Volume 48, No. 5/2010(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis
A.A. Fasanmade, O.J. Adedokun, A. Olson, R. Strauss and H.M. Davis
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (297-308)
Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis
A.A. Fasanmade1, O.J. Adedokun1, A. Olson2, R. Strauss1 and H.M. Davis1
1Centocor Research and Development, Inc., Malvern, PA, and 2RW Johnson Pharmaceutical Research and Development, San Diego, CA, USA
Objectives: Infliximab, an IgG1 monoclonal antibody (mab), has large inter-individual serum concentration variability. The objective was to determine the extent of the association of baseline albumin concentration and infliximab disposition in patient with ulcerative colitis. Method: Data from 728 patients with ulcerative colitis from two clinical trials were analyzed to evaluate trends between infliximab pharmacokinetics and serum albumin, or liver or kidney function. Response in the placebo and treated groups were compared by baseline serum albumin concentrations (SAC) groups. Results: Patients with higher SAC maintained higher infliximab concentrations, lower clearance, and longer half-life than patients with lower SAC. When analyzed by SAC quartiles, patients in the highest quartile had several-fold greater trough infliximab concentrations when compared with those in the lowest quartile. These observations were consistent in both studies and at different dose levels. Generally, clinical response in patients did not vary with SAC when the SAC was within the normal range, apparently because serum infliximab concentrations remained at therapeutic levels. However, patients with SAC lower than the normal laboratory reference range had much lower median serum infliximab concentrations and lower response rates compared with patients within normal SAC. Infliximab pharmacokinetics did not correlate with SGOT or creatinine clearance. Conclusions: It is hypothesized that the common rescue pathway for both albumin and IgG involving the neonatal Fc receptor may be responsible for the relationship between serum albumin and serum infliximab levels. Baseline albumin level may serve as a valuable and convenient measure of mab pharmacokinetic expectations in these patients.Correspondence to:
A. Fasanmade, PhD
Pharmacokinetics, Modeling & Simulation
Clinical Pharmacology Sciences
Centocor Research and Development, Inc.
200 Great Valley Parkway
Malvern, PA 19355, USA
Email: adedigbo@hotmail.com
Original Research
Thorough QT study of the effect of fesoterodine on cardiac repolarization
B. Malhotra, N. Wood, R. Sachse and K. Gandelman
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (309-318)
Thorough QT study of the effect of fesoterodine on cardiac repolarization
B. Malhotra1, N. Wood2, R. Sachse3 and K. Gandelman1
1Pfizer Inc, New York, NY, USA, 2Pfizer Global Research and Development, Sandwich, Kent, UK and 3Schwarz BioSciences, Monheim, Germany
Objective: Fesoterodine 4 mg and 8 mg once daily are indicated for the treatment of overactive bladder. A thorough QT study was conducted to investigate the effects of fesoterodine on cardiac repolarization. Materials and methods: In this parallel-group study, subjects were randomly assigned to receive double-blind fesoterodine 4 mg, fesoterodine 28 mg, or placebo or open-label moxifloxacin 400 mg (positive control) for 3 days. Electrocardiograms (ECGs) were obtained on Days –1 (baseline), 1, and 3. The primary analysis was the time-averaged changes from baseline for Fridericia’s-corrected QT interval (QTcF) on Day 3. Results: Among 261 subjects randomized to fesoterodine 4 mg (n = 64), fesoterodine 28 mg (n = 68), placebo (n = 65), or moxifloxacin 400 mg (n = 64), 256 completed the trial. The least squares mean changes in QTcF from baseline were 21.1, 20.5, 18.5, and 31.3 ms (maximum), and –5.1, –4.2, –5.2, and 7.6 ms (time-averaged at Day 3) for placebo, fesoterodine 4 mg, fesoterodine 28 mg, and moxifloxacin, respectively. The lower limit of the 95% confidence interval exceeded 5 ms for moxifloxacin. Conclusions: The results indicate that fesoterodine is not associated with QTc prolongation or other ECG abnormalities at either therapeutic or supratherapeutic doses.Correspondence to:
B. Malhotra, PhD
Senior Director
Clinical Sciences, Pfizer Inc
685 3rd Avenue, New York, NY 10017, USA
Email: bimal.k.malhotra@pfizer.com
Original Research
Prescribing for migraine with the focus on selective 5HT1-receptor agonists: a pharmacy database analysis
I. Truter
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (319-326)
Prescribing for migraine with the focus on selective 5HT1-receptor agonists: a pharmacy database analysis
I. Truter
Drug Utilization Research Unit (DURU), Department of Pharmacy, Nelson Mandela Metropolitan University, Port Elizabeth, South Africa
Objective: The primary aim was to determine the prescribing patterns and cost of drugs for migraine focusing on selective 5HT1-receptor agonists (triptans) in a primary care patient population. Methods: A retrospective drug utilization consumption study was conducted. Data were obtained from a South African national private pharmacy group. The database consisted of all central nervous system prescriptions dispensed by the pharmacy group for 2008. Results: A total of 22,102 patients (71.05% females) received 43,144 items for migraine a cost of R3,622,552 (average cost of R83.96 per item). The average age of patients was 44.90 (SD = 13.83) years, with 70.76% of patients between 30 and 59 years of age. A two-sample t-test assuming equal variances was conducted to compare prescribing to females and males. There was a significant difference. There were proportionally more females in the younger age groups and proportionately more males over 60 years. Patients were prescribed an average of 1.95 items for migraine over the year. The Lorenz curve was used to illustrate skewness in prescribing. Clonidine was the most frequently prescribed active ingredient (46.15%), followed by the combination of cyclizine, ergotamine and caffeine (29.62%). The agents for the prophylaxis of migraine (clonidine, flunarizine and pizotifen) accounted for 50.48% of prescribing frequency, but only 29.04% of cost. The triptans accounted for 18.94% of prescribing frequency and 53.54% of cost. Rizatriptan was the most frequently prescribed triptan. Conclusions: The findings were generally in agreement with other studies, but a lower prescribing rate for triptans was observed.Correspondence to:
I. Truter
Drug Utilization Research Unit (DURU)
Department of Pharmacy
PO Box 77000
Nelson Mandela Metropolitan University
Port Elizabeth, 6031, South Africa
Email: ilse.truter@nmmu.ac.za
Original Research
Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors
T. Kimura, S. Kashiwase, A. Makimoto, M. Kumagai, T. Taga, Y. Ishida, K. Ida, Y. Nagatoshi, H. Mugishima, M. Kaneko and J.S. Barrett
Abstract
Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors
T. Kimura1,10, S. Kashiwase1, A. Makimoto2, M. Kumagai3, T. Taga4, Y. Ishida5, K. Ida6, Y. Nagatoshi7, H. Mugishima8, M. Kaneko9 and J.S. Barrett10
1Department of Pharmacy, Tokyo Women’s Medical University Hospital Center, 2Division of Pediatric Oncology, National Cancer Hospital Center, 3Department of Pediatric Oncology, National Center for Child Health and Development, Tokyo, 4Department of Pediatrics, Shiga University of Medical Science Hospital, Shiga, 5Department of Pediatrics, Shizuoka Cancer Center, Shizuoka, 6Department of Pediatrics, The University of Tokyo Hospital, Tokyo, 7Department of Pediatrics, National Kyushu Cancer Center, Fukuoka, 8Department of Pediatrics, Nihon University Itabashi Hospital, Tokyo, 9Department of Pediatric Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan, and 10Laboratory for Applied PK/PD, Clinical Pharmacology and Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Objective: A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40 – 45 mg/m2/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. Method: 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. Result: CPT-11 exhibited a mean clearance (CL) of 15.31 ± 5.95 (l/h) (13.06 ± 3.58 (l/hr/m2)) and AUC0–∞ of 3547.0 ± 1406.5 (ng × h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 × CBW0.75 (ωCL = 21.7%), Vss (l) = 2.66 × CBW (ωVss = 21.2%), Vc (l) = 1.13 × CBW, inter-compartment CL (l/h) = 0.257 × CBW0.75. Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0–2 of SN-38 (r = 0.73 and r = 0.73). Conclusion: Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW0.75 would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.Correspondence to:
T. Kimura
Department of Pharmacy
Tokyo Women’s Medical University Hospital
8-1 Kawadacho, Shinjuku-ku
Tokyo, 162-8666, Japan
Email: t.kimura@pha.twmu.ac.jp
Original Research
Effect of combination of zafirlukast and quercetin on baroreflex sensitivity and endothelin production in rats with myocardial infarction
T. Kezeli, N. Gongadze, Z. Chapichadze, K. Bakuridze and K. Chirakadze
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (335-341)
Effect of combination of zafirlukast and quercetin on baroreflex sensitivity and endothelin production in rats with myocardial infarction
T. Kezeli1, N. Gongadze2, Z. Chapichadze3, K. Bakuridze2 and K. Chirakadze1
1Department of Pharmacology, Faculty of Medicine, State University, 2Department of Pharmacology, State Medical University, and 3Department of Pharmacology, State Regulation Agency for Medical Activity, Tiflis, Georgia
The purpose of this study was to evaluate the influence of zafirlukast (Z), quercetin (Q) and their combination on baroreflex sensitivity (BRS), endothelin-1 (E1) plasma concentration and the severity of ventricular arrhythmias (VA) occurring during myocardial infarction (MI). In anaesthetized Wistar rats, MI was induced by ligation of the left anterior descending coronary artery (CAL). Animals were divided into the five groups: I – sham-operated (SO); II – CAL; III – CAL+Z (0.25 mg/kg intraperitoneally 1 hour prior and 12 – 24 hour after CAL); IV – CAL+Q (1.5 mg/kg by i.v. injection after anesthesia and every 24 hour during 72 hour); V – CAL+Z+Q as above. CAL after 1 hour was accompanied by high incidence of VA associated with a significant mortality (68% at 72 hour) as compared with SO rats. In survived rats BRS was greatly attenuated (0.44 ± 0.08 ms/mmHg) vs. SO animals (0.92 ± 0.14 ms/mmHg, p < 0.05) that correlated to increase E1 plasma concentration (9.2 ± 0.6 pg/ml) vs. SO rats (2.9 ± 0.4 pg/ml, p < 0.001). Q did not influence markedly on the severity of VA or rats mortality, while Z and Z+Q decreased mortality in rats in compare to II group of animals (from 68% – 42% and 30%), increased the reduced BRS resulting from MI (+38.5% and +55.4%, p < 0.05) and blunted the increase of E1 (–34.8% and –43.5% respectively, p < 0.05). Our results suggested a possible beneficial combine action of Z and Q on MI.Correspondence to:
K. Bakuridze
Tbilisi State Medical University
Department of Pharmacology
33 Vazha-Pshavela ave, 0177 Tiflis, Georgia
Email: kakha26@yahoo.com
Bioavailability Section
Relative bioavailability study with two oral formulations of topiramate using a validated UPLC-MS/MS method
I. Saavedra, E. Tamayo, A. Gamboa, J. Sasso, N. Varela, I. Moreno, D. Marchant, D. Cáceres and L. Quiñones
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (342-348)
Relative bioavailability study with two oral formulations of topiramate using a validated UPLC-MS/MS method
I. Saavedra1, E. Tamayo1, A. Gamboa1, J. Sasso1, N. Varela1, I. Moreno1, D. Marchant1, D. Cáceres2 and L. Quiñones1
1Laboratory of Pharmacokinetics and Bioavailability, IFT, Molecular and Clinical Pharmacology Program, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, and 2Epidemiology Division, School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile
Changes in bioavailability of anticonvulsant drugs such as topiramate may cause loss of or worsened seizure control. Thus, the purpose of this study was to evaluate, in a double-blind crossover design, the bioavailability between two oral formulations of topiramate in healthy volunteers after a single dose. The protocol, approved by the Institutional Committee of Ethics, consisted of administration of 1 tablet of 100 mg of topiramate of each formulation (Toprel™ and Topamax™), to 20 healthy volunteers after a 12 h overnight fast, using an open, two-period, randomized, crossover and double-blind design. Thus, the plasma concentrations (Cp) of topiramate were measured at predetermined intervals of time, from 0 to 24 h, using a validated UPLC-MS/MS method. Based on plasma concentration-time profiles we obtained the following pharmacokinetic parameters: AUC0–∞ 63,418.31 ± 22,141.69 and 67,094.70 ± 22,487.2 ngh/ml; AUC0–24: 30,421.02 ± 9,964.0 and 30,489.35 ± 9,407.17, ng × h/ml; tmax: 2.77 ± 1.76 and 1.95 ± 1.89 h; Cmax: 2,143.33 ± 724.26 and 2,262.51 ± 751.12 ng/ml, for A (Toprel™) and B (Topamax™), respectively. All these differences were not statically significant with 90% confidence interval. The test of bioequivalence showed that Cmax, AUC0–24 and AUC0–∞ parameters are found within the range of 0.8 – 1.25 recommended by the FDA with a probability of bioequivalence of 100%. In accordance with these results, we can conclude that Toprel™ 100 mg, A (Test), is a bioequivalent generic and interchangeable with Topamax™ 100 mg, B (Reference).Correspondence to:
L.A. Quiñones, Biochemist
IFT, Molecular and
Clinical Pharmacology Program
Biomedical Sciences Institute
Faculty of Medicine
University of Chile
PO Box 70111
Santiago 7, Chile
Email: lquinone@med.uchile.cl
Bioavailability Section
Bioequivalence of 250 mg lysine clonixinate tablets after a single oral dose in a healthy female Mexican population under fasting conditions
G. Marcelín-Jiménez, A.C.P. Ángeles, A. García, M. Morales, L. Rivera and A. Martín-del-Campo
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 5/2010 (349-354)
Bioequivalence of 250 mg lysine clonixinate tablets after a single oral dose in a healthy female Mexican population under fasting conditions
G. Marcelín-Jiménez1, A.C.P. Ángeles1, A. García1, M. Morales1, L. Rivera1 and A. Martín-del-Campo2
1Clinical Pharmacology Research Service and 2Mental Health Department, Hospital General de México, Mexico City, Mexico
Objective: To evaluate the bioequivalence between two 250 mg-tablets of lysine clonixinate, Dorixina Forte® (Siegfried Rhein, México) as reference product, and Prestodol® (Farmaceúticos Rayere, S.A., México) as test formulation. Methods: 26 healthy adult female Mexican volunteers received a single oral dose of 250-mg lysine clonixinate under fasting conditions. The drug was administered following a randomized, two-period, two-sequence, cross-over design. Twelve serial blood samples were collected up to 8 h after dosing, and clonixin (CLX) was measured by ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry. Decimal logarithm values of Cmax and area under the curve (AUC) were used to construct a classic confidence interval at 90% (90% CI). Bioequivalence was established if 90% CI of mean ratios (test/reference) fall within the 0.8 – 1.25 range. Results: Volunteers formed a homogeneous population in terms of age (27.2 ± 6.3 years), weight (55.9 ± 6.5 kg), height (1.6 ± 0.04 m), and body mass index (BMI) (22.91 ± 2.03 kg/m2). Reference formulation exhibited the following pharmacokinetics: Cmax (32.39 ± 8.32 µg/ml); tmax (0.64 ± 0.2 h); AUC0–8h (48.92 ± 16.51 µg.h/ml); t1/2 (1.3 ± 0.24 h); CLapp (5.64 ± 1.99 l/h), and Vdapp (10.22 ± 2.9 l). Concerning bioequivalence, 90% CI were: Cmax (82.32 – 98.79), AUC0–t (94.59 – 106.29), and AUC0–inf (94.61 – 106.42), with a statistical power of > 0.90 at every tested interval. Conclusions: This single-dose study found that both 250-mg immediate-release tablets of lysine clonixinate met the Mexican regulatory criteria for bioequivalence in these volunteers.Correspondence to:
G. Marcelín-Jiménez, PhD
Servicio de Investigación de Farmacología Clínica (405-E)
Hospital General de México
Dr. Balmis No. 148, Col. Doctores
06726 México, D.F., México
Email: gabmarcelin@hotmail.com
