Volume 49, No. 8/2011(August)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers
C.A. Paterson, D. Jacobs, S. Rasmussen, S.P. Youngberg and N. McGuinness
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (477-490)
Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers
C.A. Paterson1, D. Jacobs2, S. Rasmussen3, S.P. Youngberg3 and N. McGuinness2
1Pfizer, Inc., Cary, NC, 2Pfizer, Inc., Bridgewater, NJ, and 3Celerion, Inc., Lincoln, NE, USA
Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce renal complications in patients taking loop diuretics. This study investigated the pharmacokinetic/pharmacodynamic effects and safety profile of orally administered diclofenac sodium, ibuprofen and diclofenac epolamine topical patch (DETP) on furosemide in healthy adult subjects. Methods: This open-label, randomized, 5-way crossover study was conducted in 40 subjects (aged 19 – 45 y). Diclofenac (75 mg taken orally twice daily), DETP (1.3% applied topically twice daily), or ibuprofen (800 mg taken orally thrice daily) was administered for 3 consecutive days, followed by co-administration with furosemide (given intravenously as 20 mg/2 min). Plasma furosemide and NSAID concentrations, urine furosemide, sodium and potassium concentrations and urine output were determined throughout the 24 h period following furosemide administration. Results: Orally administered ibuprofen significantly increased furosemide AUC0–t (37%) and AUC0–inf (36%) and decreased total body CL (27%), Rmax (19%) and CLR (23%) geometric mean ratios compared with furosemide control. Oral and topical diclofenac had no pharmacokinetic effects on furosemide. Ibuprofen increased sodium excretion (Ae0–24, 16%) and decreased sodium Rmax (15%), and oral diclofenac decreased urine output (Vu0–24, 15%). DETP had no effect on furosemide pharmacodynamics; total systemic exposure to diclofenac during DETP treatment was < 1% that of oral diclofenac. Treatments were generally safe, with 25 subjects reporting a total of 112 adverse events. Conclusions: Pharmacodynamic effects were seen with oral diclofenac (urine output) and ibuprofen (urine sodium excretion). Furosemide also affected plasma and urine pharmacokinetic profiles. Pharmacologic effects of DETP on furosemide were not observed under these conditions. Additional research is warranted to delineate the potential interactions of other NSAIDs with furosemide and other loop diuretics.Correspondence to:
Dr. D. Jacobs
Senior Director of Pfizer, Inc.
400 Crossing Boulevard
Bridgewater, NJ 08807, USA
Email: David.Jacobs@Kingpharm.com
Original Research
Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study
T.D. Bethke, M. Hartmann, A. Hünnemeyer, G. Lahu and C.H. Gleiter
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (491-499)
Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study
T.D. Bethke1, M. Hartmann1, A. Hünnemeyer1, G. Lahu1 and C.H. Gleiter2
1Nycomed GmbH, Konstanz, and 2Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany
Objective: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast and its active main metabolite roflumilast N-oxide were characterized. Materials and methods: Patients (n = 12) with severe renal impairment (creatinine clearance CLCR < 30 ml/ min/1.73 m²; otherwise healthy) and matched (sex, age, weight, and height) healthy control subjects (n = 12; CLCR > 80 ml/min/1.73 m²) were enrolled into an open-label, parallelgroup study. Single dose (500 μg, p.o.) pharmacokinetics and safety/tolerability of roflumilast and roflumilast N-oxide were compared between both groups. Results: A minor decrease of exposure (area under the plasma concentration-time curve from time zero to infinity (AUC0–∞), maximum plasma concentration (Cmax)) and a small increase in elimination half-life (t1/2) of roflumilast (–1%; –6%; +19%, respectively) and roflumilast N-oxide (–%; ND; +30%, respectively) were observed in renally impaired patients compared with healthy subjects. No relevant differences in safety and tolerability were observed between groups. Conclusions: The pharmacokinetic changes observed in patients with renal impairment are of small magnitude without clinical importance. A dose adjustment or a change in the administration interval of roflumilast is not necessary in patients with renal impairment.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: thomas.bethke@nycomed.com
Original Research
Pharmaco-epidemiologic study of the prescription of contraindicated drugs in a primary care setting of a university: a retrospective review of drug prescription
A.A.H. Dhabali, R. Awang and S.H. Zyoud
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (500-509)
Pharmaco-epidemiologic study of the prescription of contraindicated drugs in a primary care setting of a university: a retrospective review of drug prescription
A.A.H. Dhabali, R. Awang and S.H. Zyoud
WHO Collaborating Centre for Drug Information, National Poison Centre, Universiti Sains Malaysia (USM), Penang, Malaysia
Background: The prescription of contraindicated drugs is a preventable medication error, which can cause morbidity and mortality. Recent data on the factors associated with drug contraindications (DCIs) is limited world-wide, especially in Malaysia. Aims: The objectives of this study are 1) to quantify the prevalence of DCIs in a primary care setting at a Malaysian University; 2) to identify patient characteristics associated with increased DCI episodes, and 3) to identify associated factors for these DCIs. Methods: We retrospectively collected data from 1 academic year using computerized databases at the Universiti Sains Malaysia (USM) from patients of USM’s primary care. Descriptive and comparative statistics were used to characterize DCIs. Results: There were 1,317 DCIs during the study period. These were observed in a cohort of 923 patients, out of a total of 17,288 patients, representing 5,339 DCIs per 100,000 patients, or 5.3% of all patients over a 1-year period. Of the 923 exposed patients, 745 (80.7%) were exposed to 1 DCI event, 92 (10%) to 2 DCI events, 35 (3.8%) to 3 DCI events, 18 (2%) to 4 DCI events, and 33 patients (3.6%) were exposed to 5 or more DCI events. The average age of the exposed patients was 30.7 ± 15 y, and 51.5% were male. Multivariate logistic regression analysis revealed that being male (OR = 1.3; 95% CI = 1.1 – 1.5; p < 0.001), being a member of the staff (OR = 3; 95% CI = 2.5 – 3.7; p < 0.001), having 4 or more prescribers (OR = 2.8; 95% CI = 2.2 – 3.6; p < 0.001), and having 4 or more longterm therapeutic groups (OR = 2.3; 95%CI = 1.7 – 3.1; p < 0.001), were significantly associated with increased chance of exposure to DCIs. Discussion and conclusions: This is the first study in Malaysia that presents data on the prevalence of DCIs. The prescription of contraindicated drugs was found to be frequent in this primary care setting. Exposure to DCI events was associated with specific socio-demographic and health status factors. Further research is needed to evaluate the relationship between health outcomes and the exposure to DCIs.Correspondence to:
A.A.H. Dhabali, MPharm (Clin Pharm), PhD
National Poison Center
Universiti Sains Malaysia (USM)
11800 Penang, Malaysia
Email: dahbali@yahoo.com
Original Research
A systematic review of available clinical evidence – filgrastim compared with lenograstim
H. Sourgens and F. Lefrère
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (510-518)
A systematic review of available clinical evidence – filgrastim compared with lenograstim
H. Sourgens1 and F. Lefrère2
1University of Münster, Münster, Germany, and 2Service de Biothérapie, Hôpital Necker, APHP, Paris, France
Background: Filgrastim (Neupogen®, Amgen) and lenograstim (Granocyte®, Chugai Pharma) are chemically different granulocyte colony-stimulating factors (G-CSFs). Based on receptor-binding studies and in vitro potency assessment, a clinical superiority of lenograstim versus filgrastim has been postulated together with potential cost savings favouring lenograstim over filgrastim. Objectives: To compare the clinical efficacy of filgrastim and lenograstim based on current Summaries of Product Characteristics (SPCs) for both products taking into account published clinical trials in patients and healthy volunteers. Search strategy and selection criteria: PubMed and citation lists of published articles were used to identify clinical trials with direct comparisons of filgrastim and lenograstim. All available clinical information directly comparing filgrastim and lenograstim has been accepted for evaluation. Data collection: A total of 16 studies compared filgrastim with lenograstim. Four studies had a randomized, parallel-group design, 4 had a cross-over design and 8 studies were uncontrolled. Results: Available data do not suggest a clinically remarkable difference between filgrastim and lenograstim in chemotherapy-induced neutropenia and the mobilisation of peripheral blood progenitor cells (PBPC) in patients and healthy donors. Conclusions: Both G-CSFs are recommended for clinical use according to instructions in the respective SPCs; there is no reason to prefer lenograstim over filgrastim in any of the approved indications for both. Costs calculations need to consider the advent of biosimilar filgrastim in Europe.Correspondence to:
Prof. Dr. med. H. Sourgens
Valleystr. 25
81371 München
Email: info@sourgens.de
Original Research
Pharmacokinetics of hydralazine, an antihypertensive and DNA-demethylating agent, using controlled-release formulations designed for use in dosing schedules based on the acetylator phenotype
A. Gonzalez-Fierro, D. Vasquez-Bahena, L. Taja-Chayeb, S. Vidal, C. Trejo-Becerril, E. Pérez-Cardenas, E. de la Cruz-Hernández, A. Chávez-Blanco, O. Gutiérrez, D. Rodriguez, Z. Fernandez and A. Duenas-González
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (519-524)
Pharmacokinetics of hydralazine, an antihypertensive and DNA-demethylating agent, using controlled-release formulations designed for use in dosing schedules based on the acetylator phenotype
A. Gonzalez-Fierro1, D. Vasquez-Bahena1, L. Taja-Chayeb1, S. Vidal1, C. Trejo-Becerril1, E. Pérez-Cardenas1, E. de la Cruz-Hernández1, A. Chávez-Blanco1, O. Gutiérrez1, D. Rodriguez2, Z. Fernandez2 and A. Duenas-González
1Division of Basic Research, Instituto Nacional de Cancerologia, 2CIDAT, SA. de C.V., and 3Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autonóma de Mexico (UNAM), Instituto Nacional de Cancerología (INCan), Mexico City, ISSEMYM Cancer Center, Toluca, Estado de México, México
Purpose: The antihypertensive hydralazine has recently been repositioned as DNA demethylating for the epigenetic therapy of cancer. As the acetylator phenotype is the key determinant of its plasma levels, the dose of hydralazine needs to be adjusted for the acetylation status of patients. Methods: The pharmacokinetics of orally administered hydralazine was evaluated in 26 healthy volunteers (13 slow and 13 fast acetylators) after a single dose of 182 mg administered as a controlled-release tablet. Plasma levels of hydralazine were analyzed in 85 cancer patients treated with this formulation at a dose of 83 mg/day and 182 mg/day for slow and fast acetylators, respectively. Results: The Cmax and tmax of hydralazine for fast acetylators were 208.4 ± 56.9 SD ng/ml and 2.8 ± 2.5 h, respectively. The corresponding results for slow acetylators were 470.4 ± 162.8 ng/ml, and 4.4 ± 3.1 h. Healthy volunteers who were fast acetylators had no clinically significant changes in blood pressure and heart rate or any other side-effect, however, slow acetylators had transient episodes of headache, tachycardia and faintness. Among 85 cancer patients that received either 182 mg or 83 mg of hydralazine daily, according to their acetylator status, the mean concentrations of hydralazine in plasma were 239.1 ng/ml and 259.2 ng/ml for fast and slow acetylators, respectively. These differences were not significantly different, p = 0.3868. Conclusions: The administration of dose-adjusted controlled-release hydralazine according to the acetylation status of cancer patients yields similar levels of hydralazine.Correspondence to:
A. Duenas-González, MD, PhD
Primer piso, Edificio de Investigación
San Fernando 22
Tlalpan 14080, Mexico City, Mexico
Email: alfonso_duenasg@yahoo.com
Bioavailability Section
Comparative bioavailability of two sildenafil tablet formulations after single-dose administration in healthy Thai male volunteers
S. Kanjanawart, D. Gaysonsiri, P. Tangsucharit, S. Vannaprasaht, K. Phunikhom, T. Kaewkamson, N. Wattanachai and W. Tassaneeyakul
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (525-530)
Comparative bioavailability of two sildenafil tablet formulations after single-dose administration in healthy Thai male volunteers
S. Kanjanawart, D. Gaysonsiri, P. Tangsucharit, S. Vannaprasaht, K. Phunikhom, T. Kaewkamson, N. Wattanachai and W. Tassaneeyakul
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Objective: To compare the rate and extent of absorption of two sildenafil tablet formulations (Tonafil®, T.O. Chemicals (1979) Ltd., Thailand as a test formulation and Viagra®, Pfizer Pty Limited., Australia as a reference formulation) in healthy Thai male volunteers after single-dose administration under fasting condition. Methods: A randomized crossover study with a washout period of 2 weeks was conducted in 20 healthy Thai male volunteers. The volunteers received either 100 mg of the reference or test formulation. Blood samples were collected at 0, 0.16, 0.33, 0.67, 1, 1.5, 2, 2.5, 4, 6, 9 and 12 h after drug administration. The plasma sildenafil concentrations were determined using a validated high performance liquid chromatography method. The pharmacokinetic parameters of sildenafil were calculated from the observed plasma concentration-time profiles by using a non-compartmental model. Results and conclusions: The geometric means, Cmax, of the reference and the test formulations were 696.42 and 734.06 ng/ml. The mean values of the AUC0–t and AUC0–inf of the test formulation were 2,073.03 and 2,237.37 ng × h/ml, while those of the reference formulation were 1,950.26 and 2,078.06 ng × h/ml. The geometric mean ratios (%) and 90% confidence intervals (CI) of the test and reference products for the log transformed Cmax, AUC0–t and AUC0–inf of sildenafil were 105.40% (95.0 – 116.95%), 106.30% (99.74 – 113.28%) and 107.67% (100.83 – 116.48%). These values were within 80 to 125% of the US-FDA and the Thai-FDA criteria and therefore it can be concluded that the test formulation was bioequivalent to the reference formulation both in terms of rate and extent of absorption after single-dose administration under fasting condition.Correspondence to:
Dr. W. Tassaneeyakul
Department of Pharmacology
Faculty of Medicine
Khon Kaen University
Khon Kaen, 40002, Thailand
Email: wichitt@kku.ac.th
