Volume 45, No. 6/2007(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacodynamics
Assessment of the safety, tolerability, and PK/PD properties of two new formulations of subcutaneously administered IFN-β1a: a double-blind, placebo-controlled comparison with the currently available formulation
Abstract
C. Brearley, A. Jaber, M. Bertolino, A. Priestley and M. Seiberling
1Merck Serono International S.A., Geneva, Switzerland, 2Instituto di Ricerche Biomediche “Antoine Marxer” RBM SpA, Merck Serono International S.A., Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, 3LCG Bioscience, Bourn Hall, Bourn, Cambridge, UK, and 4Swiss Pharma Contract Ltd., Allschwil, Switzerland
Objective: Application-site disorders are well-known adverse events (AEs) associated with subcutaneous (s.c.) injection. With high-dose, high-frequency interferon (IFN)-β1a (Rebif®) these AEs are generally mild but may lead to the discontinuation of some patients. The objective of this study was to compare the safety, tolerability, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of two new formulations of Rebif® (Rebif New Formulation: RNF1 and RNF2) with the current formulation (hereafter referred to as R) and placebo. Methods: In this double-blind, placebo-controlled, parallel-group, Phase I study, healthy volunteers of both sexes were randomized 1:1:1:1 to receive a single 0.5 ml s.c. dose of RNF1, RNF2, R or placebo (normal saline). The three active treatments contained 44 µg IFN-β1a. During the 24-hour post-dose period, safety and tolerability assessments were conducted and blood samples were taken at regular intervals for PK and PD analyses. Pain intensity on injection was measured using the short-form McGill questionnaire and a 100 mm visual analogue scale (VAS). Further safety assessments were performed and blood samples taken at 24-hour intervals until Day 7 post-dose, with a final post-study visit 10 – 14 days after dosing. Results: A total of 48 subjects (22 men, 26 women) were recruited and allocated equally to each treatment (12 subjects per group). AEs were reported by 10 subjects in each active treatment group and by 3 subjects in the placebo group. All AEs were consistent with the known safety profile of R. The number of treatment-emergent AEs was lower in the RNF2 group than the RNF1 or R groups (21, 31 and 33 events, respectively). Redness at the injection site was mostly mild and occurred in fewer subjects in the RNF2 group (n = 3) than the RNF1 or R groups (n = 7 and n = 4, respectively). Injection site pain was reported by 1 subject in the RNF2 group, compared with 4, 6 and 3 subjects, respectively, in the RNF1, R and placebo groups. The worst pain intensity, as measured by VAS, was lower in the RNF2 and RNF1 groups than either the R or placebo groups. There was considerable intersubject variability in the PK and PD profiles of the three formulations of IFN-b1a. Nevertheless, the PK and PD characteristics of RNF2 were similar to those of R. Conclusions: The results from this study suggest that RNF2 may offer improved tolerability compared with the current formulation of R, but retains comparable pharmacokinetic and pharmacodynamic characteristics. Correspondence to:
M. Bertolino
Merck Serono
Chemin des Mines 9
1211 Geneva 20, Switzerland
Email: mauro.bertolino@merckserono.net
Pharmacodynamics
Rosuvastatin reduces interleukin-6-induced expression of C-reactive protein in human hepatocytes in a STAT3- and C/EBP- dependent fashion
Abstract
C. Mayer, H.-J. Gruber, E.-M. Landl, S. Pailer, H. Scharnagl, M. Truschnig- Wilders and W. März
1Clinical Institute of Medical and Chemical Laboratory Diagnostics,
Medical University Graz, Austria, 2LURIC study LLC, Freiburg, Germany
Objective: It has been speculated that the reduction in vascular events by statins may not only be due to lowering of cholesterol, but also to the decrease in plasma C-reactive protein (CRP). In the present study we investigated the possibility that rosuvastatin directly affected CRP expression in stimulated human hepatocytes. Methods: Interleukin 6 (IL-6) stimulated human hepatoma cells (Hep3B) and primary human hepatocytes (PHH) were incubated with various concentrations of rosuvastatin (0.3 – 1 µM) for 24 hours. CRP expression was determined using ELISA and quantitative real-time RT-PCR. The activation of STAT3 and C/EBP was investigated utilizing transcription factor assays (TransAM). Results: IL-6 increased CRP secretion by up to 5-fold in Hep3B and 6.6-fold in PHH. Rosuvastatin reduced CRP expression by 32% and 46% in Hep3B and PHH, respectively. IL-6 increased CRP mRNA up to 32-fold. At 1 µM, rosuvastatin reduced CRP mRNA by 73% compared to IL-6-stimulated cells. IL-6 activated the transcription factors STAT3 and C/EBP up to 2.6-fold and 2.2-fold, respectively. Rosuvastatin (1 µM) attenuated the activation of STAT3 and C/EBP by 48% and 54%, respectively. Conclusions: Our results show a direct inhibitory effect of rosuvastatin on IL-6-induced expression of CRP in liver cells. Statins may lower CRP by inhibiting its production in the liver rather than by exerting systemic anti-inflammatory effects. The effects of rosuvastatin in reducing the levels of CRP in plasma may have clinical utility in addition to its effects on atherogenic lipoproteins.Correspondence to:
C. Mayer
Clinical Institute of Medical and Chemical Laboratory Diagnostics
Medical University Graz
Auenbruggerplatz 15
8036 Graz, Austria
Email: claudia.mayer@klinikum-graz.at
Pharmacodynamics
Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics
Abstract
G. Fauler, C. Abletshauser, W. Erwa, R. Löser, K. Witschital and W. März
1Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Austria, 2Medical Department, Novartis Pharma, Nürnberg, 3Fujisawa Deutschland, and 4BioProof AG, Munich, Germany
Objective: Statins inhibit the rate-limiting step in cholesterol biosynthesis, the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase. Statins are usually taken in the evening as the HMG-CoA reductase activity is high during the night. This recommendation might not apply if statins are given as extended-release (ER) formulations. The present study investigated the influence of time of intake of fluvastatin 80 mg ER on cholesterol biosynthesis. Main objectives were to measure the change in 24-hour urinary mevalonic acid excretion, to determine plasma concentrations of mevalonic acid and fluvastatin and to monitor triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. Methods: This was a randomized, 2-period crossover study in 26 hypercholesterolemic patients who received a single daily dose of fluvastatin both in the morning and in the evening. Results: At baseline, the amount of mevalonic acid was 204.9 ± 68.1 µg/g creatinine. After a single dose of fluvastatin mean urine values of mevalonate were significantly reduced to 129.8 ± 66.2 µg/g (evening) and to 118.7 ± 34.3 µg/g (morning; n.s. between groups), thus representing a reduction of about 39%. Compared to baseline, plasma mevalonate concentrations were decreased by fluvastatin resulting in similar 24-hour profiles after the morning and the evening dosage. The pharmacokinetics of fluvastatin were similar in both periods of the study, with higher plasma concentrations for several hours following the evening dosage. Conclusion: This study demonstrates that fluvastatin ER is equally effective in inhibiting cholesterol biosynthesis when given once daily in the morning and once daily in the evening.Correspondence to:
Dr. G. Fauler
Clinical Institute of Medical and Chemical Laboratory Diagnostics
Medical University Graz
Auenbruggerplatz 30
8036 Graz, Austria
Email: guenter.fauler@meduni-graz.at
PK/PD Modeling
Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor – in healthy subjects
Abstract
W. Mueck, M. Becka, D. Kubitza, B. Voith and M. Zuehlsdorf
1Clinical Pharmacology and 2Department of Biometry, Pharmacometry,
Bayer HealthCare AG, Wuppertal, Germany
Objective: Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor being developed for the prevention and treatment of thromboembolic disorders. This analysis aimed to define population models for the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy males. Methods: Non-linear, mixed-effect modeling was used to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) from subjects in a phase I, multiple-ascending-dose study. Subjects received 5 mg rivaroxaban once, twice or three times daily, or 10, 20 or 30 mg rivaroxaban twice daily. Results: The population PK of rivaroxaban were well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 l/h and 55 l, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution for rivaroxaban at steady state was ~ 70 l. Residual (unexplained) variability was 25%. FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory Emax model; prothrombin time (PT) and rivaroxaban plasma concentrations correlated with a linear model, with a slope of 4.6 s/(100 µg/l). Inter-individual variability was low for the correlation with PT. The models derived were used to define sampling windows for population PK/PD modeling in Phase II studies. Conclusions: This analysis confirms that rivaroxaban has predictable, dose-proportional PK and PD. The linear correlation between rivaroxaban plasma concentrations and PT suggests that this test might be useful to assess rivaroxaban exposure in patients, if required.Correspondence to:
W. Mueck
Clinical Pharmacology
Bayer HealthCare AG
Aprather Weg 18a
42117 Wuppertal, Germany
Email: wolfgang.mueck@bayerhealthcare.com
Therapeutics
Suppression of gastric acid with intravenous esomeprazole and omeprazole: results of 3 studies in healthy subjects
Abstract
K. Röhss, C. Wilder-Smith, J. Kilhamn, M. Fjellman and T. Lind
1AstraZeneca R&D, Mölndal, Sweden, 2Brain-Gut Research Group, Bern, Switzerland
Objective: To identify the optimal pharmacodynamic dosing regimen for esomeprazole administered intravenously (i.v.) and to compare acid suppression with various esomeprazole i.v. and omeprazole i.v. dosing regimens. Methods: A total of 90 healthy Helicobacter pylori-negative subjects participated in three randomized, crossover studies of esomeprazole i.v. Comparative acid output study: an open-label study that compared single 40 mg i.v. doses (administered over 30 min) of esomeprazole and omeprazole. Dose-ranging study: an open-label study that compared acid control with five different doses of esomeprazole i.v., administered over 24 h. Comparative pH study: a double-blind study that compared esomeprazole i.v. and omeprazole at doses of 80 mg (over 30 min) + 8 mg/h (for 23.5 h). Results: In the comparative acid output study, estimated mean pentagastrin-stimulated acid output was reduced from 33.9 mmol/h at baseline to 5.4 mmol/h at 4 – 5.5 h with esomeprazole vs. 9.5 mmol/h with omeprazole (p < 0.001). In the dose-ranging study, the 80 + 8 mg/h regimen provided a greater mean time with pH > 6 (12.6 h) than the lower doses (11.0 and 10.7 h for 40 + 8 mg/h and 80 + 4 mg/h, respectively) and significantly more time with pH > 4 (21.5 vs. 19.7 and 19.2 h, respectively; p < 0.05). In the comparative pH study, the mean number of h with pH > 4 was similar between esomeprazole (21.4 h) and omeprazole (21.1 h). Conclusions: Esomeprazole was superior to omeprazole in reducing stimulated acid secretion. Control of intragastric pH was similar for esomeprazole and omeprazole at a dose of 80 + 8 mg/h. An esomeprazole i.v. dosage regimen of 80 + 8 mg/h appeared to be optimal for acid suppression in healthy subjects under study.Correspondence to:
K. Röhss AstraZeneca R&D Pepparedsleden 1 Mölndal, 431 83, Sweden
Email: Kerstin.Rohss@astrazeneca.com
Therapeutics
Efficacy and safety of abciximab in combination with cilostazol in patients undergoing stenting
Abstract
E.H. Hong, M.Y. Kim, J.E. Park, M.H. Lee, J.M. Oh and W.G. Shin
1Department of Pharmacy, Sejong Hospital, Gyeonggi-do,
2College of Pharmacy and Research Institute of Pharmaceutical Sciences,
Seoul National University, Seoul, and 3Department of Biostatistics and Computing, Yonsei University, Seoul, Korea
Objective: To evaluate the short- and long-term efficacy and safety of abciximab and cilostazol in patients with acute MI and unstable angina undergoing intracoronary stenting. Methods: Acute-phase (7 and 30 days), 6-month and long-term composite outcomes involving death, myocardial infarction or urgent target vessel revascularization (TVR) together with other outcomes (composite outcomes involving death, MI and elective TVR with restenosis and stroke) were evaluated retrospectively in a total of 175 patients. Safety outcomes were assessed using data on the incidence of bleeding and thrombocytopenia at Day 7 and Day 30. Results: Of 175 patients, 83 (47.4%) patients received abciximab. At 7 and 30 days, the composite outcome for the group treated with cilostazol alone and that treated with abciximab in combination with cilostazol did not differ significantly. The composite outcomes at 6 months and 1 year were significantly lower in the abciximab plus cilostazol group (relative risk 0.35, 95% CI 0.13 – 0.90, relative risk 0.28, 95% CI 0.10 – 0.78, respectively). The incidence of major bleeding at the access-site and in the gastrointestinal tract and minor bleeding were significantly higher in the group receiving abciximab plus cilostazol group at 7 days (relative risk 3.33, 95% CI 1.66 – 6.65, relative risk 9.98, 95% CI 1.29 – 77.07, relative risk 1.96, 95% CI 1.06 – 3.62, respectively) and at 30 days (relative risk 3.33, 95% CI 1.66 – 6.65, relative risk 5.54, 95% CI 1.25 – 24.56, relative risk 1.96, 95% CI 1.06 – 3.62, respectively). Conclusion: The combination of abciximab and cilostazol showed an improvement in major cardiac incidents at 6 months and 1 year of the treatment when compared to the group receiving cilostazol alone. However, abciximab did not improve the incidence of death but increased the risk of bleeding complications.
Correspondence to:
W.G. Shin, PharmD, PhD
Associate Professor
College of Pharmacy and Research Institute
of Pharmaceutical Sciences
Seoul National University
San 56-1, Sillim-dong, Gwankak-gu, Seoul 151-742, Korea
Email: wgshin@snu.ac.kr
Bioavailability Section
Digoxin bioequivalence study: determination in human plasma by microparticle enzyme immunoassay
Abstract
N. Carter do Carmo Borges, A. Guermani, J.A. Mazucheli, G. Duarte Mendes and R.A. Moreno
1Synchrophar Pesquisas Clínicas, Campinas, Brazil, 2Department of Pharmacology, and 3Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil
Objective: In this study a bio-analytical method for digoxin quantification was developed using Abbott AxSYM® Digoxin II with fluorescence detection to assess the bioequivalence of two digoxin tablet formulations (Digox 0.25 mg tablet from Pharlab Ind. Ltd., Brazil as test formulation and Digoxin® 0.25 mg tablet from Laboratório Glaxo SmithKline, Brazil as reference formulation). Material and methods: 30 healthy volunteers (both sexes) received a single oral dose of digoxin in an open, randomized, two-period crossover study with a seven half-life washout interval of at least (21 days). Plasma samples were obtained over a 288-h interval after each oral administration of digoxin. The present method utilizes microenzyme particle immunoassay technology, in which the digoxin in the sample binds to anti-digoxin-coated microparticles and after separation; digoxin-alkaline phosphatase conjugate binds to the available sites remaining. Digoxin concentrations are calculated from the fluorescent products generated as a result of substrate (4-methylumbelliferyl) passage through the matrix cell. Results: The method was shown to be specific and sensitive with good accuracy and precision. The geometric mean and 90% confidence intervals (CI) for the Digox/Digoxin® ratio were 107.62% (96.71 – 119.80%) for AUC0–t, 97.15% (80.54 – 117.19%) for AUC0–inf, and 91.23% (83.55 – 99.62%) for Cmax. Conclusion: Since the 90% CI for the parameters were all within the 80 – 125% interval proposed by the US Food and Drug Administration Agency, the two formulations were considered bioequivalent in terms of rate and extent of absorption.Correspondence to:
N. Carter do Carmo Borges, MD, PhD, FACC, FACP
38, Dr. Candido Gomide Street
Campinas, SP 13073-200, Brazil
Email: medney@synchrophar.com
Bioavailability Section
Bioequivalence of ciprofloxacin tablet formulations assessed in Indonesian volunteers
Abstract
Y. Harahap, B. Prasaja, E. Indriati, W. Lusthom and Lipin
1Department of Pharmacy, Faculty of Mathematics and Sciences,
University of Indonesia, 2Clinisindo Laboratories, Jakarta, Indonesia
Aim: Determination of the bioequivalence of two ciprofloxacin tablet formulations (test formulation manufactured by Novell Pharmaceutical Laboratories, Indonesia, reference formulation from Quimica Farmaceutica Bayer, Spain). Subjects and methods: 24 healthy volunteers received each of the two ciprofloxacin formulations at a dose of 500 mg in a 2-way crossover design. Blood samples were obtained prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after drug administration. Plasma concentrations of ciprofloxacin were monitored using high-performance liquid chromatography over a period of 24 h after administration. The pharmacokinetics parameter AUC0-24h, AUC0-¥ and Cmax were tested for bioequivalence after log-transformation of data and ratios of tmax were evaluated nonparametrically. Results: The point estimates and 90% confidence intervals for AUC0-24h, AUC0-¥ and Cmax were 97.55% (92.71 – 102.6%), 97.63% (92.90 – 102.59%) and 95.84% (89.95 – 102.10%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. Conclusion: These results indicate that two medications of ciprofloxacin are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
Dr. Y. Harahap, MS
Department of Pharmacy
Faculty of Mathematics and Sciences
University of Indonesia
Depok 16424, Indonesia
Email: yahdiana03@yahoo.com
