M. Kotsuma¹, T. Tokui¹, S. Freudenthaler² and K. Nishimura^{1 1}Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan, and ²Risk Management, Daiichi Sankyo Europe GmbH, Munich, Germany Purpose: Pactimibe is a novel ACAT inhibitor. The pharmacokinetics of pactimibe and its pharmacologically inactive plasma metabolite, R-125528, of which the main clearance pathway is CYP2D6, was affected by coadministration of quinidine. The aim of this study was to investigate the influence of CYP2D6 polymorphism on pharmacokinetics of pactimibe and R-125528. In addition, exposure was examined after multiple doses of pactimibe sulfate in CYP2D6 poor metabolizer (PMs). Methods: 24 healthy male Caucasian volunteers, genotyped as extensive, intermediate, and poor metabolizers, were received single dose of 25 mg pactimibe. In a multiple-dose study, six CYP2D6 PMs received 100 mg pactimibe for 21 days and exposure of pactimibe and R-125528 was examined. Results: In contrast to the mild 1.7-fold increase in AUC_0-inf of pactimibe, a marked 3.1-fold increase in AUC_0-tz of R-125528 was observed in CYP2D6 PMs. After multiple doses of 100 mg pactimibe to CYP2D6 PMs, the accumulation ratio of R-125528 reached 8.8-fold, however, the exposure of R-125528 in CYP2D6 PMs was covered by the exposure in additional metabolite safety testing. Conclusions: Although CYP2D6 polymorphism greatly affected the pharmacokinetics of R-125528 rather than pactimibe, the exposure in CYP2D6 PMs after a multiple dose of 100 mg pactimibe sulfate was covered by additional non-clinical metabolite safety testing. The finding is clinically informative with respect to the safety testing of drug metabolite present at disproportionately high levels in a special population with specific genetic back ground.Correspondence to:
M. Kotsuma; Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Email: kotsuma.masakatsu.gu@daiichisankyo.co.jp

B. Malhotra¹, Z. Guan¹, N. Wood² and K. Gandelman^{1 1}Pfizer Inc, New York, NY, USA, and ²Pfizer Global Research and Development, Sandwich, Kent, UK Objective: Fesoterodine is a new antimuscarinic agent for the treatment of overactive bladder. Following oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active moiety: 5-hydroxymethyl tolterodine (5-HMT). The cytochrome P450 (CYP) enzymes are not involved in the formation of 5-HMT; however, CYP2D6 and CYP3A4 provide 2 alternative pathways for further metabolism and inactivation of 5-HMT. Materials: Single oral doses of 4 mg, 8 mg or 12 mg of fesoterodine sustained-release tablets in the fasted state and 8 mg in a fed state. Methods: This single-center, open-label, randomized, crossover study investigated the effects of fesoterodine in healthy volunteers comprised of CYP2D6 extensive metabolizers (EMs; n = 16) and CYP2D6 poor metabolizers (PMs; n = 8) after either an overnight fast or a high-fat and high-calorie breakfast. Adverse events, vital signs, ECG recordings and laboratory tests were monitored for safety assessment. Results: For the principal active moiety, 5-HMT, the maximum plasma concentration (C_max), area under the concentration-time curve from time zero to time of last measurable concentration (AUC_0-t) and amount excreted in urine (Ae) increased proportionally with dose in both EM and PM subjects. The mean C_max and AUC_0-t in PMs were approximately twice those observed in EMs. CYP2D6 status had no effect on time to reach C_max (5 h), renal clearance (~250 ml/min), or half-life (~8 h). Fesoterodine was well tolerated at all doses. While the incidence of dry mouth increased from 8 – 12 mg, all occurrences were mild-to-moderate. Conclusions: Fesoterodine demonstrated a pharmacokinetic (PK) profile that was favorable for once-daily dosing. The systemic exposure to 5-HMT increased proportionally with dose and was about 2-fold higher in PMs compared with EMs. There was no clinically relevant effect of food on the PK of fesoterodine. Fesoterodine was well tolerated at all dose levels studied.Correspondence to:
B. Malhotra, PhD; Director – Clinical Sciences, Pfizer Inc, New York, NY 10017, USA
Email: bimal.k.malhotra@pfizer.com

M. Vaz-da-Silva¹,², A.I. Loureiro¹, A. Falcao³, T. Nunes¹, J.-F. Rocha¹, C. Fernandes-Lopes¹, E. Soares¹, L. Wright¹, L. Almeida¹,² and P. Soares-da-Silva¹,^{2 1}Department of Research and Development, BIAL, S. Mamede do Coronado, ²Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Oporto, Porto, Portugal, ³⁴Health Consulting, Cantanhede, Portugal Objective: It has been postulated that trans-resveratrol may act as an antioxidant, cardioprotective, neuroprotective and cancer chemopreventive agent. The objective of this study was to investigate the effect of food on the bioavailability of trans-resveratrol following oral administration. Material and methods: Single-centre, open-label, randomized, 2-way crossover study on 24 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 7 days or more. On each of the study periods subjects were administered a single-dose of 400 mg of trans-resveratrol following either a standard high fat content meal or 8 hs of fasting. Results: There was a large interindividual variability in the trans-resveratrol pharmacokinetic parameters. Mean ± SD maximum plasma concentration (C_max) was 42.2 ± 36.6 ng/ml in fed and 47.3 ± 30.0 ng/ml in fasting conditions. Median time to C_max (t_max) was 2.0 h in fed and 0.5 h in fasting (p < 0.0001). The fed/fasting geometric mean ratio (GMR) and 90% confidence interval (90% CI) were 79.4 and 53.8, 117.0% for C_max, and 106.0 and 86.8, 128.0% for the area under the plasma concentration-time curve (AUC_0-¥). The 90% CI for the GMR of AUC_0-¥ and C_max fall outside the usual bioequivalence acceptance range of 80, 125%, but that of AUC_0-¥ was close to the bioequivalence standard. Conclusion: The rate of absorption of trans-resveratrol following an oral 400 mg single-dose was significantly delayed by the presence of food, as reflected by C_max and t_max. However, the extent of absorption, as reflected by AUC_-¥, was not affected in a relevant way.Correspondence to:
Prof. P. Soares-da-Silva; Department of Research and Development BIAL, A, Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal
Email: psoares.silva@bial.com

P.-W. Wang¹, S.Y. Wang²,³ and C.-J. Huang²,^{3 1}Department of Psychiatry, Kaohsiung Kai-Suan Psychiatric Hospital, ²Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, and ³Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan A man with schizophrenia received regular haloperidol ester therapy, but his psychotic symptoms were not mitigated. A combination of zotepine and haloperidol was then used to relieve the psychotic symptoms. However, the patient developed spontaneous ejaculations, which occurred many times a day while undergoing haloperidol and zotepine therapy. These events were not preceded by sexual stimulation and were not associated with a pleasurable sensation. The discomfort disappeared after discontinuing zotepine. Zotepine-induced spontaneous ejaculation was, therefore, diagnosed. There are few reports of drug-related spontaneous ejaculation. Clinicians need to recognize the possibility of zotepine-related spontaneous ejaculation because sexual side effects have an impact on medical adherence.Correspondence to:
C.-J. Huang, MD; Department of Psychiatry, Kaohsiung Medical University, 100 Shin-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC

Email: d810100@cc.kmu.edu.tw

L. Almeida¹,², R. Coelho³, A. Albino-Teixeira²,⁴ and P. Soares-da-Silva¹,^{2 1}Department of Research and Development, BIAL-Portela, SA, S. Mamede do Coronado, ²Institute of Pharmacology and Therapeutics, Faculty of Medicine, ³Service of Psychiatry and Mental Health, Faculty of Medicine, ⁴Institute for Molecular and Cell Biology (IBMC), University of Oporto, Porto, Portugal Objective: Some complaints that are reported as adverse drug reactions by healthy subjects during participation in Phase I studies are common complaints in healthy individuals from the normal population. The objective of this study was to compare the incidence of complaints in a group of 192 healthy volunteers in Phase I studies with a control group of 112 healthy subjects who matched the Phase I group participants in terms of demographic and socioeconomic characteristics, and to investigate the relationship between some psychological factors and the incidence of complaints. Methods: Both groups completed a questionnaire on the incidence of complaints during the previous 2 – 4 weeks. Trait anxiety was assessed by the trait scale of the State-Trait Anxiety Inventory (STAI-T), depressive mood by the Beck’s Depression Inventory-II (BDI-II) and perceived self-efficacy by the Self-Efficacy Scale (SES). Results: Compared to the control group, Phase I volunteers presented a significantly lower incidence of stomach pain, back pain, limb or joint pain, headaches, fainting spells, palpitations, shortness of breath, constipation, loose stools or diarrhea, nausea, gas or indigestion, feeling nervous or anxious, feeling restless, getting tired very easily, muscle tension, aches, or soreness, and concentration difficulties. Significant positive correlations were found between the STAI-T and BDI-II scores and the incidence of several complaints; inversely, the SES score correlated negatively with several complaints. Conclusion: The incidence of complaints in healthy subjects is not of a random character and depends on psychological characteristics. Volunteers in Phase I studies are a self-selected sample with a lower tendency to report non-drug-related adverse events than their peers from the general population. The impact of this self-selection bias on the assessment of tolerability during Phase I studies deserves further evaluation.Correspondence to:
Dr. L. Almeida; Department of Research and Development BIAL, A Av. da Siderurgia Nacional, 4745-457, S. Mamede do Coronado, Portugal
Email: luis.almeida@bial.com

T. Maiguma¹, Y. Hayashi², S. Ueshima², H. Kaji¹, T. Egawa¹, K. Chayama⁴, T. Morishima⁴, Y. Kitamura³, T. Sendo², Y. Gomita¹ and D. Teshima^{1 1}Department of Clinical Pharmacy, School of Pharmacy, Shujitsu University, ²Department of Hospital Pharmacy, Okayama University Hospital, ³Department of Clinical Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, ⁴Department of Pediatrics, Okayama University Hospital, Okayama, Japan Objective: Oral mucositis is a major toxicity in the high-dose methotrexate (HD-MTX) treatment for children with acute lymphoblastic leukemia (ALL). The first aim of this study was to evaluate the relationship between the MTX serum concentration and occurrence of oral mucositis in pediatric ALL patients. The second aim was to clarify the relationship between MTX exposure and epidermal keratinocyte cell injury using an in vitro study. Methods: 49 patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-HR02 protocol. This protocol involves HD-MTX treatment (3 g/m² for 24-h i.v. infusion). The MTX serum concentrations were measured by a fluorescence polarization immunoassay. The relationship between oral mucositis and MTX serum concentrations 48 and 72 h after administration was determined. The cell toxicity of MTX for human epidermal keratinocytes was analyzed by using a cell viability assay (WST-1 assay). In addition, pharmacokinetic evaluation for clearance, AUC extrapolated from 48 h to infinity (AUC_48h-¥) and elimination half-life (t_1/2b) were done using the 1-compartmental models. Results: Oral mucositis occurred in 24 patients (49.0%), in whom 20 patients (83.3% in oral mucositis group) showed WHO severity Grade 1 or 2. Only 4 patients (16.7% in oral mucositis group) showed Grade 3 severity. 22 patients (44.9%) had oral mucositis in the group with a concentration under 10^{–6 M 48 h after MTX administration. There was no significant deference among the cell viabilities in the concentrations of 10–6 M, 10–5 M and 10–4 M 48 h after the MTX exposure. However, the cell viability obtained 24 h after the MTX exposure was significantly different from the respective cell viability 48, 72 and 96 h after the MTX exposure. In the group with oral mucositis, the clearance decreased significantly (p = 0.042), and the t_1/2b (p = 0.025) and AUC_48h-¥ (p = 0.025) increased significantly compared with the non-symptom group. Conclusions: It seems that there is no significant relationship between the serum MTX concentration and oral mucositis. This in vitro study has demonstrated that the cell injury was related to the duration of MTX exposure rather than a high MTX concentration.}Correspondence to:
D. Teshima, PhD; Department of Clinical Pharmacy, School of Pharmacy, Shujitsu University, 1-6-1, Nishi-kawara, Okayama 703-8516, Japan
Email: teshima@shujitsu.ac.jp

A.C. Franco Spínola¹, S. Almeida¹,², A. Filipe¹, R.I. Neves¹, M. Tanguay³ and M. Yritia^{4 1}Medical Department, Grupo Tecnimede, Sintra, Portugal, ²Department of Pharmacology and Therapeutics, Universidad Autonoma de Barcelona, Spain, ³Anapharm, Québec, Canada, and ⁴Anapharm Europe S.L. c/ Encuny ²², Barcelona, Spain This study was conducted in order to compare the bioavailability of two tablet formulations containing 1,000 mg levetiracetam, (S)-a-ethyl-2-oxo-1-pyrrolidine acetamide, 102767-28-2 CAS registry number. 18 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 36.0 hours post-dosing. Levetiracetam levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC-MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time 0 to time of last non-zero concentration (AUC_last) and from time zero to infinitive (AUC_inf) and maximum observed concentration (C_max), were determined from the levetiracetam concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 88.98 – 108.75% for C_max, 99.90 – 104.81% for AUC_last and 100.11 – 105.23 %for AUC_inf this is, within the predefined ranges. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.Correspondence to:
A.C. Franco Spínola; Medical Department, Tecnimede Sociedade Tecnico-Medicinal S.A., Zona Industrial da Abrunheira R. da Tapada Grande, n.º 2 Abrunheira 2710-089 Sintra, Portugal
Email: dmed.ct.tecnimede@mail.telepac.pt