, M. Blasco1, P. Hergueta1, M. Rodríguez-Téllez1, R. Romero1, F.J. Pellicer1 and J.M. Herrerías1
1Gastroenterology Service, Virgen Macarena University Hospital, Seville, 2Gebro Pharma Ltd., Barcelona, and 3Investigation Central Service in Health Sciences, Cádiz University, Cádiz, Spain
Objective: To assess the effect of a 2-week treatment with dexibuprofen, in comparison with ibuprofen and diclofenac, on pepsinogen plasma concentrations and gastrointestinal mucosa, as well as the correlation of these changes with gastrointestinal mucosal injury. Methods: 60 patients with rheumatologic disease in chronic therapy with NSAID, were included. After a 7-day run-in period patients were randomly assigned to receive a 14-day treatment with dexibuprofen (Group A; Day 1 – 3 = 400 mg t.i.d; Day 4 – 14 = 400 mg b.i.d.), ibuprofen (Group B; Day 1 – 3 = 800 mg t.i.d; Day 4 – 14 = 800 mg b.i.d.) or diclofenac (Group C; Day 1 – 3 = 50 mg t.i.d; Day 4 – 14 = 50 mg b.i.d.). Upper gastrointestinal endoscopy (Day 15), capsule-endoscopy (Day 16, 7 patients of each group) and determination of pepsinogen plasma concentrations were performed (basal and Day 15). A semiquantitative scale was designed for the assessment of the gastrointestinal mucosa. Results: No differences in plasma pepsinogen were found between treatment groups or gastrointestinal injury grades or between basal and post-therapy determinations. Dexibuprofen showed gastroduodenal mucosal injury in fewer patients (42.1%) than was the case with ibuprofen (5%; p = 0.003) and diclofenac (30%; p = N.S.). Dexibuprofen administration was also associated with more patients having no intestinal mucosal damage (42.86% vs. 28.7% in the diclofenac group and 14.29% in the ibuprofen group; p = 0.0175). The rate of clinical adverse events was similar in Groups A, B and C (28%, 38% and 34%). Conclusions: Dexibuprofen showed a lower rate of gastroduodenal and intestinal mucosal injury. This effect was not mediated by modifications of plasma pepsinogen levels.Correspondence to:
Á. Caunedo Álvarez
Gastroenterology Service
Virgen Macarena University Hospital
Avda. Dr. Fedriani
41071 Seville, Spain
Email: jmhg@us.es
Drug Interactions
Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients
H. Holdaas, E. Hagen, A. Åsberg, K. Lund, A. Hartman, S. Vaidyanathan, P. Prasad, Y.-L. He, C.-M. Yeh, H. Bigler, M. Rouilly and J. Denouel
Abstract
H. Holdaas1, E. Hagen1, A. Åsberg2, K. Lund1, A. Hartman1, S. Vaidyanathan3, P. Prasad3, Y.-L. He3, C.-M. Yeh3, H. Bigler4, M. Rouilly4 and J. Denouel5
1Department of Medicine, National Hospital, Oslo, 2Department of Pharmacology, School of Pharmacy, University of Oslo, Norway, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 4Novartis Pharma AG, Basel, Switzerland, 5Novartis Pharma SAS, Rueil-Malmaison, France
Objective: To assess the pharmacokinetic interaction between cyclosporine and extended-release fluvastatin (fluvastatin XL), 80 mg for 7 days, in stable renal transplant recipients. Methods: This was a single-center, open-label study. 17 renal transplant recipients received their standard cyclosporine therapy (Days 1 – 9) plus a once-daily single oral dose of fluvastatin XL, 80 mg (Days 2 – 8). Blood samples were collected and cyclosporine (whole blood) and fluvastatin (plasma) concentrations determined by radioimmunoassay and HPLC fluorescence detection, respectively. Pharmacokinetic parameters were calculated using non-compartment analysis and fluvastatin results were compared with historical controls. Results: Treatment with fluvastatin XL, 80 mg for 7 days, had no significant effect on either the AUC0-12 (3,644 ng ´ h/ml in the absence of fluvastatin vs. 3,534 ng ´ h/ml in the presence of fluvastatin) or the Cmax of cyclosporine (983 ng/ml in the absence of fluvastatin vs. 945 ng/ml in the presence of fluvastatin). Co-administration of fluvastatin XL also had no effect on the tmax, t1/2 or apparent clearance (CL/F) of cyclosporine in renal transplant patients. The AUC and Cmax for fluvastatin XL in the presence of cyclosporine (AUC0-24 1,192 ng ´ h/ml, Cmax 271 ng/ml) were approximately 2-fold higher compared with historical data for fluvastatin XL alone in healthy volunteers (AUC0-24 630 ng ´ h/ml, Cmax 102 ng/ml) but lower than the historical data for fluvastatin IR, 40 mg b.i.d. alone in healthy volunteers (AUC0-24 1,340 ng ´ h/ml, Cmax 443 ng/ml). Tmax, t1/2 and trough levels of fluvastatin in the presence of cyclosporine were also similar to the historical controls. Concomitant administration of cyclosporine and fluvastatin XL was well tolerated by renal transplant recipients. Conclusions: Fluvastatin XL, 80 mg, and cyclosporine do not show clinically relevant pharmacokinetic interactions.Correspondence to:
H. Holdaas, MD, PhD
Department of Medicine
National Hospital
Sognsvannsveien 20
0027 Oslo, Norway
Email: hallvard.holdaas@rikshospitalet.no
Pharmacokinetics
Plasma pharmacokinetics of desmopressin following sublingual administration: an exploratory dose-escalation study in healthy male volunteers
I.M. Steiner, S.T. Kaehler, R. Sauermann, H. Rinösl, M. Müller and C. Joukhadar
Abstract
I.M. Steiner1, S.T. Kaehler2, R. Sauermann1, H. Rinösl1, M. Müller1 and C. Joukhadar1,3
1Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Vienna General Hospital, Medical University of Vienna, 2Medical Department, Gebro Pharma GmbH, Fieberbrunn, 3Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy, Vienna General Hospital, Medical University of Vienna, Austria
Objective: Desmopressin is usually administered intranasally in the treatment of central diabetes insipidus or nocturnal enuresis. The sublingual administration of desmopressin is expected to be an alternative to the intranasal route with advantages to children and to patients with allergic rhinitis or chronic rhinosinusitis. Therefore, the present study was carried out to explore the time-versus-concentration profile of desmopressin in plasma after sublingual administration to healthy volunteers. Subjects and methods: A total of 16 healthy male volunteers were enrolled in this open, exploratory, 1-period, randomized, dose-escalation study. Volunteers received a single sublingual dose of either 20, 40, 80, 160, 240 or 320 mg of desmopressin acetate. Desmopressin plasma concentrations were measured over a 12-hour period using a validated radioimmunoassay method. Safety and tolerability were assessed simultaneously. Results: Plasma concentrations of desmopressin were below the lower limit of quantification (LLOQ) of 5 pg/ml for doses lower than 80 mg. For the doses of 160 – 320 mg the time-versus-concentration profiles were higher than the LLOQ. The area under the curve from 0 – 12 h (AUC0-12h) was 54.66 ± 25.92 pg × h/ml after the 160 mg dose, 104.38 ± 79.10 pg × h/ml following the 240 mg dose and 133.18 ± 181.84 pg × h/ml following the 320 mg dose. Given the data from previous experiments, the time-versus-concentration profile of desmopressin in plasma after a sublingual dose of 240 mg appeared to be in the range of previously published data on an intranasal dose of 20 mg. Sublingual administration of desmopressin proved to be safe and was well tolerated by all volunteers. Conclusion: A very high inter-individual variability in desmopressin plasma concentrations was detected after sublingual administration. A sublingual dose of 240 mg of desmopressin appeared to result in a pharmacokinetic profile comparable to 20 mg administered intranasally. These data, however, need to be verified in a separate well-designed prospective clinical study.Correspondence to:
C. Joukhadar, MD
Department of Clinical Pharmacology
Medical University of Vienna
Währinger Gürtel 18 – 20
1090 Vienna, Austria
Email: christian.joukhadar@meduniwien.ac.at
Biavailability Section
Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product
J.F. Marier, I. Morin, D. Al-Numani, M. Stiles, G. Morelli, S.K. Tippabhotla, T. Vijan, A.K. Singla, M. Garg, M. Di Marco and T. Monif
Abstract
J.F. Marier1, I. Morin1, D. Al-Numani1, M. Stiles2, G. Morelli1, S.K. Tippabhotla3, T. Vijan3, A.K. Singla3, M. Garg3, M. Di Marco1 and T. Monif3
1MDS Pharma Services, St-Laurent (Montréal), Quebec, Canada, 2MDS Pharma Services, Lincoln, Nebraska, USA, 3Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India
Objective: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successfully for more than a decade to treat human immunodeficiency virus (HIV) infection. The objective of the current study was to determine the bioequivalence between a generic capsule formulation of efavirenz and the innovator product. Material and methods: A total of 41 healthy subjects (34 males and 8 females) received a single 200 mg oral dose of efavirenz as the generic (Ranbaxy-Efavirenz, Ranbaxy Laboratories Ltd.) and innovator (Sustiva, Bristol-Myers Squibb) capsule formulations under fasting conditions in a randomized, 2-way crossover study. Multiple blood samples were collected over 72 hours and plasma concentrations of efavirenz were assayed using an LC/MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. Results: Plasma concentrations of efavirenz peaked within 2.5 hours and then declined in a multi-exponential manner for both formulations. At 72 hours post dose, all plasma concentrations of efavirenz were above the LOQ of the assay (10 ng/ml). Mean area under the curve from 0 – 72 hours (AUC0-72) and maximum plasma concentrations (Cmax) of efavirenz for the generic capsule formulation were 22,840 ng ´ h/ml and 1,199 ng/ml, respectively. Ratios and 90% confidence intervals of PK parameters between the two formulations were within 80.0 – 125.0%, suggesting that the two capsule formulations resulted in similar rate and extent of bioavailability under fasting conditions. Adverse events were similar in nature and frequency for the two formulations. Conclusions: Based on the above results, the generic capsule formulation of efavirenz developed by Ranbaxy should be as effective as the innovator product.Correspondence to:
Dr. T. Monif
Director, Department of Clinical Pharmacology and Pharmacokinetics
Ranbaxy Laboratories Ltd.
Plot No. 20, Sector-18, Udyog Vihar Industrial Area
Gurgaon 122 001, Haryana, India
Email: tausif.monif@ranbaxy.com
Biavailability Section
Effect of food intake on the bioavailability of almotriptan, an antimigraine compound, in healthy volunteers: an open, randomized, crossover, single-dose clinical trial
J.M. Jansat, A. Martinez-Tobed, E. Garcia, X. Cabarrocas and J. Costa
Abstract
J.M. Jansat1, A. Martinez-Tobed1, E. Garcia2, X. Cabarrocas2 and J. Costa3
1Department of Pharmacokinetics and Drug Metabolism and 2Medical Department, Almirall Prodesfarma S.A., Barcelona, Spain
3Department of Clinical Pharmacology, Hospital Universitari “Germans Trias i Pujol”, Universitat Autònoma de Barcelona, Spain
This open, randomized, crossover, single-dose clinical trial evaluated the possible pharmacokinetic interaction between a single oral dose of almotriptan 25 mg, a 5-HT1B/1D receptor agonist for the acute treatment of migraine, and food intake in healthy volunteers. The influence of food intake in the rate and extent of almotriptan absorption was evaluated by bioequivalence criteria. Tolerability and safety of treatment were also assessed. 16 healthy volunteers (8 men and 8 women, aged 19 – 27 years) received a crossed single oral dose of almotriptan 25 mg under fasting and fed conditions, separated by a 7-day washout period. The treatment given under fasting condition was considered as reference. Plasma levels of almotriptan were analyzed using high-performance liquid chromatography (HPLC) and UV detection at 227 nm. The 90% confidence intervals (CI) for the logarithmically transformed Cmax and AUC0-¥ values of almotriptan under fasting and fed conditions (97.8 – 124% and 102.9 – 108.2%, respectively) fell into the predetermined accepted range of 80 – 125%. No statistically significant differences in Cmax, tmax, AUC0-¥, MRT and t1/2 were observed under fasting and fed conditions between men and women. Tolerability of treatments was good throughout the whole study period. In conclusion, administration of almotriptan 25 mg is bioequivalent under fasting and fed conditions in healthy men and women. Therefore, it is unlikely that concomitant food intake would produce clinically relevant differences in therapeutic effect with almotriptan at the dose studied here. Correspondence to:
J.M. Jansat, MD
Department of Pharmacokinetics and Drug Metabolism
Almirall Prodesfarma, S.A., Research Center
Laurea Miro 408-410
08980 Sant Feliu de Llobregat, Barcelona, Spain
Email: jmjansat@almirall.es
Lettter to the Editor
Levocetirizine in patients with chronic idiopathic urticaria: results of a multicenter clinical practice study
O. Pfaar, H. Wrede, C. Barth, I. Hansen and L. Klimek
Abstract
O. Pfaar, H. Wrede, C. Barth, I. Hansen and L. Klimek
