Volume 46, No. 3/2008(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Clinical Trials
Healthy subjects volunteering for Phase I studies: Influence of curiosity, exploratory tendencies and perceived self-efficacy
L. Almeida, T.B. Kashdan, R. Coelho, A. Albino-Teixeira and P. Soares-da-Silva
Abstract
L. Almeida, T.B. Kashdan, R. Coelho, A. Albino-Teixeira and P. Soares-da-Silva
1Department of Research and Development, BIAL (Portela & Co., SA), S Mamede do Coronado, 2Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Oporto, Porto, Portugal, 3Department of Psychology, George Mason University, Fairfax, VA, USA, 4Service of Psychiatry and Mental Health, Faculty of Medicine, and 5Institute for Molecular and Cell Biology (IBMC), University of Oporto, Porto, Portugal
Objective: To test the hypothesis that trait-curiosity and perceived self-efficacy influence the willingness of healthy subjects to volunteer for participation in Phase I studies. Materials and methods: A group of healthy subjects who had never participated in clinical studies (“index group”) were invited to participate in a Phase I study. They were assessed with regard to trait curiosity (Curiosity and Exploration Inventory; CEI-T) and perceived self-efficacy (Self-Efficacy Scale; SES) and subjects who accepted the invitation to participate were compared with those who refused and with a group of healthy subjects who had previously participated in clinical studies (“validation group”). Results: A significant positive correlation was found between the willingness to participate and the CEI-T total score (R = 0.28; p < 0.01), exploratory tendencies (R = 0.34; p < 0.001), SES total score (R = 0.30, p < 0.01), initiative and persistence (R = 0.29, p < 0.01), planning/goal setting (R = 0.19, p < 0.05) and social self-efficacy (R = 0.29; p < 0.01). The “index group” subjects who accepted the invitation to participate showed significantly greater CEI-T exploratory tendencies (Z = –3.334, p = 0.001, Mann-Whitney test) and total scores (Z = –2.703, p < 0.01) and greater SES total score (Z = –3.131, p < 0.01), initiative and persistence (Z = –3.065, p < 0.01), planning/goal setting (Z = –2.173, p < 0.05) and social self-efficacy (Z = –2.954, p < 0.01) than subjects who refused. No differences were found between the subjects in the “index group” who accepted the invitation and subjects in the “validation group”. Using a logistic regression model, both CEI-T exploratory tendencies and SES initiative/persistence were significant predictors of participation. Conclusion: Subjects higher in curiosity/exploration and in perceived initiative/persistence are more willing to volunteer for Phase I studies. The impact of these self-selection biases on Phase I study results is unknown but deserves further evaluation.
Correspondence to:
Dr. L. Almeida; Department of Research and Development, BIAL (Portela & Co., SA), S Mamede do Coronado, Portugal
Email: luis.almeida@bial.com
Pharmacokinetics
Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate
J. Maia, L. Almeida, A. Falcão, E. Soares, F. Mota, M.A. Potgieter, J.H. Potgieter and P. Soares-da-Silva
Abstract
J. Maia, L. Almeida, A. Falcão, E. Soares, F. Mota, M.A. Potgieter, J.H. Potgieter and P. Soares-da-Silva
1Department of Research and Development, BIAL (Portela & Ca SA), S. Mamede do Coronado, 24Health Limited, Cantanhede, Portugal, and 3Farmovs-Parexel, University of the Free State, Bloemfontein, South Africa
Objective: Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. Methods: ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n = 8, control group), and in patients with mild renal impairment (n = 8), moderate renal impairment (n = 8), severe renal impairment (n = 8), and end-stage renal disease requiring hemodialysis (n = 8). Results: ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. Conclusions: ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance < 60 ml/min.Correspondence to:
Prof. P. Soares-da-Silva; Department of Research and Development, BIAL, À Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal
Email: Psoares.silva@bial.com
Pharmacodynamics
Calcium balance during calcitriol and paricalcitol administration in healthy humans
V. Hafner, C. Rutsch, R. Ding, T. Heinrich, L. Diedrichs, H. Schmidt-Gayk, I. Walter-Sack, J. Bommer and G. Mikus
Abstract
V. Hafner, C. Rutsch, R. Ding, T. Heinrich, L. Diedrichs, H. Schmidt-Gayk, I. Walter-Sack, J. Bommer and G. Mikus
1Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, 2Department of Endocrinology, Limbach Laboratory, Heidelberg and 3Heimdialyse, Heidelberg, Germany
Objective: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. Methods: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 µg/day) and calcitriol (0.5 µg/day). Results: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03 ± 0.69 pmol/l), whereas paricalcitol had no effect. Conclusion: Using a dosing ratio of 1 : 3 for calcitriol : paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.Correspondence to:
Prof. Dr. G. Mikus; Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Universitiy of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Email: gerd.mikus@med.uni-heidelberg.de
Pharmacodynamics
Hemodynamic effects of dobutamine in patients with an exacerbation of chronic systolic heart failure treated with low doses of carvedilol
F. Triposkiadis, P. Dalampiras, G. Kelepeshis, J. Skoularigis and G. Sitafidis
Abstract
F. Triposkiadis, P. Dalampiras, G. Kelepeshis, J. Skoularigis and G. Sitafidis
Department of Cardiology, Larissa University Hospital, Larissa, Greece
Although most patients in Europe with systolic heart failure (SHF) are treated with β-blocking agents at doses significantly lower than the recommended dose, there is limited information available regarding the hemodynamic effects of dobutamine in this patient population. Therefore, a study was carried out in patients (n = 31) admitted to the University Hospital, Larissa, Greece with an acute exacerbation of chronic SHF (25 men and 6 women, mean age 58 years, range 32 – 80 years, left ventricular (LV) ejection fraction <= 0.35) and a systolic blood pressure between 85 and 110 mmHg. All patients underwent a complete echocardiographic/ Doppler examination before and immediately after a 24-hour intravenous dobutamine infusion (2.5 – 10 µg/kg/min). Of the patients admitted to the study, 22 (71%) had been treated by practicing physicians and the mean carvedilol dose at admission was 16 ± 9 mg daily (6.25 – 50 mg daily). Dobutamine was associated with a small increase in LV ejection fraction (from 26.3 ± 4.3% to 27.8 ± 4.3%, p = 0.005), a non-significant increase in heart rate (71.4 ± 11 vs. 68 ± 18 beats/min, p = 0.19) and cardiac output (3.52 ± 1 l/min vs. 3.74 ± 1.06 l/min, p = 0.14) and a significant decrease in the E-wave deceleration time (146.2 ± 65 msec vs. 142.6 ± 58.3 msec, p = 0.04). Thus, in patients with SHF, treated with low doses of carvedilol, the favorable hemodynamic effects of dobutamine are blunted and alternative inotropic agents should be used.Correspondence to:
F. Triposkiadis, MD, FESC, FACC; Professor of Cardiology, Director, Department of Cardiology, Larissa University Hospital, P.O. Box 1425, 411 10 Larissa, Greece
Email: ftriposkiadis@yahoo.com
Therapeutic Drug Monitoring
Therapeutic drug monitoring of vancomycin in severe sepsis and septic shock
M. Vázquez, P. Fagiolino, A. Boronat, M. Buroni and C. Maldonado
Abstract
M. Vázquez, P. Fagiolino, A. Boronat, M. Buroni and C. Maldonado
1Pharmaceutical Sciences Department, Therapeutic Drug Monitoring Service, Faculty of Chemistry, and 2Intensive Care Department, Faculty of Medicine, University Hospital, Montevideo, Uruguay
Background: The sudden changes (increase in capillar permeability, edema formation, vasodilation and hypotension) observed in septic patients and the measurements taken in order to revert this situation make vancomycin concentrations difficult to interpret. Therapeutic drug monitoring (TDM) of vancomycin is routinely performed at steady state, target concentrations are peaks between 20 and 40 mg/l and troughs of 5 – 10 mg/l. Lately, continuous infusion of vancomycin (CIV) has been used as an alternative mode of administration mainly in critically ill patients with sepsis or septic shock. Despite this novel mode of administration, the need of drug monitoring in this population is under discussion. Objective: The aim of our study was to test the usefulness of a multi-compartment model in order to understand the rapid changes that occur in critically ill patients. Materials and methods: A prospective, cohort study was carried out in the intensive care unit of the University Hospital. 25 intensive care unit adults patients with severe sepsis or septic shock receiving vancomycin in CIV modality for documented gram-positive infections were included in the study. Once the infusion was started, blood samples were drawn periodically and analized by fluorescence polarisation immunoassay (FPIA, TDx, Abbott Laboratories, Chicago, IL, USA). A multi-compartment model was used to predict vancomycin level evolution throughout the treatment of patients with sepsis. Results: High doses of vancomycin were administered in order to rescue patients from septic shock. Plasma drug concentration dropped while clinical condition of patients worsened. Conversely, drug levels increased spontaneously once the infection was reverted. The theoretical model provided greater insight into pharmacokinetic features related with the use of vancomycin in septic patients. Conclusions: There was consistency between the model based prediction and the experimental data so dose adjustment was performed in order to reach target concentrations above 20 mg/l and an initial dose of 3 grams of vancomycin per day was recommended to reach these levels.Correspondence to:
Prof. M. Vázquez; Pharmaceutical Science Department, Faculty of Chemistry, P.O.Box 1157, General Flores 2124, Montevideo 11800, Uruguay
Email: mvazquez@ fq.edu.uy
Drug Utilization
A cross-sectional study of prescribing patterns in chronic psychiatric patients living in sheltered housing facilities
S.G. Schorr, A.J.M. Loonen, J.R.B.J. Brouwers and K. Taxis
Abstract
S.G. Schorr, A.J.M. Loonen, J.R.B.J. Brouwers and K. Taxis
1Department of Pharmacy, Division of Pharmacotherapy and Pharmaceutical Care, GUIDE, University of Groningen and 2Delta Psychiatric Center, Poortugaal, The Netherlands
Objective: To analyze prescribing patterns of chronic psychiatric patients living in sheltered housing facilities, to identify the extent of polypharmacy and to estimate associated risks in this patient group. Methods: In a retrospective cross-sectional study the prescription data of 323 chronic psychiatric patients (average age 48.5 years) living in sheltered housing facilities in Rotterdam, The Netherlands, were analyzed. Prescription data were obtained from pharmacy-dispensing records. Results: Patients received on average 4.6 drugs (95% CI, 4.3 – 4.9). The most frequently prescribed drugs were as expected antipsychotics, benzodiazepines and antimuscarinic drugs. Overall 25% (n = 81) of patients received two or more antipsychotic drugs. A high proportion of patients (38%, n = 124) received one benzodiazepine, and 15% (n = 50) received two or more benzodiazepines. Conclusion: Patients in our study received a worryingly high number of drugs, and a quarter of the population was subject to antipsychotic polypharmacy. This increases the risk that drug-drug interactions, adverse drug reactions and noncompliance occur. Our study indicates potentially low quality of prescribing and shows the need for reviewing and special monitoring of pharmacotherapy in this patient group.Correspondence to:
Dr. K. Taxis; University of Groningen, Department of Pharmacy, Division of Pharmacotherapy and Pharmaceutical Care, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Email: k.taxis@rug.nl
Bioavailability Section
Comparative bioavailability of two sertraline tablet formulations after single-dose administration in healthy Thai volunteers
W. Tassaneeyakul, S. Kanchanawat, D. Gaysonsiri, S. Vannaprasath, P. Paupairoj, K. Kittiwattanagul, S.K. Tippabhotla, A. Khuroo, B.K. Panigrahy, S. Reyar and T. Monif
Abstract
W. Tassaneeyakul, S. Kanchanawat, D. Gaysonsiri, S. Vannaprasath, P. Paupairoj, K. Kittiwattanagul, S.K. Tippabhotla, A. Khuroo, B.K. Panigrahy, S. Reyar and T. Monif
1Department of Pharmacology, Faculty of Medicine, Khon Kaen University, 2Khon Kaen Rajanagarindra Psychiatric Hospital, Khon Kaen, Thailand and 3Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
Objective: To compare the bioavailability of two sertraline tablet (50 mg) formulations (Serlift from Ranbaxy Laboratories Ltd., Gurgaon Haryana, India, as a test formulation and Zoloft from Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia, as a reference formulation) in 24 healthy Thai male volunteers under fasting condition. Materials and methods: A randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover study with a washout period of 3 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours following drug administration. Plasma concentrations of sertraline were determined using validated LC-MS/MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS software for Windows, release 9.1 (SAS Institute Inc., Cary, NC, USA). Results: The ratio of least square means and the 90% confidence intervals (CI) of the log-transformed data were 0.9950 (0.9111 – 1.0866) for Cmax, 1.0153 (0.9576 – 1.0764) for AUC0-t and 1.0110 (0.9510 – 1.0747) for AUC0-¥. In addition, the median tmax values for the test and reference formulations were similar (5.00 h). The 90% CI for Cmax, AUC0-t and AUC0-¥ were within the 0.8 – 1.25 interval of the US-FDA. Conclusions: The test formulation (Serlift, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India) is bioequivalent to the reference formulation (Zoloft, Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia) both in terms of rate and extent of absorption after single-dose administration under fasting condition.Correspondence to:
Dr. T. Monif; Department of Clinical Pharmacology and Pharmacokinetics,
Ranbaxy Research Laboratories, Gurgaon 122015, Haryana, India
Email: tausif.monif@ranbaxy.com
