Volume 54, No. 9/2016(September)
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Original Research
Pharmacokinetic model analysis of interaction between phenytoin and capecitabine
Shohei Miyazaki, Hiroki Satoh, Masayuki Ikenishi, Miyuki Sakurai, Mutsuaki Ueda, Kaori Kawahara, Rie Ueda, Tohru Ohtori, Kenji Matsuyama, Akiko Miki, Satoko Hori, Eiji Fukui, Eitaro Nakatsuka, and Yasufumi Sawada
Price
42.00 $
Page No. 657
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (657-665)
Pharmacokinetic model analysis of interaction between phenytoin and capecitabine
Shohei Miyazaki1, Hiroki Satoh1, Masayuki Ikenishi2, Miyuki Sakurai3, Mutsuaki Ueda2, Kaori Kawahara3, Rie Ueda3, Tohru Ohtori4, Kenji Matsuyama4, Akiko Miki1, Satoko Hori1, Eiji Fukui3, Eitaro Nakatsuka2, and Yasufumi Sawada1
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 2Department of Pharmacy, Tenri Hospital, Nara, 3Department of Pharmacy, Hyogo Prefectural Amagasaki Hospital, Hyogo, and 4Faculty of Pharmacy, Kinki University, Osaka, Japan
Objective: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. Methods: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. Results: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day–1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. Conclusions: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.Correspondence to:
Yasufumi Sawada, PhD
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Email: [email protected]
Original Research
Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes
Jianguo Li, Weifeng Tang, Robert F. Storey, Steen Husted, and Renli Teng
Price
42.00 $
Page No. 666
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (666-674)
Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes
Jianguo Li1, Weifeng Tang2, Robert F. Storey3, Steen Husted4, and Renli Teng2
1Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca LP, Waltham, MA, 2Clinical Pharmacology, AstraZeneca LP, Gaithersburg, MD, USA, 3Department of Cardiovascular Science, University of Sheffield, Sheffield, UK, and 4Department of Medicine, Hospital Unit West, Herning/Holstebro and Department of Clinical Pharmacology, Institute of Biomedicine, University of Aarhus, Denmark
Objective: Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX. Methods: 32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed. Results: A one-compartment model with population mean PK parameters of firstorder absorption rate constant (0.67/h), apparent systemic clearance (14 L/h), and apparent volume of distribution (221 L) was shown to best describe the PK profile of ticagrelor. Patients co-administered moderate CYP3A inducers or inhibitors increased (by 110%, 95% confidence interval (CI), 52 – 192%) or decreased (by 64%, 95% CI, 39 – 73%) apparent ticagrelor clearance, respectively, while habitual smoking decreased apparent ticagrelor clearance by 22% (95% CI, 19 – 25%). Ticagrelor bioavailability was 21% (95% CI, 19 – 22%) lower at treatment initiation (visit 1) versus subsequent visits. Compared with Caucasian patients, ticagrelor bioavailability was 39% (95% CI, 33 – 46%) higher in Asian patients and 18% (95% CI, 6 – 28%) lower in Black patients. Conclusions: In the current analyses, the population PK models developed for ticagrelor and AR-C124910XX described the data obtained in the DISPERSE-2 and PLATO studies well, and were consistent with previous phase I PK studies.Correspondence to:
Dr. Jianguo Li
Quantitative Clinical Pharmacology
Early Clinical Development
AstraZeneca Pharmaceuticals
35 Gatehouse Drive, Waltham, MA 02451, USA
Email: [email protected]
Original Research
Role of oral propranolol in the treatment of infantile subglottic hemangioma
Xiao-Yan Li, Ying Wang, Lei Jin, and Jia-Rui Chen
Price
42.00 $
Page No. 675
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (675-681)
Role of oral propranolol in the treatment of infantile subglottic hemangioma
Xiao-Yan Li, Ying Wang, Lei Jin, and Jia-Rui Chen
Department of Otolaryngology-Head and Neck Surgery, Children’s Hospital of Shanghai, Shanghai, China
Objective: To determine the efficacy of oral propranolol for the treatment of infantile subglottic hemangioma. Methods: 17 children (13 females and 4 males) with a median age at onset of treatment of 5 months were included in this study. Propranolol was administered after the presence of subglottic hemangioma was confirmed by laryngoscopy and a CT scan of the trachea with contrast. Propranolol was started at 1 mg/kg per day divided into 3 doses. Heart rate and blood pressure were monitored during treatment. If no side effects were observed, then the dose was increased to 1.5 mg/kg per day on the second day. Results: 14 patients (82%) showed clinical improvement within 1 week of treatment initiation. In each of these patients, the diameter of the subglottic stenosis caused by the hemangioma decreased, and the hemangioma became lighter in color. Two children with cutaneous hemangiomata also exhibited significant improvements in their cutaneous lesions after treatment. One patient’s treatment was stopped after 2 weeks for personal reasons (family issue). After treatment cessation, this patient’s respiratory symptoms recurred and increased in severity over the next 2 weeks. The patient was restarted on propranolol, and the symptoms disappeared. One patient only partially responded to propranolol. One patient continued with a tracheostomy for 15 months due to the diffuse nature of the lesion and was just recently decannulated. One patient initially did not respond to propranolol and developed residual disease after open resection; this patient finally responded to propranolol after 6 months of therapy and was recently weaned off the drug. Conclusion: Oral propranolol is a safe and effective treatment for infantile subglottic hemangiomata and may be used as a first-line therapeutic modality.Correspondence to:
Jia-Rui Chen, MD
Department of Otolaryngology-Head and Neck Surgery
Children’s Hospital of Shanghai, Shanghai, China
Email: [email protected]
Original Research
Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod
Jihan Huang, Mengying Li, Yinghua Lv, Juan Yang, Ling Xu, Jingjing Wang, Junchao Chen, Kun Wang, Yingchun He, and Qingshan Zheng
Price
42.00 $
Page No. 682
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (682-692)
Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod
Jihan Huang*, Mengying Li*, Yinghua Lv, Juan Yang, Ling Xu, Jingjing Wang, Junchao Chen, Kun Wang, Yingchun He, and Qingshan Zheng
Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Objective: This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods: In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. Results: The 90% confidence intervals (CIs) for AUC0–12h, AUC0–∞, and Cmax were 97.3 – 118.7%, 96.9 – 118.7%, and 95.1 – 109.8%, respectively, within the 80 – 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. Conclusions: The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special populations.
*Jihan Huang and Mengying Li contributed equally to this work.Correspondence to:
Kun Wang, MD
or
Yingchun He
Center for Drug Clinical Research
Shanghai University of Traditional Chinese Medicine
1200#, Cailun Rd, Pudong New District, Shanghai, 201203, China
Email: [email protected] or [email protected]
Original Research
Effects of paclitaxel liposome and capecitabine in the treatment of advanced gastric cancer by clinical observation
Mingjie Lu, Tongshan Wang, and Jian Wang
Price
42.00 $
Page No. 693
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (693-697)
Effects of paclitaxel liposome and capecitabine in the treatment of advanced gastric cancer by clinical observation
Mingjie Lu*, Tongshan Wang*, and Jian Wang
Department of Oncology, Jiangsu Provincial People’s Hospital, Nanjing, China
Objective: To evaluate the clinical effectiveness and side effects of paclitaxel liposome and capecitabine in the treatment of 34 cases with advanced gastric cancer. Method: For 64 patients with advanced gastric cancer, 30 cases were treated with docetaxel, cisplatin, and 5-fluorouracil (DCF group, control group), and 34 cases were treated with paclitaxel liposome and capecitabine (PC group, experimental group). DCF group: 75 mg/m2 of docetaxel, d1; 20 mg/m2 of cisplatin, d1-5; 350 mg/m2 of 5-fluorouracil, 4 – 6 hours of intravenous drip, d1-5, a cycle of 21 days. PC group: 135 mg/m2 of paclitaxel liposome, d1; 2,000 mg/m2.d of capecitabine, oral dose of twice per day, d1-14, a cycle of 21 days. Result: Control group: the chemotherapy with a total of 122 cycles, with an average of 4.07 cycles; 2 cases of complete remission (CR), 12 cases of partial remission (PR), 7 cases of stable disease (SD), and 9 cases of development of progressive disease (PD); 46.7% of the immediate efficacy (remission rate (RR)), 70% of the disease control rate (DCR), 6.9 months of median PFS, and 12.5 months of median OS. Experimental group: the chemotherapy with a total of 169 cycles, with an average of 4.97 cycles; 14 cases of PR, 9 cases of SD, and 11 cases of PD; 46.7% of the immediate efficacy (RR), 70% of the disease control rate (DCR), 6.9 months of median progression-free survival (PFS), and 12.5 months of median overall survival (OS). There were no remarkable differences in RR, DCR, PFS curve, or OS curve for the two groups. The major toxicity of the two groups was hematological toxicity. The incidence of grade III – IV leucopenia in the control and experimental group was 56.7% and 17.6%, respectively. And the incidence of grade III – IV anemia was 13.3% and 2.9%, respectively. Conclusion: As an ideal schema in first-line therapy for advanced gastric cancer, paclitaxel liposome combined with capecitabine is generally well tolerated in clinical use, and is worth further extension.
*Authors contributed equally.Correspondence to:
Jian Wang
Department of Oncology
Jiangsu Provincial People’s Hospital
Guangzhou Road 300, Nanjing, 210029, China
Email: [email protected]
Original Research
Pharmacokinetics of a nanocrystal-containing megestrol acetate formulation: a single-dose, randomized, open-label, 2-part, 2-period crossover study in healthy Korean subjects
Dong Woo Chae, Hankil Son, Jinju Guk, and Kyungsoo Park
Price
42.00 $
Page No. 698
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (698-704)
Pharmacokinetics of a nanocrystal-containing megestrol acetate formulation: a single-dose, randomized, open-label, 2-part, 2-period crossover study in healthy Korean subjects
Dong Woo Chae1#2, Hankil Son1#2, Jinju Guk1#2, Changhun Park3, and Kyungsoo Park1#2
1Department of Pharmacology, Yonsei University College of Medicine, 2Brain Korea 21 Plus Project for Medical Science, Yonsei University, and 3Clinical Trial Center, Severance Hospital, Seoul, Republic of Korea
Objective: The conventional suspension of megestrol acetate contains micronized megestrol acetate, which was recently discovered to have a disadvantage of decreasing bioavailability when taken in a fasting state. Since megestrol acetate is taken to increase appetite, this property becomes a discouraging factor. To improve upon this, an advanced formulation was developed using a nanocrystal drug-delivery system. This study was conducted to compare the safety and pharmacokinetic characteristics between the conventional formulation of megestrol acetate and a generic version of the advanced formulation containing nanocrystals. Methods: This was a randomized, open-label, 2-period, 2-treatment, crossover, single-dose, 2-part study (part 1 fasting and part 2 fed), conducted in healthy males aged between 20 and 50 years with weight within ± 20% of ideal body weight having no congenital abnormalities or chronic diseases. Different subjects were used in part 1 and part 2, but subjects received a single dose of the reference and test drugs separated by a 14-day washout period. Blood sampling was performed up to 120 hours after dosing using a pre-specified sampling time scheme. Primary pharmacokinetic parameters were Cmax and AUClast of the test and reference formulations of megestrol acetate. Bioequivalence evaluation was based on the standard criterion of 80 – 125% for the 90% confidence interval of geometric mean ratios of test to reference drugs calculated for the pharmacokinetic parameters. To monitor adverse events, both subject interviews and physical examinations were done on a regular time basis. Results: 80 subjects (n = 40 each part) were enrolled, and 79 completed the study. The 90% CIs of the geometric mean ratios of Cmax and AUClast were 4.4625 – 5.6018 and 1.3602 – 1.6418, respectively, for part 1, and 0.9793 – 1.1327 and 0.7721 – 0.8431, respectively, for part 2. No significant difference was discovered in the incidence of adverse events (AEs) when test and reference treated groups were compared. Conclusions: Our findings suggest that the test formulation of megestrol-acetate-containing nanocrystals is better absorbed and has higher bioavailability compared to the reference formulation in a fasting state. This should allow for a lower dose and better patient compliance.
ClinicalTrials.gov identifier: NCT02446353Correspondence to:
Kyungsoo Park, PhD, MD
Department of Pharmacology
Yonsei University College of Medicine
134 Shinchondong, Seodaemun-gu,
Seoul 120-752, Republic of Korea
Email: [email protected]
Original Research
An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects
Xia Chen, Qian Zhao, Jianyan Zhang, Tao Liu, Ji Jiang, and Pei Hu
Price
42.00 $
Page No. 705
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (705-711)
An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects
Xia Chen*, Qian Zhao’, Jianyan Zhang, Tao Liu, Ji Jiang, and Pei Hu
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China
Aim: This study investigated the pharmacokinetics of sitagliptin and metformin after multiple oral doses of the sitagliptin/metformin fixed-dose combination (MK0431A) tablet in healthy Chinese volunteers. Methods: This was a singlecenter, randomized study in 24 healthy adults. Subjects received twice-daily doses of MK0431A 50-mg/500-mg tablet and 50-mg/850-mg tablet for 7 days. Serial blood and urine samples were collected at predefined time points for bioassay of sitagliptin and metformin. Safety was assessed throughout the study. Results: Based on consecutive trough concentrations, the steady states of sitagliptin and metformin were reached after twice-daily administration of MK0431A tablets for 5 days. After the last dose, the mean ± SD (standard deviation) peak sitagliptin concentration of 167.3 – 22.52 and 174.1 ± 22.16 ng/mL was reached in a median tmax of 2.25 – 3 hours. The mean ± SD Cmax of metformin appeared in a median tmax of 1.75 – 2.25 hours at 888.3 ± 195.19 and 1,337 ± 269.19 ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively Mean ± SD AUC0–12h of sitagliptin was between 1,404 ± 147.48 and 1,374 ± 179.12 h×ng/mL, while mean ± SD AUC0–12h of metformin were 6,015 ± 854.98 and 8,587 ± 1,715.93 h×ng/mL with MK0431A 50 mg/500 mg and 50 mg/850 mg, respectively. Approximately 75% sitagliptin and 40% metformin were excreted unchanged in the urine, corresponding to a renal clearance of 17.84 – 18.27 L/h for sitagliptin and 27.11 – 27.94 L/h for metformin. Conclusion: No clinically-significant pharmacokinetic difference was identified between Chinese and foreign healthy volunteers regarding sitagliptin and metformin with multiple doses of MK0431A tablets. The treatments were well tolerated.
*Both authors contributed equally.Correspondence to:
Pei Hu, MD
Clinical Pharmacology Research Center
Peking Union Medical College Hospital
41 Damucang Alley, Xicheng District, Beijing 100032, China
Email: [email protected]
Case Report
Reversible hard palate hyperplasia associated with amlodipine use: case report
Xinwen Wang, Qing Liu, Guangying Dong, and Qintao Wang
Price
42.00 $
Page No. 712
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (712-715)
Reversible hard palate hyperplasia associated with amlodipine use: case report
Xinwen Wang1, Qing Liu1, Guangying Dong2, and Qintao Wang2
1Department of Oral Medicine and 2Department of Periodontology, State Key Laboratory of Military Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, China
Calcium channel blockers (CCBs) are medications often used in the clinical management of hypertension and coronary artery disease. Gingival enlargement is a common side effect of CCB administration with no other oral tissue hyperplasia being reported. Thus, gingival enlargement is considered to be a tissue-specific side effect of CCBs. Here, we report for the first time a case of CCB-related palate hyperplasia in a patient suffering from oral lichen planus and the possible reasons for its occurrence.Correspondence to:
Guangying Dong, DDS, PhD
or
Qintao Wang, DDS, PhD
Department of Periodontology
State Key Laboratory of Military Stomatology
School of Stomatology
the Fourth Military Medical University
145 Changle West Road, Xi’an,
Shaanxi Province, 710032, China
Email: [email protected]
Case
Report
Amoxicillin-induced aseptic meningitis: case report and review of published cases
Viktorija Erdeljić Turk, Iveta Šimić, Ksenija Makar-Aušperger, Matea Radačić-Aumiler
Price
42.00 $
Page No. 716
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (716-718)
Amoxicillin-induced aseptic meningitis: case report and review of published cases
Viktorija Erdeljić Turk1, Iveta Šimić1,2, Ksenija Makar-Aušperger1, Matea Radačić-Aumiler1
1Division of Clinical Pharmacology, Department of Medicine, University Hospital Zagreb and 2Medical School, University of Zagreb, Zagreb, Croatia
Objective: Amoxicillin-induced aseptic meningitis (AIAM) is an extremely rare adverse reaction with only 12 reported cases. The term aseptic meningitis refers to patients who have clinical and laboratory evidence for meningeal inflammation with negative routine bacterial cultures. Since the exact pathogenesis is still unknown and clinical signs and cerebrospinalfluid (CSF) findings vary greatly, AIAM is usually a diagnosis of exclusion. Case summary: We report a clinical case of a patient referred to the clinical pharmacology outpatient clinic for consultation on suspected recurrent AIAM and a review of published cases. Conclusions: This report adds to the evidence-base of AIAM and emphasizes the importance of taking a thorough medication history in individuals with suspected meningitis. Considering the wide utilization of amoxicillin, it is important that healthcare providers are aware of AIAM.
Correspondence to:
Viktorija Erdeljić Turk, MD, PhD
Department of Clinical Pharmacology
Department of Medicine
University Hospital Zagreb
Kišpaticeva 12, 10 000 Zagreb, Croatia
Email: [email protected]
Case Report
Lichenoid drug eruption caused by imatinib mesylate in a Chinese patient with gastrointestinal stromal tumor
Jing-Ru Luo, Xiao-Jun Xiang, and Jian-Ping Xiong
Price
42.00 $
Page No. 719
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (719-722)
Lichenoid drug eruption caused by imatinib mesylate in a Chinese patient with gastrointestinal stromal tumor
Jing-Ru Luo*, Xiao-Jun Xiang*, and Jian-Ping Xiong
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Imatinib mesylate, the first agent approved for the treatment of unresectable or metastatic gastrointestinal stromal tumor, is a tyrosine kinase inhibitor targeting (KIT) and the platelet-derived growth factor receptor-α and -β. However, imatinib administration can be accompanied by various adverse events. Here we report a case of Lichenoid drug eruption (LDE) that appeared 24 weeks after commencement of imatinib in a 73-year-old man with gastrointestinal stromal tumor (GIST). The skin lesions were distributed over his face, trunk and limbs, which improved only after discontinuation of imatinib therapy. To the best of our knowledge, this is the first report of imatinib-induced LDE in the Chinese population.
*Jing-Ru Luo and Xiao-Jun Xiang contributed equally to this work.Correspondence to:
Prof. Jian-Ping Xiong
Department of Oncology
The First Affiliated Hospital of Nanchang University
17 Yongwaizheng Rd., Nanchang 330006, China
Email: [email protected]
Bioavailability Section
Bioequivalence assessment of two pregabalin capsules in healthy Mediterranean Arab volunteers
Abdel Naser Zaid, Naim Kittana, Ayman Mousa, Nadia Ghazal, and Rana Bustami
Price
42.00 $
Page No. 723
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (723-731)
Bioequivalence assessment of two pregabalin capsules in healthy Mediterranean Arab volunteers
Abdel Naser Zaid1, Naim Kittana1, Ayman Mousa2, Nadia Ghazal3, and Rana Bustami4
1Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine, 2R&D Department Avalon Pharma (Middle East Pharmaceutical Industries Co. Ltd.), Riyadh, KSA, 3Naratech Pharma Consultancy, and 4Pharmaceutical Research Unit, Amman, Jordan
Background:Treatment of neuropathic pain has always been challenging, not only from the pharmaco-therapeutic/toxicological point of view, but also due to the unpredictable pharmacokinetic (PK) variations among different generic formulations of the same drug, which require further dose optimization. Objectives: This progressive work aims to evaluate the bioequivalence (BE) of a generic product of 150 mg pregabalin capsule (antineuropathic drug) vs. the reference brand drug Lyrica®. Method: An LC-MS/MS bioanalytical method was developed and validated according to the International Conference on Harmonization (ICH) guidelines in order to be used for the analysis of pregabalin in plasma. BE of capsules was tested by comparison against the reference brand capsules in accordance with the requirements of the declarations of Helsinki, the current Good Clinical Practice (GCP) Guidelines and the ICH. The resulting data were compared against corresponding pregabalin data published on other human races. Results: The relationship between concentration and peak area ratio was found to be linear within the range 0.096 – 6.068 µg/mL for pregabalin. The correlation coefficient (r) was equal to 0.9983. Statistical comparison of the main PK parameters showed no significant difference between test and reference. The mean Cmax values for test and reference were 4.290 and 4.164 µg/mL, and the mean AUC0–last values were 24.275 h×µg/mL and 23.674 h×µg/mL, respectively. The 90% CIs of geometric mean ratios (test/reference) for pregabalin were 100.34 – 104.78%, 100.34 – 104.70%, and 95.65 – 110.96% for AUC0–last, AUC0–∞, and Cmax, respectively, thus fall within the international specified BE limit (80 – 125%). Both products were well tolerated by all the volunteers and there were no significant differences on physical examination or in vital signs and laboratory tests between groups. All volunteers completed the study and were discharged in good health. Conclusion: The tested generic capsules appear to be bioequivalent to the reference brand and are expected to have a similar efficacy and safety profile.Correspondence to:
Abdel Naser Zaid
Prof. of Pharmaceutical Chemistry and Technology
Head of Department of Pharmacy
Faculty of Medicine & Health Sciences
An-Najah National University, Nablus
P.O. Box 7, Palestine
Email: [email protected]
Bioavailability Section
Steady-state bioequivalence 2-way crossover study of two quetiapine prolonged-release 400 mg tablet formulations in normal male and female healthy subjects under fasting conditions
Fethi Trabelsi, Negar Gharavi, Magdalene Kalovidouris, and Martha Nikolaidou
Price
42.00 $
Page No. 732
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 9/2016 (732-742)
Steady-state bioequivalence 2-way crossover study of two quetiapine prolonged-release 400 mg tablet formulations in normal male and female healthy subjects under fasting conditions
Fethi Trabelsi1, Negar Gharavi1, Magdalene Kalovidouris2, and Martha Nikolaidou2
1Bio Pharma Services Inc., Toronto, ON, Canada and 2Pharmathen, Marousi Attica, Greece
Objective: The purpose of this study was to assess bioequivalence between a generic and a brand quetiapine 400 mg prolonged-release (PR) formulation (Pharmathen S.A.; AstraZeneca Seroquel Prolong®) in healthy volunteers under steady-state conditions. Methods: Randomized, open-label, steady-state, 2-way crossover design in 48 subjects under fasting conditions. As a quetiapine dose of 400 mg was suspected to be high when administered to healthy subjects, we proceeded with an innovative design where subjects were titrated up using 150 mg, 200 mg, and 300 mg daily doses; first treatment (days 4 – 9) and second treatment (days 10 – 15), and then a tapering down phase (days 16 – 17). Blood samples were collected in EDTA K2 tubes prior to each dosing and over a 24-hour sampling schedule on days 9 and 15. Quetiapine was measured in plasma using LC-MS/MS assay (range 2.5 – 2,000 ng/mL). Pharmacokinetic analyses were performed using non-compartmental method to evaluate AUCτ, Cmax, and Cmin. ANOVA was performed on the ln-transformed data and 90% confidence interval (90% CI) was determined. Bioequivalence was concluded if the 90% CI of AUCτ, Cmin, and Cmax fell within 80.00 – 125.00%. Results: 46 volunteers completed the study and were included in the analyses. Arithmetic mean (SD) for AUCτ were 7,161.18 (3,687.10) ng×h/mL and 7,184.27 (3,304.29) ng×h/mL, Cmax were 595.61 (345.98) ng/mL and 597.06 (253.67) ng/mL, and Cmin were 119.47 (84.24) ng/mL and 124.22 (137.68) ng/mL, respectively, for the test and reference. All pharmacokinetic parameters met the acceptance criteria as the 90% CI felt within 95.98 – 104.21%, 91.48 – 105.89%, and 86.32 – 104.49% for AUCτ, Cmax, and Cmin, respectively. Both formulations were well tolerated and no serious adverse events were reported. Conclusion: Our innovative design allowed safe administration of quetiapine 400 mg PR daily doses to healthy volunteers. Both Pharmathen and AstraZeneca formulations were well tolerated and bioequivalent under steady-state conditions.
Correspondence to:
Fethi Trabelsi, PhD
Bio Pharma Services Inc.
4000 Weston Road, Toronto, ON, M9L 3A2, Canada
Email: ftrabelsi@
biopharmaservices.com
