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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48– No. 9/2010 (563-570)

The safety of healthy volunteers in First-in-Man trials – an analysis of studies conducted at the Bayer in-house ward from 2000 to 2005

G. Wensing¹, I.-A. Ighrayeb¹, O. Boix² and M. Böttcher¹

¹Clinical Pharmacology and ²Pharmacometrics, Bayer Schering Pharma AG, Wuppertal, Germany
Objective: The Northwick Park incident has focused the attention on the risk of healthy volunteers participating in Phase I First-in-Man (FiM) studies irrespective of biologicals or small molecules being applied. However, only few data on the safety of healthy volunteers receiving small molecules in FiM trials are available. This study reports on the safety of healthy volunteers participating in single dose FiM studies performed with small molecules at the Bayer in-house study ward in Wuppertal from 2000 to 2005. Methods: From 2000 to 2005, 24 FiM dose escalation studies with small molecules were performed. Twenty studies were performed with oral formulations and four studies with intravenous formulations. 1,094 young healthy male subjects were included into the studies. 77 subjects dropped out before receiving any study medication. The remaining 1,017 study participants (mean age 31.8 ± 6.5 years (range: 18 – 46 years)) received 1,160 treatments, 792 with active drug and 368 with placebo. Results: In total, 586 adverse events (AE) occurred equaling 0.51 AE/treatment and 0.58 AE/ subject. 128 AEs occurred under placebo (0.35/treatment) and 458 under active drug (0.58/treatment). 98.3% of AEs were of mild or moderate intensity. Adverse events with a frequency > 2% were headache (17.1%), nasopharyngitis (7.3%), flushing (7.0%), feeling hot (5.5%), nausea (4.1%), nasal congestion (3.9%), dizziness (3.4%), diarrhea (3.24%), Alanine aminotransferase (ALT) increase (2.6%) and orthostatic hypotension (2.4%). In only 5 out of 1,160 treatments (0.4%) a serious adverse event occurred. Two cases of hypotension were related to the mode of action of CNS compounds and judged to be drug-related while the other three events (muscle enzyme elevation (2 ×), prolonged orthostatic reaction (1 ×) were not drug-related. None of the serious adverse events was medically worrying or required hospitalization. Conclusion: The incidence of adverse events in FiM trials with small molecules in our center between 2000 and 2005 and the severity of AEs is comparable to what has been reported previously for Phase I trials with small molecules [3, 4]. It reflects our experience with FiM trials of more than 25 years in which no medically worrying or hospitalization requiring serious adverse event occurred.Correspondence to:
Prof. Dr. G. Wensing
Clinical Pharmacology, Clinical Pharmacodynamics CV/H
Bayer Schering Pharma AG
Aprather Weg 18a, 42096 Wuppertal, Germany
Email: georg.wensing@bayerhealthcare.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (571-576)

Adverse drug events in hospitalized patients with chronic kidney disease

Y. Hassan¹, R.J. Al-Ramahi², N.A. Aziz¹ and R. Ghazali³

¹School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia, ²School of Pharmacy, An-Najah National University, Nablus, Palestine, and ³Department of Medicine, Penang Hospital, Penang, Malaysia
Background and objective: Adverse drug events (ADEs) are a common cause of hospitalization and in-hospital complications. The aim of this study was to determine the rates, types, severity and preventability of pre-admission and in-hospital ADEs in patients with chronic kidney disease (CKD). Methods: This study was conducted at the nephrology unit at Penang General Hospital. A random sample of 300 adult patients with CKD was included. Medical records and charts were reviewed by a clinical pharmacist every work day to find any evidence of errors or complications related to drug use. If a suspected ADE was found, further investigations were carried out to assess the causality, severity and preventability of the event. Results: A total of 159 ADEs were reported in 122 (40.7%) of the patients. We found 86 suspected pre-admission ADEs in 68 (22.7%) of the patients. These were either the cause of admission for some patients or discovered by the initial physical examination and laboratory investigations. During hospitalization, 64 (21.3%) patients had 73 suspected ADEs. Out of the total 159 suspected ADEs, it was highly probable that 31 events were due to medication, while 61 were of lower probability, and 67 were merely possible. A total of 48 (30.2%) events was considered preventable. 46 events (28.9%) were serious, 93 (58.5%) were less serious and 20 (12.6%) were insignificant. The medication classes most frequently involved in ADEs were diuretics, antibacterials, drugs used for diabetes mellitus, antithrombotic agents, mineral supplements and antihypertensive drugs. Conclusion: ADEs are very common in hospitalized CKD patients, and some of these events are preventable. The service of a clinical pharmacist may help to reduce ADEs.Correspondence to:
Y. Hassan, PharmD
Professor of Clinical Pharmacy, Clinical Preceptor for Internal Medicine Clerkship, Clinical Pharmacy Programme, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
Email: yahaya@usm.my

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48– No. 9/2010 (577-581)

Postural orthostatic tachycardia syndrome: a case report of palpitations and dizziness following prophylactic mefloquine use

A. Bhanji, C. Atkins and M. Karim

Department of Renal Medicine, Norfolk and Norwich University Hospital, Norwich, UK
Objective: The antimalarial agent mefloquine has been reported to cause a number of possible side effects. Here we describe a case demonstrating a previously unreported complication, the postural orthostatic tachycardia syndrome (POTS). Case history: A 44-year-old woman presented with symptoms of severe orthostatic intolerance (palpitations and dizziness) in combination with postural tachycardia (but no fall in blood pressure) following the use of mefloquine prophylaxis. Investigations revealed evidence of autonomic dysfunction (with loss of ECG R-R interval variation) consistent with POTS. Her symptoms responded well to beta-blockade with propranolol. Conclusion: The possibility of POTS should be considered in patients presenting with symptoms of palpitations, dizziness, presyncope or other features suggestive of autonomic dysfunction following the use of mefloquine.Correspondence to:
M. Karim
Department of Renal Medicine
Norfolk and Norwich University Hospital
Colney Lane, Norwich NR4 7UY, UK
Email: mkarim@doctors.org.uk

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (582-595)

Pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with Type 2 diabetes

Y.-L. He¹, M. Yamaguchi², H. Ito², S. Terao² and K. Sekiguchi²

¹Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA, and ²Novartis Pharma KK, Tokyo, Japan
Objective: To assess the pharmacokinetics, pharmacodynamics and safety of vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), in Japanese patients with Type 2 diabetes. Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, 62 Japanese patients with Type 2 diabetes received vildagliptin 10 mg, 25 mg or 50 mg twice daily for 7 days. Blood samples were collected for the determination of plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin and glucagon. Results: Exposure to vildagliptin (area under the plasma concentration-time curve from 0 to 12 h (AUC_0–12h) and the maximum plasma concentration (C_max)) increased in an approximately dose-proportional manner, and no accumulation was observed following multiple doses of vildagliptin (accumulation factor 1.00 – 1.02). DPP-4 activity was completely inhibited for varying durations by all doses of vildagliptin; the duration of complete DPP-4 inhibition was dose-dependent. DPP-4 inhibition after vildagliptin 50 mg twice daily remained > 80% throughout the 24-h period. Vildagliptin treatment led to a dose-dependent increase in plasma active GLP-1 levels; the overall increases (area under the effect-time course from 0 to 8 h, AUE_0–8h) after 7 days’ treatment were 1.5-, 1.7-, and 1.8-fold with vildagliptin 10 mg, 25 mg and 50 mg twice daily, respectively (all p < 0.0001 vs. placebo). Postprandial plasma glucose during the 4-h period after breakfast was significantly reduced with the 10, 25 and 50 mg vildagliptin doses by 50.3, 92.2 and 69.5 mg·h/dl, respectively. Insulin levels remained unchanged in the context of reduced glucose levels at all doses studied. Conclusions: Vildagliptin demonstrated similar pharmacokinetic and pharmacodynamic effects in Japanese patients to those observed previously in non-Japanese patients with Type 2 diabetes.Correspondence to:
Y.-L. He, PhD DMSc
Translational Science-Translational Medicine
Novartis Institutes for BioMedical Research Inc.
220 Massachusetts Avenue, Building 605
Cambridge, MA 02139-3584, USA
Email: yanling.he@novartis.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (596-607)

Population pharmacokinetics of golimumab in patients with ankylosing spondylitis: impact of body weight and immunogenicity

Z.H. Xu¹*, H. Lee²*, T. Vu², C. Hu¹, H. Yan¹, D. Baker¹, B. Hsu¹, C. Pendley¹, C. Wagner¹, H.M. Davis¹ and H. Zhou¹

¹Centocor Research and Development, Malvern and ²Center for Drug Development, Inc. Science, Department of Biopharmaceutical Sciences, University of California San Francisco, Washington, DC, USA
Aims: To develop a population pharmacokinetic (PK) model of subcutaneously administered golimumab, a human anti-tumor necrosis factor monoclonal antibody, in patients with ankylosing spondylitis (AS), estimate typical fixed and random population PK parameters, and identify significant covariates on golimumab pharmacokinetics. Methods: Serum concentration data through Week 24 of a randomized, double-blind, placebo-controlled Phase III trial of golimumab (50 or 100 mg every 4 weeks) were analyzed using a nonlinear mixed-effects modeling approach. The effects of potential covariates on golimumab were evaluated. Results: A one-compartment PK model with first-order absorption and elimination was chosen to describe the observed golimumab concentration-time data in patients with AS. Population estimates obtained from the final model for a typical 70-kg patient were: apparent systemic clearance (CL/F), 1.41 l/day (95% confidence interval (CI): 1.31 – 1.51) and apparent volume of distribution (V/F), 22.6 L (95% CI: 20.7 – 24.4). The first-order absorption rate constant (Ka) was estimated to be 1.01 day–1 (95% CI: 0.760 – 1.46). The between-subject variabilities for CL/F, V/F, and Ka were 35.2%, 38.6%, and 78.6%, respectively. Body weight was the most significant covariate, affecting both CL/F and V/F. Antibody-to-golimumab status, baseline C-reactive protein level, and sex were also identified as significant covariates on CL/F. Conclusions: A one-compartment model with first-order absorption and elimination adequately described the PK of golimumab following subcutaneous administrations in patients with AS. Body weight and anti-golimumab antibody status were found to significantly influence golimumab clearance. When a patient does not respond to the prescribed golimumab therapy, the possibility of the development of antibodies to golimumab has to be considered.Correspondence to:
H. Zhou, PhD, FCP
Centocor Research and Development, Inc.
200 Great Valley Parkway
Malvern, PA 19355, USA
Email: hzhou2@its.jnj.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (608-613)

Time course of action and pharmacokinetics of ropivacaine in adult and elderly patients following combined lumbar plexus-sciatic nerve block

J. Xiao, M.-H. Cai, X.-R. Wang, P. He and X.-R. Wang

Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai, China
Objective: Large doses of local anesthetics are needed in combined lumbar plexus-sciatic nerve block. The safety of local anesthetics is important among elderly patients. This study investigates the pharmacokinetics of ropivacaine in elderly patients with combined lumbar plexus-sciatic nerve block. Methods: Ropivacaine pharmacokinetics and the time of onset, duration of sensory and motor block were studied in adult patients (18 – 60 y) and elderly patients (>= 60 y). Combined lumbar plexus-sciatic nerve block was performed using a nerve stimulator. 0.375% ropivacaine was injected in patients. Plasma concentration of ropivacaine was determined by high performance liquid chromatography. Results: There was no significant difference in onset time and time to peak (t_max1, t_max2) between elderly patients and adult patients. Half-life time (t_1/2alpha, t_1/2beta) and the duration of sensory and motor block were longer in elderly patients (p < 0.05). While the peak plasma concentrations of (double peaks, C_max1, C_max2) wer lower in elderly patients than that in adult patients. Conclusions: Age does not affect the onset time of ropivacaine after combined lumbar plexus-sciatic nerve block but can influence the motor and sensory recovery. Local absorption of ropivacaine is slower in elderly patients compared to adults.Correspondence to:
X.-R. Wang, MD
Department of Anesthesiology, Renji Hospital
Medical School of Shangai
Jiaotong University
1630 Dongfang Road
Shanghai 200127, China
Email: xiangruiwang@gmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (614-620)

Comparative bioavailability of two risperidone orodispersible tablet products after single dose administration

W. Tassaneeyakul¹, S. Kumar², D. Gaysonsiri¹, T. Kaewkamson¹, A. Khuroo², P. Tangsucharit¹, K. Phunikhom¹, S. Vannaprasaht¹, S. Kanjanawart¹, N. Rao Thudi², R. Jain², S. Reyar² and T. Monif²

¹Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand and ²Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Research Laboratories, Haryana, India
Objectives: To compare the bioavailability of two risperidone orodispersible tablet products, Risperidone 1 mg Mouth dissolving tablet, Ranbaxy (Malaysia) Sdn. Bhd., Malaysia, as a test product and Risperdal 1 mg Quicklet, Janssen Ortho LLC, Gurabo, Puerto Rico, as a reference product, in healthy male volunteers under fasting condition. Materials and methods: A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72 and 96 h following drug administration. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone were determined using a non-compartmental model. Results: The geometric means ratios (%) and 90% confidence interval (CI) of the test and reference products for the log-transformed pharmacokinetic parameters, C_max, AUC_0–t and AUC_0–inf of risperidone were 104.49 % (92.79% – 117.66%), 100.96 % (92.15% – 110.61 %) and 97.99 % (90.72% – 105.85%). The 90% CI of geometric means ratios of the test and reference products for the log-transformed pharmacokinetic parameters, C_max, AUC_0–t and AUC_0–inf of 9-hydroxyrisperidone were 97.00%, 96.97% and 97.49%. Conclusions: The 90% CI for the geometric means ratios (test/reference) of the log-trasformed C_max, AUC_0–t and AUC_0–inf of risperidone and its major active metabolite were within the bioequivalence acceptance criteria of 80% – 125% of the US-FDA.Correspondence to:
Dr. W. Tassaneeyakul
Department of Pharmacology
Faculty of Medicine, Khon Kaen University
Khon Kaen 40002, Thailand
Email: wichitt@kku.ac.th

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (621-627)

Comparative bioavailability of two oral formulations of mycophenolate mofetil in healthy adult Uruguayan subjects: a case of highly variable rate of drug absorption

F.E. Estevez-Carrizo¹, S. Parrillo¹, M. Cedres², F.T. Estevez-Parrillo² and P. Rodriguez²

¹Center for Biomedical Sciences, University of Montevideo, and ²Center for Clinical Pharmacology Research, Hospital Italiano, Montevideo, Uruguay
Objective: To assess the bioequivalence and safety of a new formulation of mycophenolate mofetil (MMF) 500 mg (Suprimun^®, Clausen, Montevideo, Uruguay) marketed in Uruguay and other South American countries, and to test C_max/AUC as a characteristic of its absorption rate. Material and methods: A randomized, open-label, two-way, two-treatment, two-period crossover study in 24 healthy male volunteers was carried out. One tablet (500 mg) of each formulation was administered after an overnight fast. After dosing, serial blood samples were collected for a period of 36 hours. Plasma concentrations of MPA were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated. Analysis of variance was carried out using log-transformed AUC_0–36, C_max, and C_max/AUC_0–36. 90% confidence intervals and within-subject between-subject variance were calculated. The bioequivalence of the two formulations was established at the 80% – 125% acceptance limits and untransformed t_max medians were compared using Wilcoxon test. Subjects were monitored for adverse events throughout the study. Results: The means (test and reference) were 21.14 and 20.86 µg × h × ml^–1 for AUC_0–36, 24.92 and 24.18 µg × h × ml^–1 for AUC_0–inf, 11.86 and 10.76 µg × ml^–1 for C_max and 0.51 and 0.54 h^–1 for C_max/AUC_0–36. The geometric mean ratios (confidence interval 90%) of Test/Reference were 1.00 (0.95 – 1.06) for AUC_0–36, 1.09 (0.96 – 1.24) for C_max and 1.04 (0.99 – 1.09) for C_max/ AUC_0–36. The extra peaks observed are due to enterohepatic recycling of MPA. No serious or unexpected adverse events were observed during the study. Conclusions: The test formulation containing mycophenolate mofetil 500 mg met regulatory requirements for bioequivalence. Moreover, C_max/AUC shows interesting features as a putative metric to evaluate the absorption rate of highly variable drugs like mycophenolate mofetil. Generally, both formulations were well tolerated.Correspondence to:
F.E. Estevez-Carrizo, MD
Center for Clinical Pharmacology Research
Bdbeq S.A., Hospital Italiano Br. Artigas 1632, c.p.
11600 Montevideo, Uruguay
Email: Francisco.Estevez@bdbeq.com.uy

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 9/2010 (628-632)

Bioequivalence study of two generic formulations of 10 mg montelukast tablets in healthy Thai male volunteers

P. Sripalakit, S. Maphanta and A. Saraphanchotiwitthaya

Bioequivalence Test Center, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
Objective: to compare the bioavailabilities of two generic brands of montelukast available in the Thailand (Montek^® and Tomont^®) with the original brand (Singulair^®) in healthy Thai male volunteers under fasting condition. Materials and methods: A randomized, single-dose, two-period, two-sequence, crossover study design with a 1-week wash-out period was done in 24 healthy Thai male volunteers for each study. Blood samples for plasma montelukast levels were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16 and 24 h after administration, and was then analyzed using a validated HPLC method. The pharmacokinetic parameters were determined from plasma concentration-time profile of test and reference products by using non-compartment analysis. Results: In each study, the ANOVA of C_max and AUC_0-t, AUC_t–inf did not show any significant difference between two formulations and products of montelukast and the 90% confidence intervals of C_max and AUC_0-t, AUC_t–inf fell within the acceptable range of Thailand Food and Drug Administration. Conclusions: It can be concluded that Montek^® and Tomont^® are bioequivalent to Singulair^®, and that two generic products can be considered interchangeable with the reference in medical practice.Correspondence to:
P. Sripalakit, PhD
Bioequivalence Test Center
Faculty of Pharmaceutical Sciences
Naresuan University
Phitsanulok 65000, Thailand
Email: pattanas@nu.ac.th

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Volume 48, No. 9/2010(September)