R.G. Tiessen¹, J.P. Castaigne², J.F. Dreyfus², M. Nemansky¹, H.H. Kruizinga¹ and A.A. van Vliet^{1 1}PRA International, Zuidlaren, The Netherlands, and ²ConjuChem Inc. (CJC), Montreal, Canada Objective: The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated. Methods: CJC-1131 was subcutaneously injected in 8 groups (1.5 – 20.5 µg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 – 12 µg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3. Results: CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in C_max. The half-life of CJC-1131 varied from 8.9 – 14.7 days in healthy subjects and from 9.1 – 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 µg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients. Conclusions: Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.Correspondence to:
R.G. Tiessen, PhD, MD; PRA International, P.O. Box 200, 9470 AE Zuidlaren, The Netherlands

Email: TiessenRenger@PRAIntl.com

W. Dieterle¹ and T. Hengelage^{2 1}Drug Disposition Consultants, Loerrach, Germany, and ²Clinical Research and Development, Speedel Pharma AG, Basel, Switzerland Objective: Avosentan is a potent, selective endothelin A receptor blocker. The effect of food intake on the pharmacokinetics of avosentan was investigated in healthy volunteers. Methods: In a randomized, open-label, 2-period oral crossover study, 12 healthy subjects (8 males and 4 females) received Treatments A and B. Treatment A consisted of a single dose of avosentan 50 mg after a high-fat, high-calorie breakfast. Treatment B consisted of a single dose of avosentan 50 mg administered in the fasted state. Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. Results: The overall exposure to avosentan and its metabolite, as reflected by the area under the plasma concentration-time curve from time zero to infinity (AUC_0-µ), was not affected by food intake. The ratios of least square means (90% confidence interval (CI)) of AUC_0-µ for avosentan and Ro 68-5925 in the fed and fasted state were 1.06 (0.96, 1.17) and 1.05 (0.96, 1.15), respectively. The maximum plasma concentration (C_max) of avosentan and its metabolite was increased by food intake, and their apparent terminal half-life (t_1/2) was shortened. The ratios of least square means (90% CI) of pharmacokinetic parameters for avosentan and its metabolite in the fed and fasted state were C_max 1.61 (1.37, 1.90) and 1.46 (1.27, 1.67), and t_1/2 0.80 (0.69, 0.92) and 0.61 (0.51, 0.74), respectively. Single oral doses of avosentan were well tolerated under fasted and fed conditions. Conclusion: Food intake does not influence the pharmacokinetics of avosentan to a clinically relevant extent.Correspondence to:
Dr. T. Hengelage; Speedel Pharma AG, Department of Clinical Research & Development, Hirschgässlein 11, 4051 Basel, Switzerland
Email: thomas.hengelage@speedel.com

X. Zhao¹, Y.M. Cui¹, Y. Zhou¹, H.L. Zhang¹, K.P. Yeo², H. Linnebjerg⁴, L.S. Tham², P. Kothare³, L.L. Teng², K. Mace³ and D. Soon^{2 1}Peking University First Hospital, Beijing, People’s Republic of China, ²Lilly-NUS Center for Clinical Pharmacology, Singapore, ³Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA, and ⁴Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK Objectives: Exenatide is an adjunctive treatment for Type 2 diabetes. This was the first study to evaluate the pharmacokinetics, safety and tolerability of therapeutic doses (5 µg and 10 µg) of exenatide after single and multiple subcutaneous injections in healthy adult Chinese subjects. Methods: 24 healthy volunteers were randomized to receive either 5 µg or 10 µg of exenatide by subcutaneous injection. Subjects received a single injection of exenatide on Day 1, twice daily on Days 2 and 3, and once on Day 4. Serial blood samples were drawn for pharmacokinetic assessment at pre-dose and up to 12 h post dose on Day 1 and Day 4. Adverse events, vital signs, 12-lead ECG, body weight and clinical laboratory evaluations were assessed. Results: Exenatide, 5 µg and 10 µg, was rapidly absorbed with a median t_max of 1 h after single and multiple doses. Exenatide C_max and AUC_t,ss were (geometric mean (90% CI)) 145 (119 – 176) pg/ml and 370 (297 – 460) pg × h/ml, respectively, after multiple dosing with 5 µg. The C_max and AUC_t,ss were 311 (271 – 357) pg/ml and 878 (785 – 983) pg × h/ml, respectively, for 10 µg. Mean half-life (t_1/2, range 0.99 – 1.25 h), apparent volume of distribution (V_z/F, 19.2 – 22.3 l), and apparent clearance (CL/F, range 11.4 – 13.5 l/h) remained consistent between single and multiple doses and across the two dose levels. Both the accumulation ratios and linearity index approached 1.0. The most common adverse events were gastrointestinal in nature and mild in severity. The frequency of adverse events increased with dose, such that 8% of subjects who received 5 µg and 42% of subjects who received 10 µg experienced adverse events. Conclusions: Exenatide was rapidly absorbed, with similar pharmacokinetic properties following single and multiple doses. Exenatide exposure after multiple doses approximately doubled from 5 µg to 10 µg.Correspondence to:
Y.M. Cui, PhD; Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Beijing, 100034, People’s Republic of China
Email: cuiymzy@126.com

F. Haessler¹, F. Tracik², H. Dietrich³, H. Stammer⁴ and J. Klatt^{2 1}Clinic for Child Psychiatry, Neurology, Psychosomatics and Psychotherapy, University Hospital Rostock, ²Novartis Pharma GmbH, Nuremberg, ³ClinPharmCologne, MEDA Manufacturing GmbH, Cologne, and ⁴Pharmalog Institut für klinische Forschung GmbH, Munich, Germany Objectives: Primary objective was to investigate bioequivalence of Ritalin LA^® 40 mg compared to Medikinet^® retard 40 mg in healthy male volunteers under fasted and fed conditions. Secondary objectives included assessment of tolerability and determination of further pharmacokinetic parameters. The difference between the kinetic profiles of Ritalin LA^® and Medikinet^® retard with respect to breakfast intake was additionally explored. Methods: 28 subjects were randomized in this open-label, four-treatment, cross-over-design study. Pharmacokinetic evaluations included AUC_(0-inf), C_max, t_max, elimination half life (t_1/2) and mean residence time (MRT_(0-inf)). The relative bioavailability of Ritalin LA^® and Medikinet^® retard and the food effect were assessed using a 90% confidence interval (CI) based on the lower and upper endpoints of the CI for the ratios of the geometric means being within the 80 – 125% equivalence criterion. Results: 25 volunteers completed all treatment arms. Frequency of adverse events were comparable for all treatments. Under fasted condition Ritalin LA^® showed a consistent bimodal concentration time profile with two t_max peaks. Medikinet^® retard showed a steady absorption with a single t_max peak. The point estimators for AUC_(0-inf) and C_max were found to be 99.7% and 85.9%, respectively. Under fed condition both Ritalin LA^® and Medikinet^® retard showed a bimodal concentration time profile with two tmax peaks. The point estimators for AUC_(0-inf) and C_max were estimated as 89.8% and 68.6%, respectively. Conclusions: Both methylphenidate formulations were safe and well tolerated. Ritalin LA^® and Medikinet^® retard were bioequivalent in fasted state but not in fed state. Only Ritalin LA^® had a biphasic kinetic profile under both fasted and fed conditions. This difference in the kinetic profiles might be of clinical relevance and might offer a potential advantage of Ritalin LA^®.Correspondence to:
Dr. med. J. Klatt; Novartis Pharma GmbH, Roonstraße 25, 90429 Nürnberg, Germany
Email: jan.klatt@novartis.com

C. Zhang¹, L. Zhang², X. Zhang¹, L. Yang¹, S. Zhai¹ and L. Duan^{3 1}Department of Pharmacy, Peking University Third Hospital and

Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University, ²Department of Anaesthesia and ³Department of Degestion of Peking University Third Hospital, Beijing, China Objectives: The aim of this study was to construct the population pharmacokinetic model in Chinese adult patients and to characterize the factors that affect the parameters of remifentanil pharmacokinetics. Methods: 15 patients were divided randomly into two groups: Index (modeling) group and validation group. 10 patients including 99 blood samples were in the Index group and 5 patients including 56 blood samples were in the Validation group. A LC-MS/MS method was developed to determine the whole blood concentration of remifentanil. Meanwhile, population modeling was performed using the NONMEM (nonlinear mixed-effect modeling) program with a 2-compartment pharmacokinetic model. The forward inclusion-backward elimination method was used to investigate the different covariates, including age, height, total bilirubin, etc. Results: Liquid-liquid extraction was used to extract remifentanil from the blood. The calibration curve was linear from 0.5 to 50 ng/ml and the lowest limit of quantification (LOQ) was 0.5 ng/ml. The analytical method was rapid, selective and highly sensitive. The population pharmacokinetic results indicated that total bilirubin, age, alkaline phosphatase activity and gender significantly affected the parameters of remifentanil. The estimation of CL1, V1, CL2 and V2 were 1.85 l/min, 8.47 l, 1.28 l/min and 29.7 l, respectively. The population model was validated by another group of patients indicating that the model was effective and robust. Conclusion: The LC-MS/MS method for the quantification of remifentanil in human whole blood was rapid, selective and highly sensitive. The population model was acceptable and would be helpful for clinicians to assess the remifentanil pharmacokinetic parameters based on patient’s specific demographic characteristics.Correspondence to:
Prof. S. Zhai; Department of Pharmacy of Peking University Third Hospital, Beijing, China
Email: laural_chao@sohu.com

W. Mahatthanatrakul, K. Rattana, S. Sriwiriyajan, M. Wongnawa and W. Ridtitid Department of Pharmacology, Faculty of Science, Prince of Songkla University, Songkhla, Thailand Aim: To study the bioequivalence of a generic quetiapine (Quantia 200^®, manufactured by the Unison Laboratories Co., Ltd., Bangkok, Thailand) and the innovator product (Seroquel^®, AstraZeneca, Macclesfield, UK). Volunteers and methods: The study was a randomized, 2-way crossover design with a 2-week washout period in 24 healthy Thai male volunteers. After a single 200 mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the WinNonlin^® software with noncompartment model analysis. Comparative bioequivalence between the two formulations was determined by analysis of variance (ANOVA) for 2-way crossover design. Results: The mean ± SD of maximum plasma concentration (C_max), the area under the plasma concentration-time curve from 0 – 48 h (AUC_0-48) and the area under the plasma concentration-time curve from 0 to infinity (AUC_0-µ) of Quantia 200^® vs. Seroquel^® were 886.60 ± 356.50 vs. 811.34 ± 323.37 ng/ml; 3,754.41 ± 1,453.00 vs. 3,420.00 ± 1,229.6 ng × h/ml and 4,015.35 ± 1,528.25 vs. 3,769.45 ± 1,296.69 ng × h/ml, respectively. Time to reach C_max (t_max) of Quantia 200^® and Seroquel^® were 1.08 ± 0.778 and 1.10 ± 0.79 h, respectively, and thus not significantly different. The 90% confidence interval of the ratios of the logarithmically transformed of C_max, AUC_0-48 and AUC_0-µ were 98.21 – 124.37%, 94.43 – 117.03% and 94.77 – 116.61%, respectively, which were within the acceptable range of 80 – 125%. Power of the test for C_max, AUC_0-48 and AUC_0-µ was 92.1%, 96.9% and 97.4%, respectively. Conclusion: Quantia 200^®, used in this study, was bioequivalent to Seroquel^® in terms of both the rate and extent of absorption.Correspondence to:
Dr. W. Mahatthanatrakul, MD, FCFPT; Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand
Email: werawatthana.m@psu.ac.th