Volume 53, No. 1/2015(January)
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Original
Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults
Olivera Milovanovic, Jasmina R. Milovanovic, Aleksandar Djukic, Milovan Matovic, Aleksandra Tomic Lucic, Nenad Glumbic, Ana Radovanovic, and Slobodan M. Jankovic
Price
42.00 $
Page No. 1
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (1-8)
Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults
Olivera Milovanovic1, Jasmina R. Milovanovic2, Aleksandar Djukic3, Milovan Matovic4, Aleksandra Tomic Lucic5, Nenad Glumbic6, Ana Radovanovic1, and Slobodan M. Jankovic2
1Department of Pharmacy, 2Department of Pharmacology and Toxicology, 3Department of Internal Medicine – Endokrinology, 4Department of Nuclear Medicine, 5Department of Internal Medicine – Rheumatology, Faculty of
Medical Sciences, University of Kragujevac, Kragujevac, and 6Department of Special Education and Rehabilitation, Faculty for Special Education and Rehabilitation, University of Belgrade, Belgrade, Serbia
Objectives: The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. Methods: Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm–2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. Results: In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 × DD + 0.618 × PHO. Conclusions: The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.Correspondence to:
Jasmina R. Milovanovic, PhD
Department of Pharmacology and Toxicology
Faculty of Medical Sciences
University of Kragujevac, Kragujevac, Serbia
Email: [email protected]
Original
Mechanisms of action of anti-seizure drugs and the anticonvulsant screening program of the National Institute of Neurological Disorders and Stroke
Roger J. Porter, Harvey J. Kupferberg, and Bettie Jean Hessie
Price
42.00 $
Page No. 9
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (9-12)
Mechanisms of action of anti-seizure drugs and the anticonvulsant screening program of the National Institute of Neurological Disorders and Stroke
Roger J. Porter1, Harvey J. Kupferberg2, and Bettie Jean Hessie3
1Department of Neurology, University of Pennsylvania, Philadelphia, PA, and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, 2Kupferberg Consultants, LLC, Rockville, MD, and 3Consultant, Life Sciences Research, North Bethesda, MD, USA
Objective: To determine the efficacy of the Anticonvulsant Screening Program (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) in identifying new anti-seizure drugs with new mechanisms of action (MOA). The ASP does not itself identify the nature of the MOA, but on further basic investigation, many of these drugs prove eventually to have a wide variety of new and novel MOA. Methods: Data were tabulated from multiple sources, including the ASP and the literature. Results: Since it was established in 1975, the ASP has contributed to the identification of at least 9 new anti-seizure drugs. The effectiveness of the program was evaluated by ascertaining the number of MOA of the anti-seizure drugs discovered by the ASP screening techniques. Considering the MOA of drugs marketed after 1975 – and the MOA of investigational compounds not yet marketed – the ASP has contributed to the identification of anti-seizure drugs that possess 16 distinctly different MOA. Conclusion: The ever-evolving screening approach of the ASP has many characteristics of a final common pathway for anti-seizure drug discovery.Correspondence to:
Bettie Jean Hessie, BS, ELS
Life Sciences Research
10500 Rockville Pike, Suite #1114, North Bethesda, MD 20852 USA
Email: [email protected]
Original
Lack of fluconazole effects on human chemosensation
Bruno Georg Oertel, Thomas Tao Huynh, Thomas Hummel, and Jörn Lötsch
Price
42.00 $
Page No. 13
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (13-20)
Lack of fluconazole effects on human chemosensation
Bruno Georg Oertel1,2, Thomas Tao Huynh1, Thomas Hummel3, and Jörn Lötsch1,2
1Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt am Main, 2Fraunhofer Institute of Molecular Biology and Applied Ecology – Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, and 3Smell & Taste Clinic, Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany
Objective: Drug effects on the function of smell and taste are occasionally mentioned in prescription information however, most originate from anecdotal reports without even distinguishing between gustatory or olfactory deteriorations. This includes the antifungal fluconazole. Material and methods: In a randomized, placebocontrolled, double-blind, two-way crossover study, 12 healthy men and 9 healthy women (age 26.8 ± 3.7 years) took oral doses of 400 mg fluconazole or placebo once daily for 8 days. Gustatory and olfactory functions were tested before and after the treatment using clinically validated tests (“Taste Strips” and “Sniffin’ Sticks”, respectively). Results: Baseline taste scores of 12.3 ± 2.2 and 12.5 ± 1.7 for the fluconazole and placebo conditions, respectively, corresponded to normative values. Similarly, baseline (pretreatment) composite olfactory TDI scores (odor “threshold discrimination identification”) of 35.0 ± 3.2 and 35.7 ± 4.3 for men and 34.8 ± 4.2 and 35.5 ± 2.8 for women during the fluconazole or placebo conditions, respectively, corresponded to normative values. Neither gustation nor olfaction was significantly affected by the fluconazole treatment. Conclusions: The present study provided a negative result regarding fluconazole effects contrasting, for example, with those of sildenafil in a comparatively powered study [1]. Up to the tested dose of 400 mg/d, fluconazole does not have general and reproducible effects on taste and smell in healthy humans. However, it was unlikely to detect rare disturbances with the present study cohort size, and, therefore, rare fluconazole side effects on human chemosensation, as occasionally reported, remain a possibility.Correspondence to:
Bruno Georg Oertel, PhD
Fraunhofer Institute of Molecular Biology and Applied Ecology –
Project Group Translational Medicine and Pharmacology (IME-TMP)
Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
Email: [email protected]
Original
Safety monitoring of the intravenous immunoglobulin preparation Intratect® in primary and secondary immunodeficiencies: a prospective non-interventional study
Artur Bauhofer, Roland L.J. Dietrich, and Rainer Schmeidl
Price
42.00 $
Page No. 21
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (21-31)
Safety monitoring of the intravenous immunoglobulin preparation Intratect® in primary and secondary immunodeficiencies: a prospective non-interventional study
Artur Bauhofer, Roland L.J. Dietrich, and Rainer Schmeidl
Biotest AG, Corporate Clinical Research and Corporate Drug Safety, Dreieich, Germany
Objectives: To better characterize the risk profile of the intravenous immunoglobulin (IVIG) Intratect®, a non-interventional study was undertaken to systematically collect large-scale safety information under real-life conditions in patients with primary and secondary immunodeficiency. Secondary objectives were data on treatment modalities. Methods: A prospective, non-interventional study was performed at 95 centers. Results of an interim analysis are reported here. Intratect® (50 g/L) was administered at the physician’s discretion. Data were captured from patients with different causes of immunodeficiency (61.5% with malignancy) at routine clinic visits, with a particular focus on the frequency and causality of adverse events. Results: 1,313 patients were followed for a median of 294 days. At study entry, 836 patients (63.7%) were receiving therapy, most frequently IVIG treatment (37.2%). In total, 21,995 Intratect® infusions were documented (median 11 infusions per patient, median dose 200 mL). Median serum IgG level increased from 5.78 (interquartile range 3.70, 8.87) g/L at month 1 to 6.58 (4.82, 9.48) g/mL at month 12. Altogether, 689 adverse events were collected, irrespective of causality. From these, 225 (32.7%) were assessed as related to Intratect® and thus considered suspected adverse drug reactions (ADRs). Thus, the ADR rate was 1.0% per infusion. Seven ADRs (7/225, 3.1%) were graded serious. In all cases, the patients had recovered or were recovering at the time of reporting. Conclusions: Use of Intratect® for immunoglobulin substitution in primary and secondary immunodeficiency under real-life conditions is associated with a low rate of suspected ADRs. Serious ADRs are rare and manageable.Correspondence to:
Prof. Dr. Artur Bauhofer
Biotest AG
Landsteiner Straße 3, 63303 Dreieich, Germany
Email: [email protected]
Original
Hemodynamic responses during induction: comparison of Marsh and Schnider pharmacokinetic models
Xiao-Yu Yang, Zhi-Bin Zhou, Lu Yang, Xue Zhou, Li-Jun Niu, and Xia Feng
Price
42.00 $
Page No. 32
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (32-40)
Hemodynamic responses during induction: comparison of Marsh and Schnider pharmacokinetic models
Xiao-Yu Yang*, Zhi-Bin Zhou*, Lu Yang, Xue Zhou, Li-Jun Niu, and Xia Feng
Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Background: Hemodynamic stability is one of the most critical concerns during induction of anesthesia. Whether the pharmacokinetic model by Marsh or the one by Schnider will produce better hemodynamic stability remains unclear. This study compared hemodynamic changes during induction between the two models. Methods: 60 patients who underwent elective surgery were randomly assigned to plasma target-controlled infusion by Marsh’s (n = 30) or Schnider’s (n = 30) model with an initial target concentration of 4 μg×mL–1. The target was then reset and gradually titrated to a sedation level with a narcotrend index (NI) below 64. Stroke volume, cardiac output, systemic vascular resistance, arterial pressure, target, and effect site concentration, and dose of propofol infused were recorded every minute during the first 25 minutes of infusion. Results: Throughout the first 25 minutes, stroke volume index and cardiac index were decreased significantly in both Marsh and Schnider groups, but no statistical difference was detected between the groups (p > 0.05). Central venous pressure (CVP), systemic vascular resistance index (SVRI), and heart rate (HR) did not significantly change during induction (p > 0.05). Time to loss of responsiveness (LOR), and time for NI to decrease to 64 was faster in Marsh than in Schnider (1.51 ± 0.8 minutes vs. 2.8 ± 1.2 min, p < 0.001; 3.3 ± 2.0 minutes vs. 5.2 ± 2.3 minutes, p < 0.01, respectively). Conclusions: When target concentrations are titrated according to NI during induction of anesthesia, Marsh’s model could induce sedation faster than Schnider’s. Meanwhile, hemodynamic changes were not observed to be statistically different between the two models. Hypotension induced by plasma target-controlled infusion of propofol could mainly be attributed to decreased stroke volume instead of vascular dilation.Correspondence to:
Xia Feng MD, PhD
Department of Anesthesiology
First Affiliated Hospital of Sun Yat-Sen University
No.58 Zhongshan 2nd Road, Guangzhou, 510080, PR China
Email: [email protected]
Original
Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants
Damayanthi Devineni, Prasarn Manitpisitkul, Nicole Vaccaro, Apexa Bernard, Donna Skee, Rao N.V.S. Mamidi, Hong Tian, Sveta Weiner, Hans Stieltjes, Sue Sha, and Paul Rothenberg
Price
42.00 $
Page No. 41
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (41-53)
Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants
Damayanthi Devineni1, Prasarn Manitpisitkul1, Nicole Vaccaro2, Apexa Bernard1, Donna Skee1, Rao N.V.S. Mamidi1, Hong Tian1, Sveta Weiner1, Hans Stieltjes3, Sue Sha1, and Paul Rothenberg1
1Janssen Research and Development, LLC, Raritan, NJ, 2Janssen Research and Development, LLC, San Diego, CA, USA, and 3Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
Objective: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. Methods: All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 μg) + ethinyl estradiol (30 μg))/day (day 1), canagliflozin 200 mg/day (days 4 – 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 – 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 – 7)) in period 1, and with canagliflozin 300 mg/day (days 1 – 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 – 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 – 7 (periods 1 and 2) (study 3). Warfarin’s pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). Results: Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin’s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. Conclusion: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were welltolerated.Correspondence to:
Dr. Damayanthi
Devineni Janssen Research and Development
LLC, 920, Route 202, Raritan, NJ 08869, USA
Email: [email protected]
Original
Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans
Angela Storka, Brigitta Vcelar, Uros Klickovic, Ghazaleh Gouya, Stefan Weisshaar, Stefan Aschauer, Gordon Bolger, Lawrence Helson, and Michael Wolzt
Price
42.00 $
Page No. 54
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (54-65)
Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans
Angela Storka1, Brigitta Vcelar2, Uros Klickovic1, Ghazaleh Gouya1, Stefan Weisshaar1, Stefan Aschauer1, Gordon Bolger4, Lawrence Helson3, and Michael Wolzt1
1Department of Clinical Pharmacology, Medical University of Vienna, Vienna, 2Polymun Scientific Immunbiologische Forschung GmbH, Klosterneuburg, Austria, 3Sign Path Pharma, Inc., Quakertown, PA, USA, and 4Nucro-Technics, Scarborough, Ontario, Canada
Introduction: Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. Material and methods: 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 – 400 mg/m2; n = 2 – 6 per group) or placebo over 2 hours intravenously. Results: Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 – 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages ≥ 120 mg/m2. Conclusion: Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity.Correspondence to:
Dr. Michael Wolzt
Department of Clinical Pharmacology
Medizinische Universität Wien
Spitalgasse 23, 1090 Vienna, Austria
Email: [email protected]
Original
Pharmacokinetic comparison of amlodipine adipate/valsartan fixed-dose combination with amlodipine besylate/valsartan fixed-dose combination in healthy volunteers
Ju-Hyun Nam, Minkyung Oh, Hyun Ji Kim, Sung Kyun Han, Eun Ji Kim, Geun Seog Song, un-Young Kim, Jae-Gook Shin, Jong-Lyul Ghim, and Ho-Sook Kim
Price
42.00 $
Page No. 66
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (66-74)
Pharmacokinetic comparison of amlodipine adipate/valsartan fixed-dose combination with amlodipine besylate/valsartan fixed-dose combination in healthy volunteers
Ju-Hyun Nam1, Minkyung Oh1, Hyun Ji Kim3, Sung Kyun Han3, Eun Ji Kim3, Geun Seog Song3, Eun-Young Kim1,2, Jae-Gook Shin1,2, Jong-Lyul Ghim1,2, and Ho-Sook Kim1,2
1Department of Pharmacology, Inje University College of Medicine, 2Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, and 3Pharmaceutical BU, CJ Cheiljedang Corp., Seoul, Republic of Korea
The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0–t were 93.5 – 100.4% and 93.2 – 98.3% for amlodipine, and 92.1 – 121.3% and 94.1 – 115.2% for valsartan, respectively. 17 adverse events occurred in 15 subjects during the study; 5 and 7 adverse drug reactions from the 5 and 6 subjects were considered to probably be related to the test and reference treatments respectively. All adverse drug reactions were in line with those known for the reference drug. All subjects recovered fully with no sequelae. A FDC of amlodipine adipate/valsartan and amlodipine besylate/ valsartan combination tablets met the regulatory criteria for bioequivalence. In addition, no significant difference was observed in the safety assessments between two treatments. Thus, the newly developed FDC of amlodipine adipate/valsartan seems to be interchangeable with amlodipine besylate valsartan combination.Correspondence to:
Ho-Sook Kim, PhD, Jong-Lyul Ghim, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Inje University College of Medicine and Busan Paik Hospital
633-165 Gaegum 2-dong, Busan Jin-gu, Busan 614-735, Korea
Email: [email protected] and [email protected]
Original
Population pharmacokinetic analysis of tacrolimus early after Chinese pediatric liver transplantation
Jian-wei Yang, Sha-sha Liao, Li-qin Zhu, Yang Zhao, Yuan Zhang, Xiao-ye Sun, Wei Rao, Wei Qu, Wen-zhuo Li, and Li-ying Sun
Price
42.00 $
Page No. 75
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (75-83)
Population pharmacokinetic analysis of tacrolimus early after Chinese pediatric liver transplantation
Jian-wei Yang1, Sha-sha Liao1, Li-qin Zhu2, Yang Zhao3, Yuan Zhang2, Xiao- ye Sun4, Wei Rao4, Wei Qu5, Wen-zhuo Li1, and Li-ying Sun5
1Basic Medical College, Tianjin Medical University, 2Department of Pharmacy, Tianjin First Central Hospital, Tianjin, 3China Food and Drug Administration, Beijing, 4Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin, and 5Department of Liver Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Objective: The purpose of this study was to describe the population pharmacokinetics (PK) of tacrolimus (TAC) in 52 Chinese pediatric patients early after liver transplantation. Methods: Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data from the first day after surgery. A total of 488 concentration data were obtained and analyzed by a nonlinear mixed-effect modeling (NONMEM) method. A number of demographic and clinical variables were tested for their influence on TAC PK parameters. Results: The PK of TAC were best described by a one-compartment model with first-order absorption and elimination. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 5.72 L/h and 131 L, respectively. The absorption rate constant (Ka) was fixed in 4.48 h–1. The inter-individual variabilities in CL/F and V/F were 13.5% and 78.1%. In the final analysis performed in all 52 patients, the post-operation day (POD) and alanine aminotransferase (ALT) influenced TAC CL/F and V/F, and total protein (TP) was the only covariate retained on V/F. Conclusion: A population PK model of TAC was developed in Chinese pediatric patients early afte liver transplantation. It identified significant relationships between the PK of TAC and the characteristics of the patients. POD, ALT, and TP were identified as the main factors influencing the PK of TAC. The developed model could be useful to optimize individual pediatric TAC dosing regimen in routine clinical practice.Correspondence to:
Dr. Liqin Zhu Department of Pharmacy
Tianjin First Central Hospital
24# Fukang Road, Nankai district, Tianjin, 300192 China
and
Dr. Liying Sun
Department of Liver Transplantation
Beijing Friendship Hospital, Capital Medical University
95 Yongan Road, XiCheng District, Beijing, 100050, China
Email: [email protected] or [email protected]
Original
Pharmacokinetics of nifedipine slow-release during sustained tocolysis
Maureen A. ter Laak, Carolien Roos, Daan J. Touw, Paul R.M. van Hattum, Anneke Kwee, Frederik K. Lotgering, Ben Willem J. Mol, Mariëlle G. van Pampus, Martina M. Porath, Marc E.A. Spaanderman, Joris A.M. van der Post, Dimitri N.M. Papatsonis, and Nils E. van ’t Veer
Price
42.00 $
Page No. 84
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (84-91)
Pharmacokinetics of nifedipine slow-release during sustained tocolysis
Maureen A. ter Laak1, Carolien Roos2, Daan J. Touw3, Paul R.M. van Hattum1, Anneke Kwee4, Frederik K. Lotgering2, Ben Willem J. Mol5, Mariëlle G. van Pampus6, Martina M. Porath7, Marc E.A. Spaanderman8, Joris A.M. van der Post9, Dimitri N.M. Papatsonis10, and Nils E. van ’t Veer1
1Department of Clinical Pharmacy, Amphia Hospital, Breda, 2Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, 3Department of Clinical Pharmacy and Pharmacology Groningen, University Medical Center Groningen, Groningen, 4Department of Obstetrics and Gynecology, University Medical Center, Utrecht, The Netherlands, 5The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia, 6Department of Obstetrics and Gynecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, 7Department of Obstetrics and Gynecology, Máxima Medical Center, Veldhoven, 8Department of Obstetrics and Gynecology, Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht, 9Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, and 10Department of Obstetrics and Gynecology, Amphia Hospital, Breda, The Netherlands
Objective: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slowrelease half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. Materials: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. Methods: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. Results: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 – 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 – 11 hours, and a distribution volume of 1.2 – 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. Conclusion: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.Correspondence to:
Maureen ter Laak, MSc.
Department of Clinical Pharmacy
TweeSteden Hospital
Dr. Deelenlaan 5, 5042 AD, Tilburg, The Netherlands
Email: [email protected]
Case Report
First case report of suspected onset of convulsive seizures due to co-administration of valproic acid and tebipenem
Atsuko Shihyakugari, Akiko Miki, Natsue Nakamoto, Hiroki Satoh, and Yasufumi Sawada
Price
42.00 $
Page No. 92
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (92-96)
First case report of suspected onset of convulsive seizures due to co-administration of valproic acid and tebipenem
Atsuko Shihyakugari1, Akiko Miki2, Natsue Nakamoto3,4, Hiroki Satoh2, and Yasufumi Sawada2
1Ain Pharmaciez Shikahama branch, 2Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 3Faculty of Health Sciences Department of Occupational Therapy, Mejiro University, and 4Hakujikai Healthcare Foundation, Tokyo, Japan
Objective: A patient presented with convulsive seizures when sodium valproate (VPA) and tebipenem pivoxil (Orapenem) were co-administered accidentally. The seizures were suspected to be caused by a reduced concentration of VPA in the blood. Case summary: A 6-year-old boy (weight: 16 kg, at the start of treatment) began sodium valproate (valproate syrup 5%) treatment for epilepsy in February 2012. At a dose of 350 mg/day, he experienced no convulsive seizures and maintained stable symptoms for the past 9 months. In December, he was prescribed 160 mg/day tebipenem pivoxil by an otolaryngologist for inflammation of the tympanic membrane. He experienced convulsive seizures the day after beginning co-administration. The concentration of VPA in his blood at this time was 30.0 μg/mL, which was lower than the optimal blood concentration. Discussion: Marked reduction of VPA concentration in the blood due to co-administration of VPA and injectable carbapenem antibiotics has been well-documented; however, this is the first report of such an interaction with tebipenem, which is an orally-administered carbapenem antibiotic. Although the mechanism of drug interaction between VPA and carbapenem antibiotics is not fully understood, it is thought that VPA blood concentrations decrease due to production of valproic acid glucuronic acid conjugates (VPA-Gluc) being promoted directly or indirectly by carbapenem antibiotics. When we assessed the patient according to the DIPS system, we calculated a score of +4 (possibility of interaction). Conclusions: The results suggest that co-administration of oral carbapenem antibiotics and VPA should be avoided.Correspondence to:
Prof. Yasufumi Sawada, PhD
Laboratory of Drug Informatics
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Email: [email protected]
Bioavailability Section
Pharmacokinetic properties of isosorbide-5- mononitrate under fasting and fed conditions in healthy male subjects
Changyun Jin, Ji-Young Jeon, Yong-Jin Im, Jin-A Jeong, Yunjeong Kim, Soo-Wan Chae, Jürgen Bentz, Thomas Kumke, and Min-Gul Kim
Price
42.00 $
Page No. 97
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 1/2015 (97-106)
Pharmacokinetic properties of isosorbide-5- mononitrate under fasting and fed conditions in healthy male subjects
Changyun Jin1,2*, Ji-Young Jeon1,2*, Yong-Jin Im1,2, Jin-A Jeong1,2, Yunjeong Kim1,2, Soo-Wan Chae1,2, Jürgen Bentz3, Thomas Kumke4, and Min-Gul Kim1,2
1Clinical Trial Center, Chonbuk National University Hospital, Jeonju, Korea, 2Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Korea, 3UCB Pharma, Brussels, Belgium, and 4UCB Pharma, Monheim, Germany
Objective: This study was performed to compare the pharmacokinetic properties and relative bioavailability of two isosorbide-5-mononitrate (5-ISMN) sustained-release drugs in healthy Korean subjects under fasting and fed conditions. Methods: A total of 60 healthy volunteers (30 each in the fasting and fed arms of the study) were enrolled in the study and were randomized to treatment. After the administration of a single dose of one of the investigational products, blood samples were collected at specific time intervals from 0 to 36 hours. The plasma concentrations of 5-ISMN were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance on logarithmically transformed data. Results: The corresponding 90% CIs of AUClast and Cmax for the test/reference geometric mean ratio were 90.75 – 98.44% and 92.28 – 98.33%, respectively, under fasting conditions. In the fed state study, the 90% CIs for the geometric mean ratio of test to reference drugs were 94.79 – 103.33% for AUClast and 99.86 – 108.02% for Cmax. Conclusion: The test product is equivalent to the reference product in subjects under fasting and fed conditions within the Korean regulatory bioequivalence criteria. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles between the test and reference drugs.Correspondence to:
Min-Gul Kim, MD, PhD
Biomedical Research Institute
Chonbuk National University Hospital
20, Geonji-ro, Deokjin-gu,
Jeonju-si, Jeollabuk-do, 561-712, Korea
Email: [email protected]
