Volume 46, No. 7/2008(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Clinical Trials
Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran
J.H. Lewis, D. Larrey, R. Olsson†, W.M. Lee, L. Frison and M. Keisu
Abstract
J.H. Lewis1, D. Larrey2, R. Olsson3†, W.M. Lee4, L. Frison5 and M. Keisu5
1Georgetown University Medical Center, Washington, DC, USA,
2Service D’Hépato-Gastroentérologie, CHU Montpellier, Hôpital Saint Eloi and INSERM U632, Montpellier, France, 3Sahlgrenska University Hospital, Gothenburg, Sweden, 4University of Texas Southwestern Medical Center at Dallas, TX, USA and 5AstraZeneca R&D Mölndal, Sweden
Aims: Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. Methods: We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). Results: RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. Conclusions: While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.Correspondence to:
J.H. Lewis, MD, FACP, FACG
Professor of Medicine, Director of Hepatology,
Georgetown University Medical Center,
3800 Reservoir Road, NW, Room M2408, Washington, DC 20854, USA
Email: lewisjh@gunet.georgetown.edu
Clinical Trials
Personality characteristics of volunteers in Phase 1 studies and likelihood of reporting adverse events
L. Almeida, A. Falcão, M. Vaz-da-Silva,, R. Coelho, A. Albino-Teixeira, and P. Soares-da-Silva
Abstract
L. Almeida1,2, A. Falcão3, M. Vaz-da-Silva1,2,5, R. Coelho4, A. Albino-Teixeira2,5 and P. Soares-da-Silva1,2
1Department of Research and Development, BIAL (Portela and Co., SA), S. Mamede do Coronado, 2Faculty of Medicine, Institute of Pharmacology and Therapeutics, 3Four Health Limited, Cantanhede, 4Service of Psychiatry and Mental Health, Faculty of Medicine and 5Institute for Molecular and Cell Biology (IBMC), University of Oporto, Porto, Portugal
Objective: To evaluate the personality characteristics of a group of participants in Phase 1 studies and to study the relation between the personality traits and the adverse events during participation. Methods: Study population consisted of 139 healthy volunteers to Phase 1 studies. Personality was assessed through the Revised NEO Personality Inventory (NEO-PI-R) and adverse events were monitored during participation. Results: Participants showed lower levels of Neuroticism (p < 0.001), and higher levels of Extraversion (p < 0.001) and Openness to Experience (p < 0.001) than the norm. In the Neuroticism domain, participants were lower in anxiety (p < 0.001), angry-hostility (p < 0.001), depression (p < 0.001), self-consciousness (p < 0.001) and vulnerability (p < 0.001), and higher in impulsiveness (p < 0.001). All facets of the Extraversion domain and all facets but “openness to esthetics” of the Openness to Experience domain were higher (p < 0.001) in the participants in relation to the norm. Participants were significantly lower (p < 0.05) on the overall Agreeableness domain, however, they were remarkably higher in altruism (p < 0.001) and trust (p = 0.001). Participants did not differ from the norm in the overall Conscientiousness domain, but they scored higher in competence (p < 0.001), achievement striving (p = 0.001) and self-discipline (p < 0.001). Females showed to report significantly more adverse events than males, and extraverted subjects showed to report less adverse events than introverted subjects. Conclusion: Participants who volunteer for Phase 1 studies, differ from the general population in their personality characteristics. Some personality characteristics may have an effect on the probability of reporting adverse events during participation. Therefore, defining a personality of a volunteer may assume significant importance in Phase 1 studies.Correspondence to:
Dr. L. Almeida
Department of Research and Development, BIAL, A Av. da Siderurgia Nacional,
4745-457 S. Mamede do Coronado, Portugal
Email: luis.almeida@bial.com
Pharmacokinetics
Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes
D. Serra, Y.-L. He, J. Bullock, G.-J. Riviere, S. Balez, S. Schwartz, Y. Wang, M. Ligueros-Saylan, V. Jarugula and W.P. Dole
Abstract
D. Serra1, Y.-L. He2, J. Bullock3, G.-J. Riviere4, S. Balez4, S. Schwartz5, Y. Wang2, M. Ligueros-Saylan2, V. Jarugula2 and W.P. Dole2
1Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2Novartis Institutes for Biomedical Research, Cambridge, MA, 3The State University of New York at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA, 4Novartis Pharma SAS, Rueil-Malmaison, France and 5Diabetes and Glandular Disease Clinic, San Antonio, TX, USA
Background: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic b-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes. Methods: Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15). Results: Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and Cmax during combination treatment were small (£ 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 – 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE0-5h reduced by 12% (p = 0.005) and AUE0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE0.5-5.5h reduced by 11% (p = 0.029) and AUE0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia. Conclusions: Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.Correspondence to:
Y.-L. He, PhD, DMSc
Exploratory Development-DMPK,
Novartis Institutes of Biomedical Research Inc., 400 Technology Square, Building 605, Cambridge, MA 02139-3584, USA
Email: yanling.he@novartis.com
Pharmacokinetics
Cytochrome P450 2C9 mediated metabolism in people with and without cancer
S.S. Shord, L.H. Cavallari, M.A.G. Viana, K. Momary, J. Neceskas, R.E. Molokie, K. Deyo and S.R. Patel
Abstract
S.S. Shord1, L.H. Cavallari1, M.A.G. Viana1, K. Momary1, J. Neceskas1, R.E. Molokie2, K. Deyo1 and S.R. Patel1
University of Illinois Medical Center, Clinical Research Center, and 1University of Illinois Colleges of Pharmacy and 2Medicine, Chicago, IL, USA
Objectives: To compare cytochrome P450 activity in people with and without cancer and examine the relationship between CYP2C9 activity and serum cytokine levels. Patients and methods: 10 subjects with cancer who were currently receiving treatment and 10 additional subjects without cancer who were matched to the subjects with cancer based on gender and race were enrolled into the study. Serial blood samples were drawn to measure tolbutamide in the plasma before and after oral tolbutamide 500 mg. Total urine excreted was collected from 0 to 12 h following the dose. Tolbutamide and its metabolites were measured in plasma and urine by HPLC. CYP2C9 genotype was determined by PCR and pyrosequencing and cytokine values were determined by ELISA. Results: The mean apparent oral clearance (cancer, 19.5 ± 10.5 vs. non-cancer, 15.8 ± 5.0 ml/min) and the mean urinary metabolic ratio from 0 to 12 h were similar (838 ± 693 vs. 775 ± 390). Neither age nor genotype statistically affected the outcomes. Mean interleukin-6 (7.2 ± 9.4 vs. 1.5 ± 1.3 pg/ml) and tissue necrosis factor-a (26.2 ± 71.2 vs. 1.5 ± 1.3 pg/ml) were 5- to 7-fold higher, respectively, in subjects with cancer. No statistically significant correlation between cytokine values and oral clearance or urinary metabolic ratio was found. Conclusions: CYP2C9 activity as measured by apparent oral clearance and urinary metabolic ratio following oral tolbutamide appear similar in people with and without cancer. Serum cytokine values appear higher in patients with cancer, although the differences did not reach statistical significance.Correspondence to:
S.S. Shord, PharmD, BCOP
University of Illinois at Chicago, College of Pharmacy (M/C 886), 833 S Wood Street, room 164, Chicago, IL 60612, USA
Email: sshord@uic.edu
Adverse Drug Reaction
Label-inconsistent use of sibutramine in spontaneous adverse drug reaction reports in Germany
J. Seebeck, F. Wulf and B. Sachs
Abstract
J. Seebeck, F. Wulf and B. Sachs
Federal Institute for Drugs and Medical Devices, Bonn, Germany
In Germany, reports on adverse drug reactions (ADRs) are centrally collected and analyzed by the Federal Institute for Drugs and Medical Devices (BfArM). During routine analysis of ADR reports related to the antiobesity drug sibutramine, we repeatedly observed descriptions of its label*-inconsistent use (*European Summary of Product Characteristics (SmPC)). In order to quantify this observation, we analyzed all sibutramine-related ADR reports received by the BfArM so far. Using the same data source, we further analyzed the effect of a Dear Doctor Letter (DDL) which was distributed in 2002 in order to reinforce the label-consistent use of sibutramine. Out of a total of 170 identified reports, 104 were considered as suitable for further analysis. Of these, applying a catalogue of 24 SmPC-derived criteria, 34% (35 reports) contained information indicative of label-inconsistent use. The individual SmPC-criteria most often violated were (% of total analyzed reports): the recommended starting dose of 10 mg/day (9%), the body mass index (BMI)-related threshold permitting drug therapy (6%), and the contraindicated “history of drug abuse” (6%). The DDL was ineffective. The observed percentage of ADR reports, indicating a label-inconsistent use of sibutramine, is considered a signal for a therapeutic risk. This signal should be addressed in a drug utilization study investigating the use of sibutramine by means of a representative patient sample.Correspondence to:
J. Seebeck, MD
Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3,
53175 Bonn, Germany
Email: joerg.seebeck@web.de
Bioavailability Section
Bioequivalence of Jusline following subcutaneous administration in healthy subjects
K.A. Al-Rubeaan, N.M. Al-Daghri, K.M. Alkharfy, O.S. Al-Attas, F.S. Hanif, N.S. Metias and S.L.B. Sabico
Abstract
K.A. Al-Rubeaan1, N.M. Al-Daghri2, K.M. Alkharfy3, O.S. Al-Attas2, F.S. Hanif1, N.S. Metias1 and S.L.B. Sabico2
1Department of Medicine, College of Medicine, 2Department of Biochemistry, College of Science and 3Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Objective: The aim of the current work is to evaluate the pharmacokinetic and pharmacodynamic profile of a new human insulin preparation (jusline) following subcutaneous administration in healthy subjects, and to compare this profile with Humulin insulin. Methods: 20 healthy male subjects received a single dose of 0.2 U/kg of test (Jusline) or reference insulin (Humulin) during an euglycemic clamp keeping blood sugar constant (90 ± 5 mg/dl) by changing the glucose infusion rate. Pharmacokinetic and pharmacodynamic measurements were taken from blood measurements of glucose, insulin, and C-peptide levels for tested insulin formulations. Results: The mean values of the individual AUC ratios were well within the 90% confidence interval (100.5% for Regular, 101.9% for NPH, and 100.0% for Premixed Regular/NPH (30/70)). Similarly, Cmax and tmax were within the bioequivalence limit (80 – 125%). The maximum GIR were 10.20 mg/kg/min and 9.72 mg/kg/min for Jusline Regular and Humulin Regular, respectively. The maximum GIR were 7.09 mg/kg/min and 7.91 mg/kg/min for Jusline NPH and Humulin NPH, respectively. The maximum GIR and tGIRmax were 6.39 mg/kg/min and 6.63 mg/kg/ min for Jusline Premixed Regular/NPH (30/70) and Humulin Premixed Regular/NPH (30/70), respectively. Both insulin products produced similar suppression of endogenous C-peptide level (–29.76% to –50.22%). Conclusion: The present study demonstrated that after subcutaneous administration, there are no significant differences between Jusline and Humulin to promote peripheral glucose uptake.Correspondence to:
K.M. Alkharfy, PharmD, PhD
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
Email: alkharfy@ksu.edu.sa
