Volume 52, No. 2/2014(February)
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Original
Treatment of severe IgA nephropathy: mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone
Xiaowei Liu, Du Dewei, Shiren Sun, Guoshuang Xu, Hongbao Liu, Lijie He and Peng Zhang
Price
42.00 $
Page No. 95
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (95-102)
Treatment of severe IgA nephropathy: mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone
Xiaowei Liu1*, Du Dewei2*, Shiren Sun1, Guoshuang Xu1, Hongbao Liu1, Lijie He1, and Peng Zhang1
1Department of Nephrology, Xijing Hospital and 2Department of Nephrology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, China
Objective: To compare the efficacy of mycophenolate mofetil (MMF)/prednisone to cyclophosphamide (CYC)/prednisone in the treatment of severe IgA nephropathy. Methods: Patients (n = 84) with severe IgA nephropathy received either MMF/prednisone (MMF group) or CYC/prednisone (CYC group). The MMF induction dose was 1.5 g/d for 6 months and the maintenance dose was 0.75 – 1.0 g/day for 12 months. The CYC induction dose was 0.8 – 1.0 g/month for 6 months and the maintenance dose was 0.8 – 1.0 g/3 months for 12 months. Laboratory tests, clinical remission rate and side effects were investigated. Results: After 18 months of treatment, the total effective rate in the MMF group was significantly higher than that of the CYC group. Patients’ 24-hour urinary protein excretion in the MMF group was lower than the CYC group. Patients’ plasma albumin and total protein in the MMF group was higher than the CYC group. MMF and prednisone reduced serum lipids, while in the CYC group serum lipids remained unchanged. There was also a lower incidence of adverse effects in the MMF group (4.76%) than in the CYC group (26.2%). Conclusion: Combination therapy with MMF and prednisone for severe IgA nephropathy achieved a higher remission rate compared to treatment with CYC and prednisone. This therapy also reduced the 24-hour urinary protein and serum lipids while increasing plasma albumin and improving renal function. The incidence of adverse effects was significantly lower in the MMF group compared to the CYC group.
*These authors have contributed equally to this work.Correspondence to:
Peng Zhang
Department of Nephrology, Xijing Hospital
The Fourth Military Medical University
Xi’an 710032, China
Email: [email protected]
Original
Two-way interaction study between ritonavirboosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects
Peter N. Morcos, Linda Chang, Mercidita Navarro, Diana Chung, Patrick F. Smith, Barbara J. Brennan, and Jonathan Q. Tran
Price
42.00 $
Page No. 103
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (103-111)
Two-way interaction study between ritonavirboosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects
Peter N. Morcos, Linda Chang, Mercidita Navarro, Diana Chung, Patrick F. Smith*, Barbara J. Brennan, and Jonathan Q. Tran**
Pharma Research and Early Development (pRED) – Virology Clinical Pharmacology, Hoffmann-La Roche Inc, Nutley, NJ, USA
Background: Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A. Methods: In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (Period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (Period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (Period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. Results: Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUCτ by 1.44-fold, with no effect on danoprevir Cmax. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUCτ and Cmax by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole. Conclusions: These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.
Current affiliations:
*d3 Medicine, Montville, NJ, USA and University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA;
**Biogen Idec, Cambridge, MA, USACorrespondence to:
Peter N. Morcos, PharmD
Pharma Research and Early Development (pRED) –
Virology Clinical Pharmacology
Hoffmann-La Roche Inc
340 Kingsland Street, Nutley, NJ 07110, USA
Email: [email protected]
Original
Osthole inhibits proliferation and induces apoptosis in human osteosarcoma cells
Yong Ding, Xiongwei Lu, Xiaopeng Hu, Jie Ma, and Huan Ding
Price
42.00 $
Page No. 112
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (112-117)
Osthole inhibits proliferation and induces apoptosis in human osteosarcoma cells
Yong Ding, Xiongwei Lu, Xiaopeng Hu, Jie Ma, and Huan Ding
The Third People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Objective: The purpose of this study was to investigate the effect of osthole on osteosarcoma cell proliferation and apoptosis. Method: Cell counting Kit-8 assay was performed to establish the effects of osthole on osteosarcoma MG-63 cell proliferation. Annexin V-FITC/PI was performed to analyze the apoptotic rate of the cells. Result: The inhibitory effects of osthole on the expression of BCL-2, BAX, and caspase-3 were detected by Western blotting. Osthole inhibited the growth of human osteosarcoma MG-63 cells by inhibiting cell proliferation and induced cell apoptosis. Western blotting demonstrated that osthole downregulated the expressions of BCL-2 and caspase-3 and upregulated the expression of BAX in human osteosarcoma cells. Conclusion: Osthole can inhibit osteosarcoma cell proliferation and induced apoptosis effectively in a dose-dependent manner through downregulating the expression of BCL-2 and caspase-3 proteins levels and upregulating the expression of BAX proteins levels.Correspondence to:
Yong Ding, MD
The Third People’s Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine
No.80 Mohe Road, Shanghai 201900, China
Email: [email protected]
Original
Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers
Herta M. Crauwels, Rolf P.G. van Heeswijk, Annemie Buelens, Marita Stevens and Richard M.W. Hoetelmans
Price
42.00 $
Page No. 118
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (118-128)
Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers
Herta M. Crauwels, Rolf P.G. van Heeswijk, Annemie Buelens, Marita Stevens and Richard M.W. Hoetelmans
Janssen Infectious Diseases BVBA, Beerse, Belgium
Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. Objective: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4. Methods: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 μg)/norethindrone (1 mg) (Days 1 – 21); Days 22 – 28 were pill-free. Only in Cycle 3 was once-daily rilpivirine (25 mg) co-administered (Days 1 – 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15, Cycles 2 and 3) and rilpivirine (Day 15, Cycle 3) were evaluated. Results: Rilpivirine coadministration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol Cmin (1.09, 1.03 – 1.16) or AUC24h (1.14, 1.10 – 1.19), but increased Cmax by 17% (1.17, 1.06 – 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89, 0.84 – 0.94; Cmin: 0.99, 0.90 – 1.08; Cmax: 0.94, 0.83 – 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. Conclusions: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.Correspondence to:
Dr. H. Crauwels
Clinical Pharmacology
Janssen Infectious Diseases – Diagnostics BVBA
Turnhoutseweg 30, 2340 Beerse, Belgium
Email: [email protected]
Original
Pharmacokinetics of a new subcutaneous diclofenac formulation administered to three body sites: quadriceps, gluteus, and abdomen
Salvatore Salomone, Cateno Piazza, Daniela Cristina Vitale, Francesco Cardì, Barbara Gugliotta, and Filippo Drago
Price
42.00 $
Page No. 129
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (129-134)
Pharmacokinetics of a new subcutaneous diclofenac formulation administered to three body sites: quadriceps, gluteus, and abdomen
Salvatore Salomone1,2, Cateno Piazza2, Daniela Cristina Vitale2, Francesco Cardì3, Barbara Gugliotta4, and Filippo Drago1
1Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, 2Pharmacokinetic Unit, Unifarm Research Center, University of Catania, 3Vittorio Emanuele General Hospital, University of Catania, Catania, Italy, and 4IBSA Institut Biochimique SA, R&D Department, Pambio-Noranco, Switzerland
Objective: To assess the relative bioavailability of a new subcutaneous (SC) diclofenac hydroxypropyl b-cyclodextrin (HPbCD) formulation administered to three body sites: quadriceps, gluteus, and abdomen. Materials and methods: This was a pilot, single-dose, randomized, three-way crossover relative bioavailability study. A total of 12 healthy subjects received a single SC injection of diclofenac HPbCD 50 mg/1 mL in the quadriceps, gluteus, or abdomen. Results: The AUC was comparable after SC diclofenac HPbCD in the quadriceps, gluteus, and abdomen. The Cmax was comparable after SC administration in the quadriceps or abdomen, and ~ 17% higher in the gluteus. The absorption was rapid (30 minutes) after administration of the treatment at any site. The treatment was well tolerated. Conclusions: The relative bioavailability of SC diclofenac HPbCD was comparable when administered to the quadriceps, gluteus, and abdomen. The new diclofenac formulation can therefore be administered subcutaneously to any of these sites without clinically significant differences. A further adequately powered study would be necessary to reveal any differences among injection sites in terms of peak plasma concentration.Correspondence to:
Barbara Gugliotta, Pharm
IBSA Institut Biochimique
Via del Piano, P.O. Box 266, 6915 Pambio-Noranco, Switzerland
Email: [email protected]
Original
Safety of blood reinfusion after local infiltration analgesia with ropivacaine in total knee arthroplasty
Bregje J.W. Thomassen, Dean Touw, Pieter van der Woude, Rudolf E. van der Flier, and Bastiaan A. in ‘t Veld
Price
42.00 $
Page No. 135
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (135-142)
Safety of blood reinfusion after local infiltration analgesia with ropivacaine in total knee arthroplasty
Bregje J.W. Thomassen1, Daan Touw2, Pieter van der Woude1, Rudolf E. van der Flier1, and Bastiaan A. in ‘t Veld3
1Department of Orthopaedic Surgery, Medical Center Haaglanden, 2Hospital Pharmacy, Central Hospital Pharmacy, and 3Department of Anaesthesiology, Medical Center Haaglanden, The Hague, The Netherlands
Objective: The authors hypothesized that it is safe to combine local infiltration analgesia (LIA) in total knee arthroplasty (TKA) with a retransfusion drain since ropivacaine concentrations would not exceed the arterial toxicity threshold concentrations of 4.3 mg/L for total and 0.56 mg/L for unbound ropivacaine. Materials and methods: 22 patients scheduled for primary TKA were included. During surgery three peri-articular injections with ropivacaine (300 mg) were given. Plasma and shed blood samples were taken at 0, 1, 3, 6, 7, and 24 hours postoperatively. Results: At 6 hours postoperatively, the total ropivacaine plasma concentration ranged from 0.26 to 1.53 mg/L and unbound ropivacaine from 0.03 to 0.12 mg/L. At 7 hours, the total ropivacaine plasma concentration ranged from 0.19 to 1.71 mg/L and unbound ropivacaine from 0.02 to 0.09 mg/L. In the collected shed blood, a total of 0.27 to 12.8 mg (median 3.73 mg) unbound ropivacaine was present. Reinfusion would lead to an addition of 3.73 mg (median) unbound ropivacaine that would be reinfused into the patient. The calculated (modeled) estimation regarding the maximum unbound ropivacaine plasma concentration showed a median value of 0.114 mg/L (IQR: 0.09, 0.12 mg/L). All concentrations were well below reported toxicity thresholds. Conclusions: The combination of LIA and reinfusion presented herein are considered safe. However, differences in pain protocol lead to changes in the safety evaluation. Compared with previous studies, the technique of administration is of greater importance for the effect on unbound ropivacaine because of unknown mechanisms.Correspondence to:
Bregje J.W. Thomassen, MSc
Department of Orthopeadic Surgery
MEdical Center Haaglanden
P.O. Box 432, 2501 CK The Hague, The Netherlands
Email: [email protected]
Original
Correlation of genotype, phenotype, and mRNA expression of CYP2D6 and CYP2C19 in peripheral blood leukocytes (PBLs)
Jan B. Kuhlmann, Georg Wensing, and Jochen Kuhlmann
Price
42.00 $
Page No. 143
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (143-150)
Correlation of genotype, phenotype, and mRNA expression of CYP2D6 and CYP2C19 in peripheral blood leukocytes (PBLs)
Jan B. Kuhlmann1, Georg Wensing2, and Jochen Kuhlmann2
1University Hospital Freiburg, Freiburg and 2Bayer HealthCare AG Institute of Clinical Pharmacology, Wuppertal, Germany
Introduction: The genetic polymorphism of drug metabolizing enzymes of the cytochrome P450 (CYP) families, especially CYP2D6 and CYP2C19, is the most important cause of variable responses of many drugs. Enzyme activity ranges from complete deficiency, so called poor metabolizers (PMs), to an ultrafast metabolism. While PMs and extensive metabolizers (EMs) can be well distinguished by genotyping, phenotyping is necessary to subdivide EMs from intermediate metabolizers (IMs). The aim of the study was to evaluate if messenger RNA (mRNA) concentration for CYP-enzymes in peripheral blood leukocytes (PBLs) will be predictive of systemic enzyme activity, allowing an easy and safe determination of metabolic activity. Methods: The genotype, phenotype, and mRNA-expression in PBLs were evaluated in 124 healthy Caucasian volunteers (males and females, age range 23 – 59 years) on three occasions (every 4 weeks). Genotyping was performed by Taqman allelic discrimination on the most common null alleles for CYP2D6 (*3, *4, *6, *7, and *8) and CYP2C19 (*2 and *3). For phenotyping CYP2D6, dextromethorphan/dextrorphan metabolic ratios were determined in collected urine (8 hours) after administration of 30 mg dextromethorphan. For phenotyping CYP2C19, we used the plasma concentration ratio of omeprazole/hydroxyomeprazole 4 hours after ingestion of 40 mg omeprazole. mRNA-expression in PBLs for CYP2D6 and CYP2C19 was measured by Taqman real-time PCR before medication and 4 hours afterwards. Results: Genotyping for CYP2D6 and CYP2C19 showed a regular distribution of EMs and PMs compared to studies of a comparable population. The median dextromethorphan/dextrorphan metabolic ratio was 0.47 in EMs/IMs and 2.29 in PMs. The median omeprazole/hydroxyomeprazole metabolic ratio was 3.06 in EMs/IMs and 35.29 in PMs. CYP2D6 and CYP2C19 mRNA expression was detected without evidence of correlation to the respective metabolic ratio. Conclusion: The results do not support the concept of using mRNA expression profiles for CYP2D6 and CYP2C19 enzymes in PBLs for prediction of systemic enzyme activity.Correspondence to:
Jan Kuhlmann, MD
Department of Medicine II, University Hospital Freiburg
Hugstetter Straße 55, 79106 Freiburg, Germany
Email: [email protected]
Original
Pharmacokinetics of simvastatin lactone and its active metabolite simvastatin hydroxy acid in healthy Chinese male and female volunteers
Weihong Yang, Hongpong Xu, Yanliang Song, Xiaofei Wang, Xinwei Ren, Dengzhi Zhao, Yaoxin Cai, Shengjun Zhang, Jianmin Huang, Li-Rong Zhang, Tianyi Zhang, and Ming Zuo
Price
42.00 $
Page No. 151
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (151-158)
Pharmacokinetics of simvastatin lactone and its active metabolite simvastatin hydroxy acid in healthy Chinese male and female volunteers
Weihong Yang1,2, Hongpong Xu3, Yanliang Song1, Xiaofei Wang1, Xinwei Ren1, Dengzhi Zhao1, Yaoxin Cai1, Shengjun Zhang4, Jianmin Huang4, Li-Rong Zhang1, Tianyi Zhang5, and Ming Zuo5
1Department of Pharmacology, School of Basic Medical Sciences, 2Department of Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, 3Zhengzhou Railway Vocational-Technical College, 4The First Affiliated Hospital of Zhengzhou University, Zhengzhou, and 5Frontage Laboratories (Shanghai) Co., Ltd, Shanghai, China
Background: Gender differences in pharmacokinetics have been reported to have important clinical consequences; however, no information about differences in the pharmacokinetics of the cholesterol-lowering drug simvastatin lactone and its metabolite, simvastatin hydroxy acid, in males and females is available. Objective: The aim of this study was to investigate the effect of gender on the pharmacokinetics of simvastatin lactone and simvastatin hydroxy acid in healthy Han Chinese volunteers. Methods: 16 healthy volunteers (8 males and 8 females) were orally administered a single dose of 40 mg simvastatin lactone after an overnight fast. Plasma was then collected 24 hours after simvastatin lactone administration. Concentrations of simvastatin lactone and simvastatin hydroxy acid were measured by high performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC/MS/MS). Results: There were no significant associations between the pharmacokinetic parameters of simvastatin lactone and gender. For simvastatin hydroxy acid, peak plasma concentrations (Cmax) and dose-normalized by the subject weight Cmax (NCmax) were higher in females than in males. Furthermore, NCmax and dose-normalized by the subject weight AUC (NAUC0–24h, NAUC0–∞) ratios of simvastatin hydroxy acid to simvastatin lactone in females were higher than in males. Conclusion: This study indicates that gender affects the plasma concentrations of active simvastatin hydroxy acid, but has no significant effect on parent simvastatin lactone. Raised plasma concentrations of simvastatin hydroxy acid in females may enhance the risk of systemic adverse effects during simvastatin lactone treatment.Correspondence to:
Prof. Li-Rong Zhang, MD
Department of Pharmacology, School of Medicine
Zhengzhou University
100 Science Road, Zhengzhou 450001, China
Email: [email protected]
Original
Pharmacokinetics of single-dose morinidazole in patients with severe renal impairment
Hao Zhang, Lu Huang, Yuan-yuan Huang, Bin Yi, Qi Pei, Hong-yi Tan, Jie Huang, Ji-shi Liu, Hong Yuan, and Guo-ping Yang
Price
42.00 $
Page No. 159
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (159-165)
Pharmacokinetics of single-dose morinidazole in patients with severe renal impairment
Hao Zhang2, Lu Huang1,3, Yuan-yuan Huang1, Bin Yi2, Qi Pei1, Hong-yi Tan1, Jie Huang1, Ji-shi Liu2, Hong Yuan1, and Guo-ping Yang1
1Center of Clinical Pharmacology, 2Department of Nephrology, the Third Xiangya Hospital, and 3College of Pharmacy, Central South University, Changsha, Hunan, China
Objective: To evaluate the pharmacokinetics of morinidazole in individuals with severe renal impairment (RI). Methods: This open-label Phase I study enrolled healthy volunteers and patients with severe RI aged 18 – 65 years. All subjects received a single infusion of sodium chloride injection with 500 mg morinidazole. Plasma and urine concentration of morinidazole and one of its metabolites (M4-1) were evaluated by using HPLC-UV and HPLC-MS/MS respectively. Pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.0 software. Results: 22 individuals (healthy: n = 11, severe RI: n = 11) received morinidazole. In both groups, maximum plasma concentration of morinidazole was reached within 1 hour, while the tmax of M4-1 differed greatly. Both AUC0–t and AUC0–∞ of morinidazole were 1.4 times higher in patients with severe RI, while M4-1 were over 7 times higher than healthy groups. Renal excretion of unchanged morinidazole was decreased by 65% in patients with RI, and M4-1 was decreased by 72%. Apparent correlation between CLcr and CL, AUC, t1/2 and CLr were seen in two groups. Conclusions: A single dose of 500 mg morinidazole is well tolerated. Changes in pharmacokinetic parameters of morinidazole and M4-1 are seen in patients with RI and may be clinically important.Correspondence to:
Prof. Guoping Yang
Center of Clinical Pharmacology, Third Xiangya Hospital
Central South University
Changsha, Hunan 410013, China
Email: [email protected]
Original
Pharmacokinetics of teriparatide after subcutaneous administration to volunteers with renal failure: a pilot study
Hiromitsu Imai, Makoto Watanabe, Tomoe Fujita, Hiroshi Watanabe, Kazuhiro Harada, Takashi Moritoyo, and ANTCliPh(Academic Network for Trials in Clinical Pharmacology) Trial 04 Study Group
Price
42.00 $
Page No. 166
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (166-174)
Pharmacokinetics of teriparatide after subcutaneous administration to volunteers with renal failure: a pilot study
Hiromitsu Imai1, Makoto Watanabe2, Tomoe Fujita3, Hiroshi Watanabe4, Kazuhiro Harada5, Takashi Moritoyo6, and ANTCliPh(Academic Network for Trials in Clinical Pharmacology) Trial 04 Study Group*
1Department of Clinical Pharmacology and Therapeutics, Oita University, Faculty of Medicine, Oita, 2Department of Cardiology, Showa University School of Medicine, Tokyo, 3Clinical Trial Center, Kitasato University, East Hospital, Kanagawa, 4Department of Clinical Pharmacology and Therapeutics, Hamamatsu University, School of Medicine, Shizuoka, 5Department of Internal Medicine, Kasaoka Daiichi Hospital, Okayama, and 6Department of Therapeutic Medicine, Ehime University, Graduate School of Medicine, Ehime, Japan
Background and objective: Teriparatide acetate was developed in the form of a synthetic analogue of the Nterminal peptide (1-34) of human parathyroid hormone for the treatment of osteoporosis; it is administered subcutaneously once weekly. However, it is not known whether the pharmacokinetics (PK) of this drug is affected by renal impairment, and this study was conducted to look into this question. Methods: A multi-center study was conducted at six hospitals in Japan. Subjects were enrolled and grouped on the basis of renal function stratified as: normal function to mild renal impairment (estimated GFR(e-GFR): ≥ 60.0 mL/min/1.73 m2) (8 subjects), moderate impairment (eGFR: 30.0 – 59.9 mL/min/1.73 m2) (5 subjects), and severe impairment (eGFR: 15.0 – 29.9 mL/min/1.73 m2) (5 subjects). The PK parameters, blood and urine electrolytes concentrations, and safety profiles were assessed following a single subcutaneous injection of teriparatide acetate (56.5 μg as teriparatide). Results: The elimination half-life (t1/2) and the mean residence time extrapolated to infinity were significantly prolonged in the group with severe renal impairment (t1/2: 5.0 hours) compared with normal to mild and moderate impairment groups (t1/2: 1.5 hours and 1.2 hours, respectively). However, virtually all of the teriparatide was eliminated from the blood after 24 hours. Given that the drug is administered once weekly, it appeared highly unlikely that accumulation of the drug in the body would become a problem even with repeated administration. There were no particular problems with safety or tolerability. Conclusions: In treatment with teriparatide acetate once-perweek formulation, prescription at the usual dosage appears to be appropriate even in renally impaired patients.
*Korou Goto, Tsutomu Kotegawa, Kyoichi Ohashi, Eiji Uchida, Yasuhiko Ikeda, Tatsunori Suzuki, Tomoko Hasunuma, Toshiaki Okumura, Yuji Kumagai, Kazuhiko Takeuchi, Naoki Inui, Takahisa Furuta, Tetsumei Urano, Hideo Mogami, Takayuki Iwaki, Norio Miyashima, Takafumi Okura, Kenichi Miyoshi, Mie Kurata, Jun Irita, Daijiro Enomoto, Bunzo Matsuura, Shinya Furukawa, Akihisa Ueda, Teruki Miyake, Masahiro Nagai, Hiroyoko Moritoyo, Hiroki Shimizu, Mitsuhiro Koizumi, Masahiro NomotoCorrespondence to:
Hiromitsu Imai, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Oita University Faculty of Medicine
Oita, 1-1 Idaigaoka, Hasama, Yufu-city, Oita, 879-5593 Japan
Email: [email protected]
Bioavailability Section
Bioequivalence assessment of two transdermal delivery systems of fentanyl in healthy Chinese volunteers
Ji Liu and Xiao Zhou
Price
42.00 $
Page No. 175
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 2/2014 (175-180)
Bioequivalence assessment of two transdermal delivery systems of fentanyl in healthy Chinese volunteers
Ji Liu and Xiao Zhou
Department of Anesthesia, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
The objective of this study was to investigate the bioequivalence of two formulations (generic preparation and Durogesic patch) of 4.2 mg fentanyl. They were assessed in relative bioavailability in 20 healthy Chinese male volunteers according to a single dose, 2-sequence, crossover randomized design. The two formulations were administered at two treatment days, separated by a washout period of 14 days. Blood samples were collected at specified time intervals over 144 hours post-dosing. Plasma samples were separated and assayed for fentanyl using a sensitive LC-MS/MS method. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The value of two formulations was as follows: Cmax, 0.789 (0.256) and 0.821 (0.278) ng/mL; tmax, 45.3 and 41.2 h; t1/2, 21.5 (8.8) and 22.6 (7.2) h; AUC0–T, 52.5 (18.6) and 55.7 (19.7) ng/mL×h; and AUC0–∞, 54.6 (19.3) and 57.5 (21.1) ng/mL×h, respectively. ANOVA and two one-sided t-test procedures showed no significant difference in log-transformed Cmax, AUC0–T and AUC0–∞ while the 90% confidence interval (CI) of the ratio of the geometric means of their values were also used to assess bioequivalence between the two formulations. Based on these statistical inferences it was concluded that the two formulations exhibited comparable pharmacokinetic profiles and that test formulation is bioequivalent to reference formulation. The point estimate (90% CI) of two formulations was: AUC0–T, 96.7% (85 – 105%); AUC0–∞, 97.5% (89 – 110%); Cmax, 96.2% (91 – 104%); tmax, 97.1% (93 – 101%), respectively.Correspondence to:
Xiao Zhou, MD
Department of Anesthesia, Shanghai Pulmonary Hospital
Tongji University School of Medicine
507 Zheng Min Rd, Yangpu District, Shanghai 200433, P.R. China
Email: [email protected]
