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Dustri-Verlag
Volume 49, No. 3/2011(March)
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Original
Medication review of community-dwelling seniors using intensified home-care service
M. Ermer and S. Harder
179
28$
Abstract
Investigations on medication burden, falling, and inappropriate dosing in renal impairment have been obtained in patients living in nursing homes. Data from home-dwelling patients in intensified ambulatory care, especially from Germany are scant. Material and method: We evaluated patients daily visited by an ambulatory care service (Cohort 1, n = 102, median age 80 y) or had care given by relatives only (cohort 2, n = 101, median age 76 y) at baseline (V1), 6 (V2) and 12 months (V3). Results: At V1 patients in Cohort 1 had 5 (median, range 3 – 15) and at V3 6 (3 – 17) medications. No differences could be observed between cohorts regarding number and pattern of medications. At V1, 30/102 patients of Cohort 1 had creatinine measured within the last 6 months, 13/30 patients had an eGFR < 50 ml/min. 6/34 medications which need dose-adjustment were unadjusted. Low surveillance of renal function and unadjusted dosing were also observed at other visits and also in Cohort 2. Within 1 year, 29/75 mobile patients in cohort 1 had a fall, 18/29 patients had a benzodiazepine prescribed regularly, whereas a benzodiazepine was prescribed in 6/46 patients which did not fall (chi2 p = 0.004). In Cohort 2, the number of falling patients was lower (19/84 mobile patients, p = 0.028). 11/19 patients had a benzodiazepine prescribed, in contrast to 5/65 patients which did not fall (chi2 p = 0.001). Conclusions: It needs to be elucidated whether a care service can contribute to medication safety in patients e.g. by reviewing medication charts and organizing for controls of ancillary laboratory values.Correspondence to:
Prof. Dr. med. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt
University Hospital Frankfurt/Main
Theodor Stern Kai 7
60590 Frankfurt am Main, Germany
Email: harder@em.uni-frankfurt.de
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (179-184)
Medication review of community-dwelling seniors using intensified home-care service
M. Ermer and S. Harder
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany Investigations on medication burden, falling, and inappropriate dosing in renal impairment have been obtained in patients living in nursing homes. Data from home-dwelling patients in intensified ambulatory care, especially from Germany are scant. Material and method: We evaluated patients daily visited by an ambulatory care service (Cohort 1, n = 102, median age 80 y) or had care given by relatives only (cohort 2, n = 101, median age 76 y) at baseline (V1), 6 (V2) and 12 months (V3). Results: At V1 patients in Cohort 1 had 5 (median, range 3 – 15) and at V3 6 (3 – 17) medications. No differences could be observed between cohorts regarding number and pattern of medications. At V1, 30/102 patients of Cohort 1 had creatinine measured within the last 6 months, 13/30 patients had an eGFR < 50 ml/min. 6/34 medications which need dose-adjustment were unadjusted. Low surveillance of renal function and unadjusted dosing were also observed at other visits and also in Cohort 2. Within 1 year, 29/75 mobile patients in cohort 1 had a fall, 18/29 patients had a benzodiazepine prescribed regularly, whereas a benzodiazepine was prescribed in 6/46 patients which did not fall (chi2 p = 0.004). In Cohort 2, the number of falling patients was lower (19/84 mobile patients, p = 0.028). 11/19 patients had a benzodiazepine prescribed, in contrast to 5/65 patients which did not fall (chi2 p = 0.001). Conclusions: It needs to be elucidated whether a care service can contribute to medication safety in patients e.g. by reviewing medication charts and organizing for controls of ancillary laboratory values.Correspondence to:
Prof. Dr. med. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt
University Hospital Frankfurt/Main
Theodor Stern Kai 7
60590 Frankfurt am Main, Germany
Email: harder@em.uni-frankfurt.de
Original
Predictability of serious adverse reaction alerts for monoclonal antibodies
V. Stanulovic, R. Zelko and S. Kerpel-Fronius
185
28$
Abstract
Objective: We analyzed the predictability of the United States Food and Drug Administration’s Medwatch safety alerts on monoclonal antibodies with the aim of assessing the adequacy of their pre-approval safety evaluation. Methods: An alert was considered observed when increased frequency, severity, or other new properties were reported for previously identified suspected adverse reactions. Results: Up until January 2010, 36 safety alerts to mAbs were issued containing 61 alert terms. Just above a half (32) of the alert terms were assessed as observed. Discussion: In addition to the observed reactions, a large proportion of unobserved reactions could have been predicted based on the mechanism of action and antibody target. Although retrospective assessment necessarily implies an element of subjectivity, there appears to be room for improvement in predicting adverse reactions to mAbs. Conclusions: Adverse reaction risk management and pharmaceutical care must focus on the observed reactions, but all effort should be made to extrapolate from the observed reactions to predict further safety issues. This should be taken into account by marketing authorization holders, prescribers, clinical trial sponsors, investigators and regulators.Correspondence to:
V. Stanulovic
Budapest, Hungary
Email: v.stanulovic@accelsiors.com
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (185-190)
Predictability of serious adverse reaction alerts for monoclonal antibodies
V. Stanulovic1, R. Zelko2 and S. Kerpel-Fronius3
1School of PhD Studies, 2Faculty of Pharmacy, University Pharmacy, Department of Pharmacy Administration, and 3Faculty of Medicine, Institute of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary Objective: We analyzed the predictability of the United States Food and Drug Administration’s Medwatch safety alerts on monoclonal antibodies with the aim of assessing the adequacy of their pre-approval safety evaluation. Methods: An alert was considered observed when increased frequency, severity, or other new properties were reported for previously identified suspected adverse reactions. Results: Up until January 2010, 36 safety alerts to mAbs were issued containing 61 alert terms. Just above a half (32) of the alert terms were assessed as observed. Discussion: In addition to the observed reactions, a large proportion of unobserved reactions could have been predicted based on the mechanism of action and antibody target. Although retrospective assessment necessarily implies an element of subjectivity, there appears to be room for improvement in predicting adverse reactions to mAbs. Conclusions: Adverse reaction risk management and pharmaceutical care must focus on the observed reactions, but all effort should be made to extrapolate from the observed reactions to predict further safety issues. This should be taken into account by marketing authorization holders, prescribers, clinical trial sponsors, investigators and regulators.Correspondence to:
V. Stanulovic
Budapest, Hungary
Email: v.stanulovic@accelsiors.com
Original
Serum CRP in patients with gout and effects of benzbromarone
C. Okuda, H. Koyama, Z. Tsutsumi, A. Yamamoto, M. Kurajoh, Y. Moriwaki and T. Yamamoto
191
32$
Abstract
Objective: C-reactive protein (CRP) is associated with increased risk for myocardial infarction, atherosclerosis, and peripheral artery diseases, while increased serum uric acid level is suggested to be independently associated with an increased risk of cardiovascular mortality. Accordingly, to investigate whether hyperuricemia is associated with serum CRP, we compared serum CRP levels between healthy subjects and patients with gout. In addition, we also examined whether benzbromarone has effects on serum CRP levels in patients with gout and the expression of CRP messenger RNA of CRP in the hepatoma cell line HuH7. Methods: In the first experiment, 40 healthy males and 43 male patients with gout were enrolled, then blood samples were drawn from each after an overnight fast. In the second experiment, 42 male patients with gout were given uric acid-lowering therapy with benzbromarone. Blood samples were drawn after an overnight fast before and 1 year after beginning benzbromarone treatment. In the third experiment, the effects of benzbromarone on IL1beta-induced CRP expression were determined in HuH7 cells. Results: Log serum CRP levels were not significantly different between the patients with gout and healthy subjects, while log serum CRP levels were decreased by 11% after benzbromarone treatment, as compared to the values before treatment (p < 0.01). In addition, log serum adiponectin levels were elevated by 2% after treatment (p < 0.01). Furthermore, our in vitro findings demonstrated that benzbromarone down-regulated IL1beta-stimulated CRP gene expression. Conclusions: These results suggest that hyperuricemia may not contribute to an increase in serum CRP level, while benzbromarone may have a favorable effect on CRP.Correspondence to:
T. Yamamoto, MD
Division of Endocrinology and Metabolism
Department of Internal Medicine
Hyogo College of Medicine
Mukogawa-cho 1-1
Nishinomiya, Hyogo 663-8501, Japan
Email: tetsuya@hyo-med.ac.jp
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (191-197)
Serum CRP in patients with gout and effects of benzbromarone
C. Okuda, H. Koyama, Z. Tsutsumi, A. Yamamoto, M. Kurajoh, Y. Moriwaki and T. Yamamoto
Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan Objective: C-reactive protein (CRP) is associated with increased risk for myocardial infarction, atherosclerosis, and peripheral artery diseases, while increased serum uric acid level is suggested to be independently associated with an increased risk of cardiovascular mortality. Accordingly, to investigate whether hyperuricemia is associated with serum CRP, we compared serum CRP levels between healthy subjects and patients with gout. In addition, we also examined whether benzbromarone has effects on serum CRP levels in patients with gout and the expression of CRP messenger RNA of CRP in the hepatoma cell line HuH7. Methods: In the first experiment, 40 healthy males and 43 male patients with gout were enrolled, then blood samples were drawn from each after an overnight fast. In the second experiment, 42 male patients with gout were given uric acid-lowering therapy with benzbromarone. Blood samples were drawn after an overnight fast before and 1 year after beginning benzbromarone treatment. In the third experiment, the effects of benzbromarone on IL1beta-induced CRP expression were determined in HuH7 cells. Results: Log serum CRP levels were not significantly different between the patients with gout and healthy subjects, while log serum CRP levels were decreased by 11% after benzbromarone treatment, as compared to the values before treatment (p < 0.01). In addition, log serum adiponectin levels were elevated by 2% after treatment (p < 0.01). Furthermore, our in vitro findings demonstrated that benzbromarone down-regulated IL1beta-stimulated CRP gene expression. Conclusions: These results suggest that hyperuricemia may not contribute to an increase in serum CRP level, while benzbromarone may have a favorable effect on CRP.Correspondence to:
T. Yamamoto, MD
Division of Endocrinology and Metabolism
Department of Internal Medicine
Hyogo College of Medicine
Mukogawa-cho 1-1
Nishinomiya, Hyogo 663-8501, Japan
Email: tetsuya@hyo-med.ac.jp
Original
Efficacy and tolerability of two oral hyoscine butylbromide formulations in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain
Z. Ge, Y. Yuan, S. Zhang, X. Hou, J. Wang, J. Cai, R. Shi, Y. Li, B. Wang, F. Ji, E. Richter and E. Schaefer
198
36$
Abstract
Aim: To compare the efficacy and tolerability of oral hyoscine butylbromide tablets and capsules in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain and to show non-inferiority of both formulations. Methods: 302 patients were entered into a randomized, double-blind, double-dummy, active-controlled 2-arm parallel group study. They were randomized to 3 days of treatment with hyoscine butylbromide tablets or capsules. In patient diaries the pain intensity was assessed on 10 cm visual analogue scales on Day 1 (0, 30, 60, 90, 120, and 180 minutes after first dose), Days 2, and 3 (maximum pain intensity once daily). Pain frequency, overall efficacy, and tolerability were assessed on verbal rating scales. Results: In the per-protocol dataset 281 patients were analyzed. The change from baseline after 180 minutes was 59% in both treatment groups; the adjusted means of pain intensity on Day 1 were reduced by –2.36 cm (tablets) and –2.31 cm (capsules). Pain intensity decreased within 30 minutes by approximately 20%. The decrease of the peak pain intensity was approximately 55% after 3 days in both treatment groups; the adjusted means after 3 days were reduced by –2.48 cm (tablets) and by –2.45 cm (capsules). Abdominal pain frequency decreased by 50% (tablets) and 42% (capsules). Both treatments were well tolerated. Drug-related adverse events were infrequent (3.5%). No serious adverse event occurred. Conclusions: Hyoscine butylbromide is effective in the treatment of recurrent gastric or intestinal spasm-like pain and well tolerated. Non-inferiority of tablets and capsules was demonstrated.Correspondence to:
Dr. E. Schaefer
Boehringer Ingelheim GmbH
Binger Straße 173
55216 Ingelheim am Rhein, Germany
Email: eckhard.schaefer@boehringer-ingelheim.com
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (198-205)
Efficacy and tolerability of two oral hyoscine butylbromide formulations in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain
Z. Ge1, Y. Yuan2, S. Zhang3, X. Hou4, J. Wang5, J. Cai6, R. Shi7, Y. Li8, B. Wang9, F. Ji10, E. Richter11 and E. Schaefer11
1Renji Hospital, 2Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 3Beijing Friendship Hospital, Capital Medical University, Beijing, 4Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 5Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, 6The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 7The First Affiliated Hospital of Nanjing Medical University, Nanjing, 8Qilu Hospital of Shandong University, Jinan, 9Tianjin Medical University General Hospital, Tianjin, 10The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, and 11Boehringer Ingelheim, Ingelheim, Germany Aim: To compare the efficacy and tolerability of oral hyoscine butylbromide tablets and capsules in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain and to show non-inferiority of both formulations. Methods: 302 patients were entered into a randomized, double-blind, double-dummy, active-controlled 2-arm parallel group study. They were randomized to 3 days of treatment with hyoscine butylbromide tablets or capsules. In patient diaries the pain intensity was assessed on 10 cm visual analogue scales on Day 1 (0, 30, 60, 90, 120, and 180 minutes after first dose), Days 2, and 3 (maximum pain intensity once daily). Pain frequency, overall efficacy, and tolerability were assessed on verbal rating scales. Results: In the per-protocol dataset 281 patients were analyzed. The change from baseline after 180 minutes was 59% in both treatment groups; the adjusted means of pain intensity on Day 1 were reduced by –2.36 cm (tablets) and –2.31 cm (capsules). Pain intensity decreased within 30 minutes by approximately 20%. The decrease of the peak pain intensity was approximately 55% after 3 days in both treatment groups; the adjusted means after 3 days were reduced by –2.48 cm (tablets) and by –2.45 cm (capsules). Abdominal pain frequency decreased by 50% (tablets) and 42% (capsules). Both treatments were well tolerated. Drug-related adverse events were infrequent (3.5%). No serious adverse event occurred. Conclusions: Hyoscine butylbromide is effective in the treatment of recurrent gastric or intestinal spasm-like pain and well tolerated. Non-inferiority of tablets and capsules was demonstrated.Correspondence to:
Dr. E. Schaefer
Boehringer Ingelheim GmbH
Binger Straße 173
55216 Ingelheim am Rhein, Germany
Email: eckhard.schaefer@boehringer-ingelheim.com
Original
Cephalosporin and penicillin cross-reactivity in patients allergic to penicillins
X.-D. Liu, N. Gao and H.-L. Qiao
206
48$
Abstract
Background: Bata-lactam antibiotics are the most commonly used antibiotics which usually cause serious IgE-mediated allergic reactions. Of all bata-lactam antibiotics, penicillins have so far been the best-studied, but the studies of cephalosporins and their cross-reactivity with penicillins are rare. We sought to evaluate the IgE response in vitro and estimate cross-reactivity between penicillins and cephalosporins in patients allergic to penicillins. Methods: We studied 87 control subjects and 420 subjects allergic to penicillins. Radioallergosorbent test (RAST) was performed to detect eight types of specific-penicillin IgE and eleven types of specific-cephalosporin IgE. The cross-reactivity and different molecules recognition by IgE were studied with a radioallergosorbent inhibition test. Results: Of 420 patients allergic to penicillins, 95 patients (22.62%) showed specific-cephalosporin IgE positive, 73 patients (17.38%) showed IgEs positive to both penicillins and cephalosporins. In specific-penicillin IgE positive group, the positive rate of specific-cephalosporin IgE was significantly higher than in specific-penicillin IgE negative group (27.14% vs. 14.57%, p < 0.01). In urticaria group, the positive rate of specific-cephalosporin IgE was significantly higher than in other symptoms group (30.65% vs. 8.11%, p < 0.05). The analysis of drugs which have the same or similar side-chains showed that benzylpenicillanyl-IgE (BPA-IgE), ampicillanyl-IgE (APA-IgE), amoxicillanyl-IgE (AXA-IgE) were respectively related to cephalothanyl-IgE (CLA-IgE), cephalexanyl-IgE (CEXA-IgE), cephalexanyl-IgE (CEXA-IgE)in sera of penicillin-allergic patients we studied, and compared with patients who had negative amoxicillin-IgE, the positive rates of specific-ampicillin IgE and specific-cephalexin IgE were significantly higher in patients who had positive amoxicillin-IgE (14.43% vs. 3.72%, 14.00% vs. 2.96%, p < 0.01). Radioallergosorbent test and radioallergosorbent inhibition test confirmed that both nuclear structure and R1 side-chain contribute to IgE recognition. Conclusions: There exists cross-reactivity between cephalosporins and penicillins; patients allergic to several penicillins are more likely to develop allergic reaction to cephalosporins; due to sensitization to the similar structural characteristics (nuclear and R1 side-chain), penicillin-allergic patients may develop cross-allergic reactions with not only first-generation but also third-generation cephalosporins.Correspondence to:
Prof. H.-L. Qiao
Department of Clinical Pharmacology
School of Medicine
Zhengzhou University
Zhengzhou 450052, China
Email: qiaohl@zzu.edu.cn
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (206-216)
Cephalosporin and penicillin cross-reactivity in patients allergic to penicillins
X.-D. Liu, N. Gao and H.-L. Qiao
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China Background: Bata-lactam antibiotics are the most commonly used antibiotics which usually cause serious IgE-mediated allergic reactions. Of all bata-lactam antibiotics, penicillins have so far been the best-studied, but the studies of cephalosporins and their cross-reactivity with penicillins are rare. We sought to evaluate the IgE response in vitro and estimate cross-reactivity between penicillins and cephalosporins in patients allergic to penicillins. Methods: We studied 87 control subjects and 420 subjects allergic to penicillins. Radioallergosorbent test (RAST) was performed to detect eight types of specific-penicillin IgE and eleven types of specific-cephalosporin IgE. The cross-reactivity and different molecules recognition by IgE were studied with a radioallergosorbent inhibition test. Results: Of 420 patients allergic to penicillins, 95 patients (22.62%) showed specific-cephalosporin IgE positive, 73 patients (17.38%) showed IgEs positive to both penicillins and cephalosporins. In specific-penicillin IgE positive group, the positive rate of specific-cephalosporin IgE was significantly higher than in specific-penicillin IgE negative group (27.14% vs. 14.57%, p < 0.01). In urticaria group, the positive rate of specific-cephalosporin IgE was significantly higher than in other symptoms group (30.65% vs. 8.11%, p < 0.05). The analysis of drugs which have the same or similar side-chains showed that benzylpenicillanyl-IgE (BPA-IgE), ampicillanyl-IgE (APA-IgE), amoxicillanyl-IgE (AXA-IgE) were respectively related to cephalothanyl-IgE (CLA-IgE), cephalexanyl-IgE (CEXA-IgE), cephalexanyl-IgE (CEXA-IgE)in sera of penicillin-allergic patients we studied, and compared with patients who had negative amoxicillin-IgE, the positive rates of specific-ampicillin IgE and specific-cephalexin IgE were significantly higher in patients who had positive amoxicillin-IgE (14.43% vs. 3.72%, 14.00% vs. 2.96%, p < 0.01). Radioallergosorbent test and radioallergosorbent inhibition test confirmed that both nuclear structure and R1 side-chain contribute to IgE recognition. Conclusions: There exists cross-reactivity between cephalosporins and penicillins; patients allergic to several penicillins are more likely to develop allergic reaction to cephalosporins; due to sensitization to the similar structural characteristics (nuclear and R1 side-chain), penicillin-allergic patients may develop cross-allergic reactions with not only first-generation but also third-generation cephalosporins.Correspondence to:
Prof. H.-L. Qiao
Department of Clinical Pharmacology
School of Medicine
Zhengzhou University
Zhengzhou 450052, China
Email: qiaohl@zzu.edu.cn
Original
Cost-effectiveness of insulin glargine versus NPH insulin for the treatment of Type 2 diabetes mellitus, modeling the interaction between hypoglycemia and glycemic control in Switzerland
M. Brändle, M. Azoulay and R.-A. Greiner
217
60$
Abstract
Objective: The objective of this study was to evaluate the short-term and long-term clinical and economic outcomes associated with insulin glargine or NPH insulin in patients with Type 2 diabetes mellitus (T2DM) inadequately controlled with oral anti-diabetic drugs in Switzerland, modeling the interaction between hypoglycemia and glycemic control (HbA1c). Methods: A validated discrete event simulation model for T2DM was used to predict incidence of short-term complications (symptomatic, nocturnal and severe hypoglycemic events) and long-term complications (microvascular and macrovascular events), life expectancy, quality-adjusted life years (QALYs) and direct medical costs in patients treated with insulin glargine or NPH insulin. The model was populated with published Swiss patient characteristics with T2DM. Baseline risks of hypoglycemic events, utility decrements of diabetes-related long-term complications and the hypoglycemia fear score were derived from the literature. Relative risk reductions of hypoglycemia adjusted for HbA1c using insulin glargine compared with NPH insulin were based on a published negative binomial meta-regression analysis. Costs of severe hypoglycemia, micro- and macrovascular events were analyzed from literature whenever possible otherwise guideline-projected resource-use estimations were valued with Swiss official prices or tariffs in 2006 CHF. Simulations were run with 1,000 patients per cohort over a time horizon of 40 years. Incremental cost effectiveness ratios (ICERs) were presented as cost per QALY and per life year gained (LYG). Future costs and clinical benefits were discounted at 3.5%. Wide-range one-way sensitivity analyses were performed. Results: Insulin glargine was associated with an improvement in quality of life (0.098 QALYs per patient) and additional life expectancy (0.05 life years gained per patient) compared to NPH insulin. Incremental costs of CHF 2,578 resulted in an ICER of CHF 26,271 per QALY and CHF 51,100 per LYG. The cost per QALY was most sensitive to changes in costs, utility decrements and relative risk reductions of hypoglycemia. Conclusions: This study evaluated, for the first time, the cost effectiveness of insulin glargine versus NPH insulin for the treatment of T2DM considering the interaction between glycemic control and hypoglycemia in Switzerland. The base case and sensitivity analyses demonstrated that insulin glargine proved to be cost-effective with respect to accepted willingness to pay thresholds and therefore represents good value for money.Correspondence to:
PD Dr. M. Brändle, MS
Division of Endocrinology and Diabetes
Department of Internal Medicine
Kantonsspital St. Gallen
9007 St. Gallen, Switzerland
Email: Michael.Braendle@kssg.ch
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (217-230)
Cost-effectiveness of insulin glargine versus NPH insulin for the treatment of Type 2 diabetes mellitus, modeling the interaction between hypoglycemia and glycemic control in Switzerland
M. Brändle1, M. Azoulay2 and R.-A. Greiner3
1Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, St. Gallen, and 2Sanofi-Aventis (suisse) sa, Meyrin, Switzerland, and 3Consultant Health Economics, Lörrach, Germany Objective: The objective of this study was to evaluate the short-term and long-term clinical and economic outcomes associated with insulin glargine or NPH insulin in patients with Type 2 diabetes mellitus (T2DM) inadequately controlled with oral anti-diabetic drugs in Switzerland, modeling the interaction between hypoglycemia and glycemic control (HbA1c). Methods: A validated discrete event simulation model for T2DM was used to predict incidence of short-term complications (symptomatic, nocturnal and severe hypoglycemic events) and long-term complications (microvascular and macrovascular events), life expectancy, quality-adjusted life years (QALYs) and direct medical costs in patients treated with insulin glargine or NPH insulin. The model was populated with published Swiss patient characteristics with T2DM. Baseline risks of hypoglycemic events, utility decrements of diabetes-related long-term complications and the hypoglycemia fear score were derived from the literature. Relative risk reductions of hypoglycemia adjusted for HbA1c using insulin glargine compared with NPH insulin were based on a published negative binomial meta-regression analysis. Costs of severe hypoglycemia, micro- and macrovascular events were analyzed from literature whenever possible otherwise guideline-projected resource-use estimations were valued with Swiss official prices or tariffs in 2006 CHF. Simulations were run with 1,000 patients per cohort over a time horizon of 40 years. Incremental cost effectiveness ratios (ICERs) were presented as cost per QALY and per life year gained (LYG). Future costs and clinical benefits were discounted at 3.5%. Wide-range one-way sensitivity analyses were performed. Results: Insulin glargine was associated with an improvement in quality of life (0.098 QALYs per patient) and additional life expectancy (0.05 life years gained per patient) compared to NPH insulin. Incremental costs of CHF 2,578 resulted in an ICER of CHF 26,271 per QALY and CHF 51,100 per LYG. The cost per QALY was most sensitive to changes in costs, utility decrements and relative risk reductions of hypoglycemia. Conclusions: This study evaluated, for the first time, the cost effectiveness of insulin glargine versus NPH insulin for the treatment of T2DM considering the interaction between glycemic control and hypoglycemia in Switzerland. The base case and sensitivity analyses demonstrated that insulin glargine proved to be cost-effective with respect to accepted willingness to pay thresholds and therefore represents good value for money.Correspondence to:
PD Dr. M. Brändle, MS
Division of Endocrinology and Diabetes
Department of Internal Medicine
Kantonsspital St. Gallen
9007 St. Gallen, Switzerland
Email: Michael.Braendle@kssg.ch
Bioavailability Section
Healthy volunteers for bioequivalence trials: predictive factors for enrollment failures – a case-control study
G.A. Yerino, E.K. Halabe and E.C. Feleder
231
28$
Abstract
Objective: To identify social predictors for enrollment failures of healthy volunteers (hv) in bioequivalence trials. Methods: Retrospective case-control study. Data was collected from clinical files of hv recruited in 13 bioequivalence trials approved by an independent IRB and local regulatory authority carried out between January and December 2009 at a Pharmacokinetic Unit in Buenos Aires, Argentina. All hv signed the Inform Consent Form. Only subjects who fulfilled all inclusion criteria required by the protocols were studied. Cases (enrollment failures): hv who fulfilled the protocols eligibility criteria but were not enrolled in the trials by their own decision. Controls: hv who fulfilled all the protocols eligibility criteria and were enrolled. Cases and controls were matched by demographic/ physical data and compared in relation to database contact, unemployment, alcoholic/ drug family environment, history of alcohol/ drug abuse, and other social variables. Chi2-test and t-test were used to compare data; variables presenting statistical difference were included in a logistic regression model. Results: A sample of 375 hv. was analyzed. Cases: 81/375(21.60%). Controls: 294/375 (78.40%). Cases did not differ from controls in relation to nationality, educational level, length of study and history of alcohol abuse. Statistical differences between cases and controls were found in non-database contact, unemployment, alcoholic environment, drug abuse environment and personal history of drug abuse. In a multivariate analysis only unemployment, (OR: 4.20, p < 0.001), non-database contact, (OR: 2.35, p = 0.004) and alcoholic environment, (OR: 1.94, p = 0.045) remained as predictive factors. Conclusion: In bioequivalence trials, an unemployment condition, and an alcoholic family environment were identified as negative predictors for effective enrollment in new healthy volunteers.Correspondence to:
Gustavo A. Yerino, MD
F.P.Clinical Pharma
4484 Juncal St., 3rd floor
Buenos Aires, Argentina
Email: gyerino@fpclinicalpharma.com.ar
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (231-236)
Healthy volunteers for bioequivalence trials: predictive factors for enrollment failures – a case-control study
G.A. Yerino, E.K. Halabe and E.C. Feleder
F.P.Clinical Pharma, Buenos Aires, Argentina Objective: To identify social predictors for enrollment failures of healthy volunteers (hv) in bioequivalence trials. Methods: Retrospective case-control study. Data was collected from clinical files of hv recruited in 13 bioequivalence trials approved by an independent IRB and local regulatory authority carried out between January and December 2009 at a Pharmacokinetic Unit in Buenos Aires, Argentina. All hv signed the Inform Consent Form. Only subjects who fulfilled all inclusion criteria required by the protocols were studied. Cases (enrollment failures): hv who fulfilled the protocols eligibility criteria but were not enrolled in the trials by their own decision. Controls: hv who fulfilled all the protocols eligibility criteria and were enrolled. Cases and controls were matched by demographic/ physical data and compared in relation to database contact, unemployment, alcoholic/ drug family environment, history of alcohol/ drug abuse, and other social variables. Chi2-test and t-test were used to compare data; variables presenting statistical difference were included in a logistic regression model. Results: A sample of 375 hv. was analyzed. Cases: 81/375(21.60%). Controls: 294/375 (78.40%). Cases did not differ from controls in relation to nationality, educational level, length of study and history of alcohol abuse. Statistical differences between cases and controls were found in non-database contact, unemployment, alcoholic environment, drug abuse environment and personal history of drug abuse. In a multivariate analysis only unemployment, (OR: 4.20, p < 0.001), non-database contact, (OR: 2.35, p = 0.004) and alcoholic environment, (OR: 1.94, p = 0.045) remained as predictive factors. Conclusion: In bioequivalence trials, an unemployment condition, and an alcoholic family environment were identified as negative predictors for effective enrollment in new healthy volunteers.Correspondence to:
Gustavo A. Yerino, MD
F.P.Clinical Pharma
4484 Juncal St., 3rd floor
Buenos Aires, Argentina
Email: gyerino@fpclinicalpharma.com.ar
Bioavailability Section
Pharmacokinetics and bioequivalence of single dose and multiple doses of immediate- and extended-release formulations of dexibuprofen in healthy Chinese subjects
M.J. Xu, C. Zou, J.H Chu, T. Wu, S.J. Liu, J. Zhang, M. Chen, F. Liu, N.N. Xiong, W.Z. Ju and H.S Tan
237
44$
Abstract
Objective: To compare the pharmacokinetic (PK) profiles and bioequivalence of the extended-release (ER) and immediate-release (IR) formulations of dexibuprofen (DI) in healthy Chinese volunteers after single dose and multiple doses. Materials: Zefen® (IR capsule, containing 150 mg DI, Suzhou No.4 Pharmaceutical Factory, Jiangsu, China) and ER capsule (containing 225 mg DI, Tianjin Zhongtian Pharmaceutical Co. Ltd., Tianjin, China). Methods: This was an open, randomized, two-period crossover study. Eligible subjects were healthy male Chinese volunteers. 22 subjects were randomly assigned to receive a single 450 mg dose of the test or reference formulation on the first day. During the next 6 days, the test group received a multiple-dose of ER DI capsule (450 mg, b.i.d.) and the reference group took a multiple-dose of IR DI capsule (300 mg, t.i.d.), respectively. Multiple blood samples were collected, and plasma concentrations of DI were analyzed using high performance liquid chromatography (HPLC) system. After a 9-day washout period, the subjects were administered the alternate formulation. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was within accepted limits. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. Results: 21 subjects completed the single dose administration and 20 subjects were evaluable for the multiple doses PK parameters. Single-dose Mean AUC0-t and AUC0-inf for ER formulation were 116.14 ± 21.54 mg·h/l and 117.60 ± 22.27 mg·h/l, and for IR formulation, were 107.25 ± 23.48 mg·h/l and 108.18 ± 23.93 mg·h/l, with the 90% CI within the limits accepted for bioequivalence. Mean Cmax for ER and IR formulations were 22.30 ± 5.17 mg/l and 30.26 ± 13.54 mg/l, respectively. And median tmax for ER and IR formulations were 4.5 h and 2.0 h. The retard quotient (delta R) for ER product was 1.9 ± 0.93, which indicated an intermediate extended release effect. Multiple-dose Mean AUC0-24 for ER formulation was 217.93 ± 41.07 mg·h/l and for IR formulation was 199.33 ± 37.32 mg·h/l. Other PK parameters of ER and IR formulations were as follows: median tmax were 4.8 h and 2.0 h, Css-max were 20.21 ± 2.69 mg/l and 19.71 ± 3.46 mg/l, Css-min were 2.47 ± 0.99 mg/l and 2.48 ± 0.99 mg/l, Cav were 9.08 ± 1.71 mg/l and 8.31 ± 1.56 mg/l, respectively. Conclusions: This study found that in these subjects, the absorption rates of the two DI formulations were not bioequivalent, but at steady state, the daily exposure provided by less frequent DI ER dosing was not significantly different from the same daily dose with DI IR capsules, administered more frequently.Correspondence to:
W.Z. Ju, PhD
Department of Clinical Pharmacology
Affiliated Hospital of Nanjing
University of Traditional Chinese Medicine
Nanjing, China
Email: njxmj@yahoo.com.cn
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (237-246)
Pharmacokinetics and bioequivalence of single dose and multiple doses of immediate- and extended-release formulations of dexibuprofen in healthy Chinese subjects
M.J. Xu1, C. Zou1, J.H Chu1, T. Wu1, S.J. Liu1, J. Zhang1, M. Chen1, F. Liu1, N.N. Xiong1, W.Z. Ju1 and H.S Tan2
1Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, and 2Department of Clinical Pharmacology, General Hospital of Nanjing Armed Forces, Nanjing, China Objective: To compare the pharmacokinetic (PK) profiles and bioequivalence of the extended-release (ER) and immediate-release (IR) formulations of dexibuprofen (DI) in healthy Chinese volunteers after single dose and multiple doses. Materials: Zefen® (IR capsule, containing 150 mg DI, Suzhou No.4 Pharmaceutical Factory, Jiangsu, China) and ER capsule (containing 225 mg DI, Tianjin Zhongtian Pharmaceutical Co. Ltd., Tianjin, China). Methods: This was an open, randomized, two-period crossover study. Eligible subjects were healthy male Chinese volunteers. 22 subjects were randomly assigned to receive a single 450 mg dose of the test or reference formulation on the first day. During the next 6 days, the test group received a multiple-dose of ER DI capsule (450 mg, b.i.d.) and the reference group took a multiple-dose of IR DI capsule (300 mg, t.i.d.), respectively. Multiple blood samples were collected, and plasma concentrations of DI were analyzed using high performance liquid chromatography (HPLC) system. After a 9-day washout period, the subjects were administered the alternate formulation. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was within accepted limits. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. Results: 21 subjects completed the single dose administration and 20 subjects were evaluable for the multiple doses PK parameters. Single-dose Mean AUC0-t and AUC0-inf for ER formulation were 116.14 ± 21.54 mg·h/l and 117.60 ± 22.27 mg·h/l, and for IR formulation, were 107.25 ± 23.48 mg·h/l and 108.18 ± 23.93 mg·h/l, with the 90% CI within the limits accepted for bioequivalence. Mean Cmax for ER and IR formulations were 22.30 ± 5.17 mg/l and 30.26 ± 13.54 mg/l, respectively. And median tmax for ER and IR formulations were 4.5 h and 2.0 h. The retard quotient (delta R) for ER product was 1.9 ± 0.93, which indicated an intermediate extended release effect. Multiple-dose Mean AUC0-24 for ER formulation was 217.93 ± 41.07 mg·h/l and for IR formulation was 199.33 ± 37.32 mg·h/l. Other PK parameters of ER and IR formulations were as follows: median tmax were 4.8 h and 2.0 h, Css-max were 20.21 ± 2.69 mg/l and 19.71 ± 3.46 mg/l, Css-min were 2.47 ± 0.99 mg/l and 2.48 ± 0.99 mg/l, Cav were 9.08 ± 1.71 mg/l and 8.31 ± 1.56 mg/l, respectively. Conclusions: This study found that in these subjects, the absorption rates of the two DI formulations were not bioequivalent, but at steady state, the daily exposure provided by less frequent DI ER dosing was not significantly different from the same daily dose with DI IR capsules, administered more frequently.Correspondence to:
W.Z. Ju, PhD
Department of Clinical Pharmacology
Affiliated Hospital of Nanjing
University of Traditional Chinese Medicine
Nanjing, China
Email: njxmj@yahoo.com.cn
