Volume 47, No. 4/2009(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors – Part C Special Pharmacology
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
Abstract
F.W. Bergert, D. Conrad, K. Ehrenthal, J. Feßler, J. Gross, K.Gundermann, B. Kluthe, W. Lang Heinrich, A. Liesenfeld, P.G. Loew, E. Luther, R. Pchalek, J. Seffrin, A. Sterzing, H.-J. Wolfring and U. Zimmermann
General Practitioners, Association of Statuatory Health Insurance Physicians in Hesse (Kassenärztliche Vereinigung in Hessen (KVH) Frankfurt (Main)), Germany
This article contains the 4th part of the Pharmacotherapy Guidelines for the Aged by Family Doctors for Family Doctors. Part 4 is dedicated to fecal incontinence and chronic constipation. The diagnostic categories are divided according to severity and dysfuntion of bowel and pelvic floor, sphincter and neural control. Therapy is also outlined. Importance is given to patient history, in particular the use and abuse of drugs that stimulate peristalsis and promote constipation. Therapy in the elderly is guided by the maxim: use the most conservative therapy possible, where stool training has considerable importance. Drug therapy based on symptoms can only be recommended when non-drug measures continue to fail. In patients with fecal incontinence: 1) opiates (which reduce colonic motility), 2) loperamide (which has the capacity to dilate the rectum) and 3) anion exchangers which have the capacity to prevent cholonic diarrhea. In patients with chronic obstipation: 1) trial: stool-forming laxatives (ensure intake of sufficient amount of fluids) 2) trial: laxatives with an osmotic effect and 3) trial: stimulating laxatives (beware abuse, do not use in cases of acute abdomen).Correspondence to:
Dr. L. von Ferber, PD; Auf dem Ufer 7, 40593 Düsseldorf, Germany
Email: Liselotte.vonFerber@uni-duesseldorf.de
Therapeutics
Pharmacist intervention in activated protein C therapy for severe sepsis: influence on health and economic outcomes
A.L. Chan, H.-J. Hsieh and S.-J. Lin
Abstract
A.L. Chan1,2, H.-J. Hsieh2 and S.-J. Lin1
1School of Pharmacy, Kaohsiung Medical University, Kaohsiung, and 2Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan
Objective: To assess the health and cost outcomes of pharmacist intervention versus non-intervention in activated protein C (drotrecogin alpha) therapy for patients with severe sepsis. Method: This is a retrospective study. We reviewed the medical records of patients aged 18 years and older who were admitted to our hospital for severe sepsis from January 1, 2003 to December 31, 2007. Only patients who are prescribed activated protein C for the treatment of severe sepsis according to the reimbursement criteria can be reimbursed by the Taiwan Bureau of National Health Insurance (BNHI). Our hospital stipulated that the criteria check list must be evaluated by a clinical pharmacist and the prescribing physician as to whether the patient is eligible to receive activated protein C. To assess the influence of pharmacist intervention on outcomes, we divided eligible patients into two groups, pharmacist-intervention group (Group A; n = 19) and non-pharmacist intervention group (Group B; n = 19). Both groups received a 96-h intravenous infusion of activated protein C at 24 µg/kg/h. We defined evident severe sepsis as concurrent antibiotic plus ventilator and/or vasopressor use. We compared group characteristics, 28-day in-hospital mortality, length of stay and direct medical costs between the two groups. One-way ANOVA was used for analysis. Results: 50% of patients in each group met the reimbursement criteria of the BNHI. Activated protein C therapy was initiated within 1.37 ± 0.4 days and 7.21 ± 7.8 days of admission to the ICU in Group A and Group B, respectively (p < 0.01). All of the patients in Group A (19/19) and 42.1% of the patients in Group B (8/19) received activated protein C within 12 – 48 h of admission to the Intensive care unit (ICU) (p < 0.01). 28-day mortality was lower for Group A than for Group B (26.7% and 43.8%, respectively). The length of stay in the ICU for patients in Group A was shorter than that in Group B (14.1 ± 7.7 vs. 19.7 ± 11.1, respectively; p < 0.079). Total direct medical costs for survivors in Group A were less than those in Group B (US$ 20,632.3 vs. US$ 24,785.8, respectively; p < 0.05). Conclusions: Pharmacist intervention in prescribing activated protein C for patients with severe sepsis might reduce direct medical costs and promote earlier initiation of therapy. The potential impact of pharmacist intervention on the timing of activated protein C therapy and the direct medical costs of treatment warrant further study.Correspondence to:
Dr. S.-J. Lin; School of Pharmacy, Kaohsiung Medical University, 100, Shi-Chuan 1st Rd., Kaohsiung, Taiwan
Email: anasjlin@kmu.edu.tw
Pharmacokinetics
Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide
G. Lahu, A. Huennemeyer, R. Herzog, N. McCracken, R. Hermann, M. Elmlinger and K. Zech
Abstract
G. Lahu1,2, A. Huennemeyer1, R. Herzog1, N. McCracken1, R. Hermann3, M. Elmlinger1 and K. Zech1
1Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, 2University of Tuebingen, Institute for Toxicology, Pharmacy and Chemistry, Tuebingen, and 3Clinical Research Appliance, Radolfzell, Germany
Objective: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. Methods: Subjects (n = 16) received single oral roflumilast 500 µg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 – 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. Results: After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. Conclusions: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.Correspondence to:
G. Lahu; Nycomed GmbH, Department of Pharmacometrics and Pharmacokinetics, Byk-Gulden-Straße 2, 78467 Konstanz, Germany
Email: gezim.lahu@nycomed.com
Pharmacokinetics
The pharmacokinetic and tolerability profile of varenicline in healthy Chinese volunteers
Y. Xiao, Y. Lv, X. Zhang, Y. Guo and T. Bergstrom
Abstract
Y. Xiao1, Y. Lv1, X. Zhang2, Y. Guo2 and T. Bergstrom3
1Institute of Clinical Pharmacology, First Hospital, Peking University, 2Pfizer Pharmaceuticals Limited, Beijing, China, 3Pfizer Inc., New York, NY, USA
Objective: Varenicline is a selective, nicotinic alpha4beta2 acetylcholine receptor partial agonist that has been licensed as a smoking cessation drug in more than 70 countries worldwide. The current study was conducted in order to evaluate its pharmacokinetic (PK) properties and tolerability in healthy volunteer Chinese smokers. Methods: This was an open-label, non-randomized study conducted over 17 days at a single center in China. Male and female subjects (18 – 45 years old) received a single, 1 mg dose of varenicline on days 1 and 10 as well as 1 mg varenicline twice daily (12-h dosing interval) on Days 4 – 9. Results: A total of 14 subjects (50% male) received varenicline as per study protocol for 8 days. The mean maximum plasma concentration of varenicline (Cmax) was 1.93-fold larger at steady state (reached on Day 8, after 4 days of repeat dosing) than following a single dose, showing accumulation of varenicline on repeat administration. Median values of tmax (time of occurrence of Cmax) were similar for both dosing regimens (3.0 and 2.5 h following single and multiple dosing, respectively). The mean elimination half-life following single and multiple dosing was 15.2 and 18.3 h, respectively. There was no evidence of time- or concentration-dependence in the PK of varenicline upon repeat dosing as the ratio of the area under the plasma concentration vs time curve (AUC) from time 0 – 12 h at steady state to the AUC from time 0 – 8 on Day 1 was nearly 1. The 2-sided 95% confidence intervals for this comparison included 1, demonstrating the linearity of the PK of varenicline for the single and multiple doses. Varenicline was safe and well-tolerated, adverse events were mild in severity and there were no abnormal laboratory tests. Conclusions: Varenicline 1 mg twice daily was safe and well-tolerated in a cohort of healthy male and female, 18- to 45-year-old Chinese smokers and demonstrated PK properties that were stable and reproducible and similar to those observed previously in Western subjects.Correspondence to:
Y. Xiao, MD, PhD; Institute of Clinical Pharmacology, First Hospital, Peking University, No. 38, Xueyuan Road,Haidian District, Beijing 100083, China
Email: xiaoyonghong@bjmu.edu.cn
Pharmacokinetics
Effect of eslicarbazepine acetate on the pharmacokinetics of metformin in healthy subjects
J.-F. Rocha, M. Vaz-da-Silva, L. Almeida, A. Falcão, T. Nunes, A.-T. Santos, F. Martins, C. Fontes-Ribeiro, T. Macedo and P. Soares-da-Silva
Abstract
J.-F. Rocha1, M. Vaz-da-Silva1, L. Almeida1, A. Falcão2, T. Nunes1, A.-T. Santos1, F. Martins3, C. Fontes-Ribeiro3, T. Macedo3 and P. Soares-da-Silva1
1Department of Research and Development, BIAL, S. Mamede do Coronado, 24Health Limited, Cantanhede, and 3CEB – Centre for Bioavailability Studies, AIBILI, Coimbra, Portugal
Purpose: Eslicarbazepine acetate (ESL) is a new voltage-gated sodium channel blocker currently in development for the treatment of neuropathic pain, including that of diabetic origin. The primary objective was to investigate the effect of ESL on the pharmacokinetics of metformin, a commonly used oral antidiabetic drug. Methods: Randomized, open-label, two-way crossover study in 20 healthy subjects. The volunteers received an 850 mg single-dose of metformin hydrochloride on two occasions – once as such and once after pre-treatment with an oral once-daily dose of ESL 1200 mg for 6 days – separated by a washout period of at least 2 weeks. The bioequivalence approach was used for assessing the effect of ESL on the pharmacokinetics of metformin. Test/Reference geometric mean ratios (GMR) and 90% confidence intervals (90% CI) were calculated for AUC0-¥, AUC0-12 and Cmax of metformin. Results: Test/Reference metformin GMR (90% CI) was 0.95 (0.86; 1.05) for AUC0-¥, 0.95 (0.88; 1.06) for AUC0-12, and 0.88 (0.77; 1.00) for Cmax. Formal bioequivalence could not be demonstrated for metformin Cmax. However, the extent of exposure to metformin, as reflected by AUC0-12 and AUC0-¥, allows the claim of bioequivalence since the 90% CI of the GMR fall within the pre-specified bioequivalence acceptance interval (0.80; 1.25). Conclusion: Once-daily administration of ESL 1,200 mg had no relevant effect on the systemic exposure to metformin pharmacokinetics in healthy subjects.Correspondence to:
P. Soares-da-Silva, MD, PhD; Department of Research & Development, BIAL, À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal
Email: psoares.silva@bial.com
Bioavailability Section
Correcting endogenous concentrations of testosterone influences bioequivalence and shows the superiority of TDS®-testosterone versus Androgel®
Z. Chik, A. Johnston, A.T. Tucker, K. Kirby and C.A. Alam
Abstract
Z. Chik1, A. Johnston2, A.T. Tucker2,3, K. Kirby4 and C.A. Alam5
1Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur Malaysia, 2Clinical Pharmacology, 3The Ernest Cooke Clinical Microvascular Unit, St Bartholomew’s Hospital, Barts & The London NHS Trust, London, UK, 4Langford Institute, North Palm Beach, FL, USA, and, 5Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, UK
Aim: Circulating concentrations of endogenous compounds such as testosterone, complicate the analysis of pharmacokinetic parameters when these compounds are administered exogenously. This study examines the influence of three correction methods of accounting for endogenous concentrations on the determination of bioequivalence between two testosterone formulations. Methods: 12 healthy males received 50 mg TDS®-testosterone, TDS®-placebo, and 50 mg Androgel® in a randomized placebo controlled study. Three correction methods (1,2 and 3) to remove the influence of endogenous testosterone from the exogenous blood concentrations data were carried out before the calculation of the AUC and Cmax. The relative bioavailabilities between two treatments were then performed for the AUC and Cmax for all the corrected and uncorrected data. Correction 4 was performed on the AUC and the Cmax values and the average values were calculated for both active treatments. Results: The relative bioavailability comparison of the AUC and Cmax, showed that the TDS®-testosterone and Androgel® was bioequivalent by using uncorrected data (CI: 93 – 120%; AUC0-12 and 88 – 117%; Cmax). However, they were not bioequivalent when using all the corrections data ((Corr. 1; CI: 52 – 106%; AUC0-12 and 50 – 258%; Cmax), (Corr. 2; CI: 71 – 655%; AUC0-12 and 87 – 286%; Cmax), (Corr. 3; CI: 67 – 315%; AUC0-12 and 88 – 157%; Cmax)). TDS®-testosterone also showed the higher AUC0-12 and Cmax compared to Androgel® for uncorrected and all the Corrections 1, 2, 3 and 4. Conclusions: Different results obtained in the relative bioavailability between TDS®-testosterone and Androgel® for uncorrected data and corrected data, suggests that correcting endogenous concentrations is important for the proper determination of bioequivalent for endogenous compounds such as testosterone.Correspondence to:
Z. Chik, PhD; Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malysia
Email: zamrichik@ummc.edu.my
Bioavailability Section
Bioavailability of a controlled-release cyclobenzaprine tablet and influence of a high fat meal on bioavailability
M.N. Gai, E. Costa and A. Arancibia
Abstract
M.N. Gai, E. Costa and A. Arancibia
Center for Development in Pharmaceutical Technology, Department of Science and Pharmaceutical Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago de Chile
Objective: To evaluate the systemic bioavailability of a new controlled release cyclobenzaprine tablet, and the influence of a high fat meal on its bioavailability. Subjects, materials and methods: 24 and 12 healthy male subjects were recruited for the bioavailability and influence of diet studies, respectively. Experimental design for both studies was an open randomized, 2-period, single dose, crossover study. In the bioavailability study, each subject received in different occasions, a single oral dose of cyclobenzaprine of immediate (10 mg) or controlled release (20 mg) tablet, followed by a 2-week washout period. In the influence of diet study, the volunteers received the controlled-release tablet concomitantly with a high fat meal or in a state of fasting. Results: In the bioavailability study, plasma cyclobenzaprine profiles were in agreement with a controlled release system. This formulation presented a 92.8% of relative bioavailability (IC 85.5 – 105%) and a significant reduction in Cmax (IC 58 – 65.5%), when compared with equal dose of the immediate release tablet. The presence of food increased AUC (11.6%) and Cmax (48%). For both parameters the calculated 90% confidence interval was not in the bioequivalence interval, 97.4 – 125.8% for AUC and 111.7 – 184.2% for Cmax. Conclusions: The controlled release tablet showed a relative bioavailability comparable with equal dose of the immediate release product and produced a significantly lower Cmax, as expected in a controlled release formulation. The concomitant administration of the tablet with a high fat meal produced an increase on its bioavailability, mainly in Cmax, with no evidence of dose-dumping.Correspondence to:
M.N. Gai, PhD; Avda Vicuna Mackenna 20, Providencia Santiago, Chile
Email: mgai@uchile.cl
Bioavailability Section
Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers
H. Lubenau, A. Sveikata, G. Gumbrevicius, J. Macijauskiene, V. Fokas, S. Kazlauskas and V. Janulionis
Abstract
H. Lubenau1, A. Sveikata2, G. Gumbrevicius2, J. Macijauskiene3, V. Fokas4, S. Kazlauskas5 and V. Janulionis6
1BioGeneriX AG, Mannheim, Germany, 2Department of Theoretical and Clinical Pharmacology, Kaunas University of Medicine, Kaunas, 3Clinic of Geriatric, Kaunas University of Medicine, Kaunas, 4CRO Biomapas, Kaunas, 5Department of Analytical and Toxicological Chemistry, Kaunas University of Medicine, Kaunas, 6Department of Applied Mathematics, Kaunas University of Technology, Kaunas, Lithuania
Objective: The objective of the study was the demonstration of bioequivalence of two recombinant human granulocyte colony-stimulating factor (G-CSF) formulations after subcutaneous administration of 5 µg/kg and 10 µg/kg comparing their pharmacokinetic and pharmacodynamic profiles in healthy subjects. Methods: This was a randomized, single dose, two-period cross-over, two-arm study with a 14 days wash-out period. In total 56 subjects were included, 28 in each dosage cohort (5 µg/kg and 10 µg/kg). Using a 1 : 1 : 1 : 1 randomization ratio, subjects were randomly assigned to one of four possible treatment-sequence groups. A single dose of test formulation (XM02) and reference product (Neupogen™, F. Hoffmann – La Roche, Ltd.) were injected. The serum G-CSF concentrations were measured by enzyme-linked immunosorbent assay (ELISA) during 48 hours after injection. The absolute Neutrophil Count (ANC) was determined by automated hematology analyzer Coulter STKSTM (Beckman Coulter, Inc.) up to 96 hours after injection. The primary pharmacokinetic (AUC0-48, AUC0-¥ and Cmax) and pharmacodynamic (ANC AUC0-96, ANC AUC0-¥ and ANCmax) variables were considered bioequivalent if the 90% confidence intervals (CI) were in the bioequivalence range of 80 – 125%. Results: 50 subjects completed the study: 24 subjects in 5 µg/kg and 26 in 10 µg/kg dosage groups. The pharmacokinetic and pharmacodynamic parameters in 5 mg/kg and 10 mg/kg group for both formulations were very close to each other. Single doses of test and reference formulations were well tolerated. The most frequent AEs were: headache, erythrocyturia and myalgia. The incidence of AEs was equally distributed across dosage and treatment groups. Conclusion: The study results demonstrated the bioequivalence of two body weight-dependent doses of XM02, a new formulation of filgrastim, and the reference product Neupogen™ after administration of a 5 µg/kg b.w. and 10 µg/kg b.w. with respect to pharmacokinetic, pharmacodynamic and safety profiles.Correspondence to:
Dr. A. Sveikata; Department of Theoretical and Clinical Pharmacology, Kaunas University of Medicine, A. Mickeviciaus St. 9, 44307 Kaunas,
Lithuania
Email: sveikata@med.kmu.lt
Bioavailability Section
Comparative bioavailability of two oral formulations of levofloxacin in healthy Mexican volunteers
M.d.C. Carrasco-Portugal and F.J. Flores-Murrieta
Abstract
M.d.C. Carrasco-Portugal1 and F.J. Flores-Murrieta1,2
1Pharmacological Research Unit, National Institute for Respiratory Diseases Ismael Cosío Villegas, and 2Section for Postgraduate Studies and Research, School of Medicine, National Polytechnic Institute, Mexico City, Mexico
Objective: To assess the bioequivalence of two levofloxacin 500 mg tablets marketed in Mexico. Material and methods: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 27 healthy male volunteers. 1 tablet of each formulation was administered with 200 ml of water after 10 h overnight fast. After dosing, serial blood samples were collected for a period of 24 h. Plasma concentrations were determined by a validated high-performance liquid chromatographic method and pharmacokinetic parameters were obtained by non-compartmental approach. Analysis of variance (ANOVA) was carried out using log-transformed AUClast, AUC¥ and Cmax and untransformed tmax, and 90% confidence intervals for AUClast, AUC¥ and Cmax were calculated. If the 90% confidence intervals (CI) for AUClast, AUC¥ and Cmax fell fully within the interval 80 – 125%, the bioequivalence of the two formulations was established. Results: The means (test and reference) for AUClast were 58.869 and 56.297 µg × h/ml, for AUC¥ were 63.456 and 60.748 µg × h/ml and for Cmax were 8.691 and 8.445 µg/ml. The geometric mean ratios of the test formulation to reference formulation for AUClast, AUC¥ and Cmax (CI) were 104.53% (102.73 – 106.36%), 104.37% (102.04 – 106.75%) and 103.45% (95.57 – 111.97%), respectively. All 90% CI for AUClast, AUC¥ and Cmax fell within the Mexican Federal Commission for Prevention of Sanitary Risks (COFEPRIS) accepted bioequivalence range of 80 – 125%. Conclusions: Based on the results, the formulations tested are bioequivalent.Correspondence to:
F.J. Flores-Murrieta, PhD; Unidad de Investigación en Farmacología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. De Tlalpan 4502, Col. Sección XVI, 14080 México, D.F., Mexico
Email: fjfloresmurrieta@yahoo.com.mx; fjfloresmurrieta@prodigy.net.mx
Announcement:
Ten years European College of Pharmaceutical Medicine. 4th Edition of its textbook “Statistics Applied to Clinical Trials”
T.J. Cleophas
