B. Genser¹, T.B. Grammer², T. Stojakovic³, R. Siekmeier⁴ and W. März²,³,^{5 1}BGStats Consulting, Graz, Austria, ²Synlab Center of Laboratory Diagnostics Heidelberg, Germany, ³Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Austria, ⁴Federal Institute for Drugs and Medical Devices (BfArM) Bonn and ⁵Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany Objective: HMG CoA reductase inhibitors (statins) have been claimed to decrease C-reactive protein (CRP), independent of their effect on low-density lipoprotein cholesterol (LDL-C). We conducted a systematic review and meta-analysis to investigate whether a relationship between the average effect of statins on LDL-C and CRP exists. Data sources: The literature search of the Medline and Cochrane databases between 1980 and August 2007 yielded 65 statin intervention studies with 94 treatment arms involving 16,260 patients reporting changes in both LDL-C and CRP. Data extraction and statistical method: From each study relative changes in LDL-C and CRP were extracted. Random effects meta-analysis was used to obtain pooled summary estimates of the average study specific LDL-C and CRP reductions, in total and stratified by dose and type of statin. Weighted correlation analysis and metaregression analysis was used to investigate the relationship between the LDL-C and CRP changes adjusted for baseline values, type of statin and dose. Results: Pooled summary estimates of statin-induced changes in LDL-C and CRP levels were –34.7% (95% CI: –37.7% to –31.8%) and –30.8% (95% CI: –39.4% to –22.3%), respectively. We found a positive correlation between the average LDL-C and CRP reduction (r = 0.49, p = 0.010) which increased when adjusting for pre-treatment concentrations (r = 0.79, p < 0.001). The effect of statins on CRP were strongly related to the changes in LDL-C and baseline concentrations, independent of the type and dose of statin used. Conclusion: Our meta-analysis shows a strong correlation between statin-induced reductions in LDL-C and CRP, which has not been evident from individual studies. Measuring CRP in addition to LDL-C in the monitoring of statin treatment is currently not warranted.Correspondence to:
Dr. W. März, MD; Synlab Center of Laboratory Diagnostics Heidelberg, PO Box 10 41 29, 69031 Heidelberg, Germany
Email: winfried.maerz@synlab.de

T. Ahmed¹, M. Sajid⁴, T. Singh³, G.S. Saini¹, T. Monif², N. Saha⁵ and K.K. Pillai^{4 1}Department of Metabolism and Pharmacokinetics, ²Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Research Laboratories, Gurgaon, ³Department of Pharmaceutical Medicine, ⁴Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi and ⁵Department of Medical Affairs and Clinical Research, Ranbaxy Research Laboratories, Gurgaon, India Objective: The objective was to study the effect of grape juice and orange juice on the pharmacokinetics (PK) and pharmacodynamics (PD) of diltiazem in healthy human volunteers. Methodology: The study design was open-label, balanced, randomized, 3-period, single-dose and crossover. A group of 12 healthy, adult, male human volunteers received a single oral dose of diltiazem 180 mg extended release capsule on three different occasions: with 200 ml of water, with 200 ml of grape juice and with 200 ml of orange juice in random order. A washout period of 7 days was kept between each study period. Serial blood samples were collected up to 24 h post dose and assayed for diltiazem using a specific and validated HPLC method. Blood pressure (BP) and ECG measurements were done at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h post dose. Analysis of variance was carried out using logarithmic transformations of AUC and C_max as well as nontransformed t_max. Results: No significant change was observed in heart rate and BP. The median t_max was identical in all three occasions. The 90% CI of the C_max ratios for orange juice/water were 104.59 – 114.86 and for grape juice/water were 93.91 – 103.13. Similarly, the 90% CI of the AUC_0-¥ ratios for orange juice and grape juice vs. water were 103.68 – 119.83 and 88.56 – 104.06, respectively. Since these values fall within the bioequivalence criteria of 80 – 120% limits, our study demonstrates absence of interaction of diltiazem with grape juice or orange juice. Conclusions: There is no significant influence of grape juice or orange juice on the pharmacokinetics and pharmacodynamics of diltiazem.Correspondence to:
Dr. T. Ahmed; Metabolism and Pharmacokinetics Department, Ranbaxy Research Laboratories, Plot No. 20, Sector 18, Udyog Vihar, Gurgaon, Haryana, India
Email: drtarandeep@gmail.com

R. Sechaud¹, A. Robeva², R. Belleli¹ and S. Balez^{3 1}Novartis Pharma AG, Basel, Switzerland, ²Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and ³Novartis Pharma SAS, Rueil-Malmaison, France Deferasirox (Exjade^®, ICL670) is a potent iron chelator, recently approved as first-line therapy for the treatment of blood-transfusion-related iron overload. Iron deposition in the heart may lead to cardiac dysfunction in patients with iron overload. Thus, the combination of cardiac glycosides and deferasirox is likely to be used in clinical practice. Objective: This study was designed to investigate the effect of deferasirox on steady-state pharmacokinetics of digoxin. As digoxin is a P-glycoprotein substrate, the trial also explored the potential of deferasirox to alter the pharmacokinetics of compounds transported by P-glycoprotein in general. Methods: An open-label, randomized, 2-period, crossover study was carried out with 16 healthy volunteers. During both treatment periods, each subject received daily oral doses of digoxin for 8 days (0.5 mg on Day 1 and 0.25 mg/day on Days 2 – 8). In one of these treatment periods, single oral deferasirox 20 mg/kg was coadministered with digoxin on Day 8. Pharmacokinetic parameters assessed at the end of each treatment period were compared using the standard statistical analysis for bioequivalence assessment. Results: Deferasirox did not alter the steady-state pharmacokinetics of digoxin. The geometric mean ratios and 90% confidence intervals for C_max and AUC_t of digoxin (with/without deferasirox) were 0.93 (0.82 – 1.06) and 0.91 (0.83 – 1.00), respectively, and thus within the equivalence limits of 0.8 – 1.25. The amount of digoxin excreted intact in urine was similarly unaltered by coadministration of deferasirox. Conclusions: This study shows that single-dose deferasirox has no effect on steady-state pharmacokinetics of digoxin. Therefore, no dose adjustment of digoxin is necessary when deferasirox and digoxin are coadministered. The lack of interaction suggests that deferasirox is unlikely to interact with P-glycoprotein substrates.Correspondence to:
Dr. R. Sechaud; Novartis Pharma AG, Exploratory Development, WSJ-210.4.20, 4002 Basel, Switzerland


Email: romain.sechaud@novartis.com

M.P. Sánchez¹, C. Gómez², J.L. Carrasco³, J. Ocaña⁴, C. von Plessing², C.G. Godoy², R. Reinbach⁵ and R. Godoy^{2 1}Faculty of Sciences Chemicals and Pharmaceutical Sciences, University of Chile, Santiago, Chile, ²Department of Pharmacy, Faculty of Pharmacy, University of Concepción, Concepción, Chile, ³Department of Public Health, Faculty of Medicine, ⁴Department of Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain and ⁵Internal Medicine Department, University of Concepción, Concepción, Chile The purpose of this study was to determine if different methods for average bioequivalence in high variability drugs coincide or not in their conclusions when applied to the same dataset, and to discuss the method validity and reliability of the conclusions. Different approaches for the evaluation of average bioequivalence were applied to the results of a bioavailability trial on the diuretic drug Furosemide. These methods included widening the bioequivalence limits according to regulatory recommendations, scaling the limits and scaling the bioequivalence statistic, jointly with evaluating alternative bioavailability measures. The methods to establish the bioequivalence limits were also combined with some alternative methods to construct confidence intervals. The decision on bioequivalence depends much more on the bioavailability measures than on the statistical approach. The reliability of the final decision lies mainly in the interpretation of these measures and on the special characteristics of each drug.Correspondence to:
J.L. Carrasco; Bioestadística, Departament de Salut Pública, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036 Barcelona
Email: jlcarrasco@ub.edu

C. Souppart¹, Q. Yin², M. Merz¹, P. Hu³, J. Jiang³ and S. Appel-Dingemanse^{1 1}Novartis Pharma AG, Basel, Switzerland, ²Novartis Institute for Biomedical Research and ³Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China Objective: Oxcarbazepine (Trileptal^®) is an antiepileptic drug used as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children. The primary objective of this study was to assess the bioequivalence of Trileptal^® oral suspension formulation vs. the film-coated tablet after single and multiple twice-daily administrations in fasted, healthy Chinese male subjects. Methods: This was an open-label, randomized, two-period crossover study in 19 healthy Chinese male subjects. Treatment periods consisted of a single dose of 300 mg oxcarbazepine (either oral suspension formulation or film-coated tablet) on Day 1, b.i.d. administrations of 300 mg from Day 4 to Day 8 inclusive, and a final dose of 300 mg on the morning of Day 9. A 1-week washout period was implemented between treatment periods. Plasma levels of 10-monohydroxy derivative (MHD), the main metabolite mediating the pharmacologic activity of oxcarbazepine, were measured by a validated liquid chromatography tandem mass spectrometry method. Bioequivalence was assessed by the MHD areas under the concentration time curve (AUCs) and maximum concentrations (C_max) of the oral suspension vs. the film-coated tablet. Safety was evaluated throughout the study. Results: Trileptal^® oral suspension formulation was bioequivalent to film-coated tablet after single dose and multiple b.i.d. administrations, as assessed by MHD AUCs and C_max. The 90% confidence intervals (CI) of the geometric mean of the MHD individual ratios were within the bioequivalence CI limits (0.80-1.25). No safety concerns were raised. Conclusions: Trileptal^® oral suspension formulation and film-coated tablets are bioequivalent in healthy Chinese males.Correspondence to:
C. Souppart, Chem Eng; Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland
Email: claire.souppart@novartis.com