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Abstract

H.-G. Eichler, P. Mavros, O. Geling, E. Hunsche and S. Kong

¹Department of Clinical Pharmacology, Vienna University Medical School, Vienna, Austria, ²Outcomes Research, Merck and Co., Inc., Whitehouse Station, NJ and ³Department of Public Health Sciences and Epidemiology, John A. Burns School of Medicine, Universi
Background: Improvement of health-related quality of life (QoL) is increasingly recognized as a major treatment goal for patients with rheumatoid arthritis (RA). There are several measures of general health status and of physical functioning for assessing treatment effects on QoL in patients with RA, however, the relationship between QoL outcomes and conventional clinical efficacy endpoints is not completely understood. Objective: To describe the association between changes in QoL and changes in other efficacy measures, among patients with RA after four weeks of treatment with etoricoxib, naproxen or placebo, and to explore differences in the association of changes in efficacy and changes in QoL parameters across treatment groups. Methods: The study used data from 1684 patients with RA enrolled in two identical clinical trials (one US and one multinational). Patients were randomized to placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily in a 2 : 2 : 1 allocation ratio. Primary efficacy endpoints were tender joint count, swollen joint count, patient global assessment of disease activity (100 mm VAS), and investigator global assessment of disease activity (0 ? 4 Likert scale). QoL assessments were based on the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form 36 (SF-36). Mean differences between baseline and week four were calculated for each parameter studied. Linear regression analysis was performed to assess the association between changes in clinical efficacy and changes in QoL parameters, adjusted for covariates. Results: The degree of association between changes in tender or swollen joint counts and changes in QoL variables was low, explaining less than 10% of the variability for most QoL variables, except bodily pain (SF-36). In contrast, changes in patient global assessment of disease activity explained 33% of the variability in the overall HAQ score, and in the physical component score (SF-36; adjusted regression models). Values for investigator global assessment of disease activity were below those for patient global assessment but above joint count measures. Results were similar between the etoricoxib, naproxen and placebo groups in the degree of association between changes in efficacy and QoL variables. Conclusion: Currently used efficacy endpoints are less than ideal predictors of change in QoL. There is no evidence from this study that the association between changes in CE endpoints and QoL was different across treatments. Our results highlight the need to assess both conventional efficacy measures and QoL in clinical trials of RA treatments.Correspondence to:
P. Mavros, PhD Outcomes Research Merck and Co. Inc., WS2E-76 One Merck Drive P.O. Box 100 Whitehouse Station, NJ 08889-0100, USA
Email: panagiotis_mavros@merck.com

Abstract

A. Lutfullin, J. Kuhlmann and G. Wensing

Institute of Clinical Pharmacology, Bayer Health Care AG, Wuppertal, Germany
Objective: This report analyzes all adverse events (AEs) which occurred in healthy volunteers in a phase I center over a five-year period. It included 142 phase I studies with a total of 1,559 participants receiving 2,955 treatments with 32 different active drugs and placebo (ratio 6.5 : 1 in terms of follow-up days). The observation period covered a total of 29,664 follow-up days. Methods: All adverse events (AEs) as well as clinically relevant laboratory findings were counted. The incidence of AEs was defined as the ratio between the number of AEs and the number of follow-up days. Severity of AEs was classified as mild, moderate and severe; serious AEs were analyzed separately. A c²-test was used to compare incidence rates of the AEs. Statistical tests based on the normal distribution were used for comparison of demographic data and relative frequencies; p < 0.05 was defined as the minimum level of significance. Results: There were 2,604 AEs and 291 different types of AEs with headache (2.23%), diarrhea (1.37%) and common cold (0.72%) being the most frequent. The overall incidence of AEs was 8.8% with no significant difference between those occurring with active drug and those on placebo when the studies were taken as a whole (8.5% vs. 9.1%), but the incidence of AEs in the active treatment groups was higher than under placebo (14.1% vs. 9.1%; p < 0.001) in placebo-controlled studies. The overall rate of AEs was 1.7 per subject and 0.9 per treatment. The vast majority of AEs were of mild or moderate intensity (99.2%). Only six AEs were serious as defined by GCP but two, a pseudoallergic reaction and a prolonged orthostatic dysregulation were rated as possibly or probably drug-related and these resolved completely. The incidence of AEs was three-fold (all AEs) and six-fold (AEs with probable relationship to study medication) higher (p < 0.001) in multiple-dose studies than in single-dose trials, and within multiple-dose trials the difference between AEs on active drug and on placebo was also significant (22.9% vs. 12.5%; p < 0.001). Irrespective of whether on active drug or placebo, AEs occurred with a significantly higher incidence on the first day of the study drug administration, in the first study period, with respect to the overall population in elderly subjects and in volunteers with a high body weight. Conclusion: AEs in phase I studies are common, but usually of mild or moderate intensity. Placebo effects and study conditions contribute significantly to the rate of their occurrence. Multiple-dose placebo-controlled studies are of particular importance in determining the substance-specific AE profile.Correspondence to:
PD Dr. G. Wensing Institute of Clinical Pharmacology Department Pharmacodynamics Bayer Health Care AG Aprather Weg, 42096 Wuppertal, Germany
Email: georg.wensing@bayerhealthcare.com

Abstract

W.J.J. Krauwinkel, R.A. Smulders, H. Mulder, P.J. Swart and M.E.J. Taekema-Roelvink

¹Clinical Pharmacology Research Department, and ²Biological Development Department, Yamanouchi Europe B.V., AC Leiderdorp, The Netherlands
Objective: The pharmacokinetics of solifenacin succinate (YM905; VesicareCorrespondence to:
W.J.J. Krauwinkel Clinical Pharmacology Research Department Yamanouchi Europe B.V. Elisabethhof 19 PO Box 108 2350 AC Leiderdorp, The Netherlands
Email: krauwinkel.nl@yamanouchi-eu.com

Abstract

A. Bur, C. Joukhadar, N. Klein, H, Herkner, G. Mitulovic, R. Schmid, E. Agneter, M. M

¹Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, ²Department of Emergency Medicine, and ³Department of Medical and Chemical Laboratory Diagnostics, University of Vienna Medical School, Vienna, Austria
Objective: Transdermal nicotine patches have become a frequently prescribed tool in smoking cessation programs during the past years. However, there is circumstantial evidence that transdermal nicotine release substantially varies with physical activity producing toxic plasma concentrations that may account for severe adverse events. Methods: We, therefore, compared nicotine release from two different transdermal nicotine systems (TDNS) at rest and during strenuous physical activity in a two-period crossover study in healthy smokers (n = 10). The subjects were randomly assigned to receive either 21 mg/day of formulation A or B on study Day 1 and 2. Patches were applied eight hours before starting standardized physical activity, and nicotine concentrations were measured in plasma and topically in the tissue layers underneath the application site by microdialysis. Results: There was no difference between groups in the mean values for area under the time-concentration curve at rest from 0 ? 8 hours AUC_0-8 (p < 0.799) and during exercise from 8 ? 11 hours AUC8-11 (p < 0.878). C_max values between groups with C_max values of 16.4 Correspondence to:
Dr. M. Brunner Department of Clinical Pharmacology Division of Clinical Pharmacokinetics University of Vienna Medical School Allgemeines Krankenhaus W
Email: martin.brunner@meduniwien.ac.at

Abstract

K.K. Midha, M.J. Rawson, G. McKay and J.W. Hubbard

¹Pharmalytics Inc., a Drug Metabolism, Drug Disposition Institute, University of Saskatchewan, ²College of Pharmacy and Nutrition, University of Saskatchewan, ³College of Medicine, University of Saskatchewan, and ⁴Pharmalytics Inc., Saskatoon, Canada
Objective: To examine the effect of the exposure measures C_max (peak exposure), AUC_E (early exposure) and AUC (total exposure) on the bioequivalence of two sustained release formulations of bupropion (i) in the fasted state and (ii), after a high fat meal. The ratio C_max/AUC (sensitive to rate of absorption) was also evaluated. Methods: A two-formulation, two-sequence, four-period replicate design study was performed in 29 healthy men and women after an overnight fast. Similarly, a two-period study was performed in 20 healthy men and women after ingestion of a high fat breakfast. Plasma concentrations of bupropion were measured by HPLC/MS/MS and the data were analyzed (SAS PROC MIXED) by the Schuirmann-Sattersthwaite procedure (four-period study) and by the two one-sided test procedure (SAS PROC GLM) (two-period study). Standard bioequivalence limits of 80 ? 125% were applied to all measures including AUC_E and C_max/AUC. Results: In the fasting study, the mean plasma concentration vs. time curves from (including over the first 24 hours) following the two administrations of each formulation were similar although there was a significant difference in median t_max between formulations. This may have contributed to a low estimate of geometric mean ratio (GMR) for AUC_E (69%) which was judged to have failed bioequivalence. There was also rather low GMRs for C_max (88%) and C_max/AUC (89%) but these measure passed because the within-subject variabilities (WSV) were relatively low (19.6% and 11.2%, respectively). Total exposure (AUC_last) met standard bioequivalence limits of 80 ? 125% easily. The raw data from the two-period fed also showed differences in the shapes of the plasma concentration vs. time curves around C_max although there was no difference in median t_max. The WSV at median t_max was high (34%) as was the GMR (117%) for AUC_E which failed, as did C_max (GMR 112%). The WSV was very high at early time points before settling into a ?plateau? at about 11%. Discussion: There was no ?spike? in the plasma concentration vs. time profiles up to median tmax or beyond and therefore there was no evidence of dose dumping of the test formulation in either fasted or fed states. No bioequivalence limits have been set for AUC_E but the application of standard BE limits of 80 to 125% meant that the fed study was clearly underpowered given the high WSV at early time points. Conclusions: More research is needed on the interesting concept of early exposure. The WSV is often high at median tmax which means that standard bioequivalence limits of 80 ? 125% may be inappropriate. Despite the lack of dose dumping, application of AUC_E to the fasting study, would have resulted in failure to declare bioequivalence since the GMR for this measure was only 69.5%. Application of a 90% confidence interval to AUCE to the fed study would have required powering to cope with the fact that this measure was highly variable.Correspondence to:
Dr. J.W. Hubbard Pharmalytics Inc. 346 ? 111 Research Drive Saskatoon, SK S7N 3R2, Canada
Email: Hubbard@duke.usask.ca

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Volume 43, No. 5/2005(May)