Volume 53, No. 7/2015(July)
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Original
Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies
Vid Stanulović, Pavla Kadlecová, Romána Zelkó, and Sándor Kerpel-Fronius
Price
42.00 $
Page No. 499
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (499-503)
Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies
Vid Stanulović1, Pavla Kadlecová2, Romána Zelkó3, and Sándor Kerpel-Fronius4
1School of PhD Studies, Semmelweis University, Budapest, 2Aprova CRO, Brno, 3Faculty of Pharmacy, University Pharmacy, Department of Pharmacy Administration, and 4Faculty of Medicine, Institute of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
Objective: Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts. Methods: Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time. Results: Until December 31, 2013 inclusive, 76 Medwatch alerts for therapeutic monoclonal antibodies were reported: 43 predictable vs. 33 unpredictable. Predictable alerts were reported at a median (IQR) of 41 (19 – 77) months after approval vs. 53 (23 – 73) months for the unpredictable alerts. The mean (SE) was 52.07 (6.69) months and 55.91 (7.06) months for the predictable and unpredictable, respectively. Although the difference of 12 months between medians of time to alert was observed, the difference was not demonstrated as significant. Cumulative frequency curves show that predictable alerts were detected sooner until month 73 after approval, when ~ 80% of alerts were detected. Immunological reactions (such as infusion reactions, anaphylaxis, and reactions duer to antibodies) were identified early; all 12 such alerts were released before the curves of cumulative frequencies cross at month 73. On the other hand, reactions occurring after the curves cross are predominantly late-occurring cancers and opportunistic infections. Conclusions: The results imply that focus on predictable reactions defined as potential risks may play a role in early detection of important safety concerns.Correspondence to:
Vid Stanulović
Semmelweis University School of PhD Studies
Üllői u. 26, 1085 Budapest, Hungary
Email: [email protected]
Original
Clinical relevance of genetic polymorphism in CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance
Shazia Kousar, Zahoor A. Wafai, Mushtaq A. Wani, Tariq R. Jan, and Khurshid I. Andrabi
Price
42.00 $
Page No. 504
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (504-516)
Clinical relevance of genetic polymorphism in CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance
Shazia Kousar1, Zahoor A. Wafai1, Mushtaq A. Wani2, Tariq R. Jan3, and Khurshid I. Andrabi4
1Department of Clinical Pharmacology, 2Department of Neurology, SKIMS, Soura, 3Department of Statistics, University of Kashmir, Hazratbal, and 4Department of Biotechnology, Science Block, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India
Aims and objectives: Variations in drug metabolizing genes are known to have a clinical impact on AED therapy. We genotyped normal and epileptic patient cohorts of monoethnic population of Kashmir valley for CYP2C9 gene and allelic polymorphism and investigated the effect of CYP2C9*2 and *3 polymorphism on the Pharmacokinetic and therapeutic and/or adverse pharmacodynamic responses to Phenytoin in the idiopathic epilepsy patients. Methods: PCR-RFLP methods were used for genotyping of 121 normal controls and 92 idiopathic epilepsy patients for CYP2C9*2 and *3 polymorphism, the results were validated by direct sequencing. Phenytoin pharmacokinetic (PK) analysis in idiopathic epilepsy patients was done using a validated EMIT assay technique. Pharmacodynamic analysis was done by evaluating clinical response to phenytoin therapy and ADR monitoring. Results: The respective frequencies of CYP2C9 *1, *2, and *3 alleles were 64%, 6.6%, 29.3%, and 58%, 9.8%, 32.6% in controls and idiopathic epilepsy patients from Kashmir valley. PK analysis revealed that AUC0–4 was a better surrogate biomarker of CYP2C9 metabolizer status compared to C4 and C0 concentrations alone. A comparison of “phenytoin response categories” among CYP2C9 Wild and Heterozygous groups did not reveal any significant difference between the groups (p = 0.3800). Conclusion: CYP2C9* 3 was the most frequent mutant allele found in healthy controls and idiopathic epilepsy patients of ethnic Kashmiri population. CYP2C9 genotype based phenytoin therapy is highly relevant in Kashmiri population due to a high incidence of genetic variations associated with therapeutic and adverse responses to phenytoin. Phenytoin AUC0–4 tends to correlate better with genetic polymorphism of CYP2C9.Correspondence to:
Dr. Shazia Kousar, PhD
Department of Clinical Pharmacology, SKIMS, Soura
Post Bag No. 27, Srinagar-190011 Kashmir, India
Email: [email protected]
Original
Efficacy and prognosis of neoadjuvant chemotherapy is correlated with breast cancer molecular classification
Xiao-li Dai, Zhong-bao Han, You-tian Yang, Jing Qiu, Yi-fei Liu, and Yi-zhong Feng
Price
42.00 $
Page No. 517
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (517-522)
Efficacy and prognosis of neoadjuvant chemotherapy is correlated with breast cancer molecular classification
Xiao-li Dai1, Zhong-bao Han1, You-tian Yang1, Jing Qiu2, Yi-fei Liu3, and Yi-zhong Feng4
1School of Medicine, Yancheng Health Vocational and Technical College, Yancheng, Jiangsu Province, 2Department of Pathology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng, Jiangsu Province, 3Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, and 4Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, P.R. China
Breast cancer is one of the most common cancers affecting women globally. Recent studies have begun to investigate the possibility of customized treatment options for individuals based on the specific cancer type. Here, we sought to analyze the relationship between the molecular classification of breast cancer and the efficacy and prognosis of neoadjuvant chemotherapy (NCT). The study included 100 breast cancer patients treated with an NCT regimen of epirubicin and docetaxel (ET) who were divided into groups based on cancer subtype (luminal, HER2 over-expression, and basal-like subtype). The nuclear classification, number of NCT cycles, pathological remission rate, and clinical curative effect, as well as the disease-free survival time (DFS) and the overall survival (OS), were compared across groups. The nuclear grade of participants in the basal-like group was significantly higher than those in the other groups but this group had fewer preoperative NCT cycles and lower pathological remission and clinical efficacy (Z = 53.245, 50.077, 62.467, χ2 = 16.082, p < 0.05). The OS and DFS of participants in the luminal subtype group were significantly higher than those in other groups while those in the basal-like subtype group were the lowest. The OS and DFS of participants who achieved pathological complete remission (pCR) through NCT treatment were significantly higher than those of the patients who had not achieved pCR through NCT treatment (χ2 = 9.558, 10.139, p < 0.05). Therefore, we conclude that when NCT (ET regimen) is used in the treatment of breast cancer, the curative effects and prognosis appear to be correlated with the molecular classification of the tumor. Based on these results, clinicians should consider the molecular classification of the individual tumor to design the most effective treatment option.Correspondence to:
Xiao-li Dai
School of Medicine
Yancheng Health Vocational and Technical College
Jiefangnan Road 263, Yancheng City 224006, Jiangsu Province, P.R. China
Email: [email protected]
Original
Effects of renal insufficiency on the elimination of fluorescein lisicol (NRL972), an investigational marker of hepatic transporter function
Christian de Mey, Emil Gatchev, and Boriana Deliyska
Price
42.00 $
Page No. 523
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (523-530)
Effects of renal insufficiency on the elimination of fluorescein lisicol (NRL972), an investigational marker of hepatic transporter function
Christian de Mey1, Emil Gatchev2, and Boriana Deliyska3
1ACPS – Applied Clinical Pharmacology Services, Mainz-Kastel, Germany, 2Department of Clinical Pharmacology & Therapeutics, and 3Department of Nephrology, MHAT “Tsaritsa Yoanna”, Sofia, Bulgaria
Background: NRL972 (Fluorescein Lisicol), a fluorescent-labelled bile salt, is an investigational marker of hepatic biliary transporter function. Objective: To investigate the pharmacokinetics (PK) of NRL972 in patients with severe (SRI: creatinine clearance (CLCr) < 30 mL/min per 1.73 m2 body surface area (BSA)) and mild-to-moderate renal insufficiency (MRI: 30 ≤ CLCr < 80 mL/min) relative to matched controls (CON: CLCr ≥ 90 mL/min). Methods: The plasma and urinary PK of NRL972 were determined after single 2-mg doses of NRL972 administered by 15-second intravenous (IV) injection. The PK were derived noncompartmentally using all data points up to 6 hours after dosing or only using the concentrations at 10 and 30 minutes after injection. Results: 17, 22, and 16 subjects were enrolled in the SRI, MRI, and CON group, respectively. NRL972 was hardly quantifiable in urine in any of the subjects groups. The plasma concentrations of NRL972 declined rapidly after dosing in mostly monoexponential fashion. The decline tended to be faster in patients with renal insufficiency: in SRI patients, the point and 95% confidence interval (CI) estimates of the group ratios (SRI/CON) were 0.691 (CI: 0.517 to 0.925) for the C(30) : C(10) concentration ratio, 0.785 (CI: 0.634 to 0.970) for t1/2, and 1.344 (CI: 1.028 to 1.757) for bodyweight normalized clearance (CL/BW); in MRI patients, the effect was slightly less. Conclusion: Renal insufficiency does not impair the elimination of NRL972; instead, there is a trend of enhanced NRL972 disposition in patients with compromised renal function. Concomitant renal impairment is unlikely to have confounding effects on the evaluation of hepatic function by NRL972 testing.Correspondence to:
PD Dr. med. Christian de Mey
ACPS – Applied Clinical Pharmacology Services
Philippsring 11, 55252 Mainz-Kastel, Germany
Email: [email protected]
Original
Pharmacokinetics and safety of intravenous oseltamivir in infants and children in openlabel studies
Flor M. Muñoz, Evan J. Anderson, Jaime G. Deville, Barry Clinch4 and Mohamed A. Kamal
Price
42.00 $
Page No. 531
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (531-540)
Pharmacokinetics and safety of intravenous oseltamivir in infants and children in openlabel studies
Flor M. Muñoz1, Evan J. Anderson2, Jaime G. Deville3, Barry Clinch4, and Mohamed A. Kamal5
1Department of Pediatrics, Baylor College of Medicine, Houston, TX, 2Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA, 3Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA, 4Roche Products Ltd, Welwyn Garden City, UK, and 5Roche Pharmaceutical Research and Early Development, New York, NY, USA
Objective: Critically ill children with influenza may be unable to swallow or absorb oral drugs. An intravenous (IV) formulation of the antiviral oseltamivir was evaluated in two prospective open-label studies. Methods: Hospitalized children aged < 1 year (NCT01053663) or 1 – 12 years (NCT01033734) with clinical or laboratoryconfirmed influenza, normal renal function, and who are unable to tolerate and/or absorb oral medication were enrolled. Patients received oseltamivir 2 – 3 mg/kg (age < 1 year) or 2.5 – 3 mg/kg (max. 100 mg; age 1 – 12 years) by slow IV infusion twice daily for up to 6 days. Blood samples were taken for pharmacokinetics and nasal swabs taken to monitor viral shedding and resistance (by reverse transcriptase polymerase chain reaction (RTPCR) and culture). Adverse events (AEs) were monitored for 30 days from treatment initiation. Results: 17 children were enrolled (9 aged < 1 year; 8 aged 1 – 12 years). On day 1, 11 patients had laboratory-confirmed influenza. Seven patients switched from IV to oral dosing before the 10th dose. Individual plasma oseltamivir carboxylate exposures (AUClast) ranged from 1,700 to 11,500 h×ng/mL. 23 AEs were reported in 10 patients; 2 were considered treatment-related (rash, infusion site erythema). Eight serious AEs (SAEs) were reported in 7 patients, including 3 deaths in patients aged < 1 year; none were considered treatment-related. Two SAEs caused treatment withdrawal. Six patients had influenza detected on or after day 11 of treatment. The oseltamivir resistance mutation H275Y was detected in three samples from 1 patient with H1N1pdm09 infection. Conclusions: IV oseltamivir was well tolerated in this sample of seriously ill children. The small patient numbers precluded any formal analysis by age group or dose.Correspondence to:
Flor Muñoz, MD
One Baylor Plaza, BCM-280, Houston, TX 77030, USA
Email: [email protected]
Original
Six-month efficacy and safety of amfepramone in obese Mexican patients: a double-blinded, randomized, controlled trial
Herman Soto-Molina, Mariel Pizarro-Castellanos, Juana Rosado-Pérez, Antonio Rizzoli-Córdoba, Eleazar Lara-Padilla, Cecilia Fernández del Valle- Laisequilla, and Juan Gerardo Reyes-García
Price
42.00 $
Page No. 541
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (541-549)
Six-month efficacy and safety of amfepramone in obese Mexican patients: a double-blinded, randomized, controlled trial
Herman Soto-Molina1, Mariel Pizarro-Castellanos2, Juana Rosado-Pérez3, Antonio Rizzoli-Córdoba2, Eleazar Lara-Padilla4, Cecilia Fernández del Valle- Laisequilla4, and Juan Gerardo Reyes-García4
1Universidad Autónoma Metropolitana Xochimilco, México, D.F., 2Dirección de Investigación, Hospital Infantil de México Federico Gómez, México, D.F., 3Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México, D.F., and 4Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, D.F., Mexico
Amfepramone, also known as diethylpropion, is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety during periods greater than 3 months has been scarcely studied. To evaluate the 6-month efficacy and safety of amfepramone treatment in obese adult Mexican patients resistant to diet and exercise, a double-blinded, randomized, and placebocontrolled clinical trial study was designed on 156 volunteers with a body mass index (BMI) greater than 30 kg/m2 and less than 45 kg/m2. Patients were randomized to receive a 75 mg tablet of amfepramone or placebo daily for 6 months. Primary outcome was the absolute body weight loss, whereas secondary outcomes were the percentage of patients who achieved at least 5% or 10% weight loss, as well as the improvement of anthropometric and metabolic parameters. Amfepramone treatment produced a superior efficacy to decrease body weight than placebo at 3 months (–4.9 ± 0.25 kg vs. –0.7 ± 0.32 kg) and 6 months (–7.7 ± 0.52 kg vs. –1.1 ± 0.7 kg). In addition, 64 and 34 patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with 8 and 0 patients on placebo. Amfepramone also significantly improved BMI and waist circumference, but it only showed a favorable tendency in the waist-hip index (WHI), glucose, total cholesterol, lowdensity lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, heart rate, systolic blood pressure, and diastolic blood pressure at 3 and 6 months. Amfepramone produced only mild adverse events, and they were presented in a greater number than placebo only at 3 months, dry mouth being the the main adverse event. Data suggest that amfepramone is effective and well tolerated in obese Mexican patients during a 6-month regimen.Correspondence to:
Gerardo Reyes-García MD, PhD
Sección de Estudios de Posgrado e Investigación
Escuela Superior de Medicina
Instituto Politécnico Nacional
Plan de San Luis y Díaz Mirón s/n,
Col. Casco de Santo Tomas,
Del. Miguel Hidalgo, 11340 México, D.F. Mexico
Email: [email protected]
Original
Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women
Rama Sivasubramanian, Abhijit Chakraborty, Marie-Laure Rouzade-Dominguez, Srikanth Neelakantham, Annamaria Jakab, Tjeert Mensinga, Eric Legangneux, Ralph Woessner, and Mike Ufer
Price
42.00 $
Page No. 550
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (550-556)
Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women
Rama Sivasubramanian1, Abhijit Chakraborty2, Marie-Laure Rouzade-Dominguez3, Srikanth Neelakantham1, Annamaria Jakab3, Tjeert Mensinga4, Eric Legangneux3, Ralph Woessner3, and Mike Ufer3
1Novartis Healthcare Private Limited, Hyderabad, India, 2Novartis Corporation, East Hanover, NJ, USA, 3Novartis Pharma AG, Basel, Switzerland, and 4QPS Clinical Development, Groningen, The Netherlands
Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18 – 40 years. In period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In period 2, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods. Results: The geometric mean ratios of EE Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval (CI): 0.90 – 1.06) and 0.94 (90% CI: 0.86 – 1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75 – 0.87) and 0.68 (90% CI: 0.63 – 0.73), respectively. Conclusions: In conclusion, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.Correspondence to:
Rama Sivasubramanian, PhD
Novartis Healthcare Pvt. Ltd.
Building # 6, Raheja Mind Space,
Hitech City, Madhapur, Hyderabad – 500 081, India
Email: [email protected]
Case Report
Acute alcohol intoxication in a child following ingestion of an ethyl-alcohol-based hand sanitizer
James H. Hertzog and Allison Radwick
Price
42.00 $
Page No. 557
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (557-560)
Acute alcohol intoxication in a child following ingestion of an ethyl-alcohol-based hand sanitizer
James H. Hertzog1,3 and Allison Radwick2
1Department of Pediatrics, Division of Critical Care Medicine and 2Department of Pharmacy, Nemours Children’s Clinic-Wilmington, Alfred I. duPont Hospital for Children, Wilmington, DE, and 3Thomas Jefferson University, Philadelphia, PA, USA
While uncommon, ingestion of ethanol-based hand sanitizers by children may be associated with significant intoxication. We report the case of a 7-year-old with acute alcohol intoxication following hand sanitizer ingestion. Alcohol elimination in this patient followed zero-order kinetics with a clearance rate of 22.5 mg/kg/h, consistent with the limited pharmacokinetic information available for children who experience alcohol intoxication from more traditional sources.Correspondence to:
James H. Hertzog, MD
Department of Pediatrics
Division of Critical Care Medicine
Alfred I. duPont Hospital for Children
1600 Rockland Road, Wilmington, DE, USA
Email: [email protected]
Case Report
Acute severe back pain radiating to the whole body during intravenous administration of amiodarone
Yiwen Yan and Hua Shen
Price
42.00 $
Page No. 561
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (561-562)
Acute severe back pain radiating to the whole body during intravenous administration of amiodarone
Yiwen Yan and Hua Shen
Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Department of International Medical Care Center, Shanghai, China
Amiodarone represents an effective antiarrhythmic drug for cardioversion of recent-onset atrial fibrillation (AF) and maintenance of sinus rhythm. Acute low back and/or epigastric pain has been reported in the medical literature as a rare side effect of amiodarone, but most cases were Europeans, one was Chinese. We present the case of a Japanese patient who experienced acute severe back pain radiating to the whole body a few minutes after intravenous (IV) infusion of amiodarone.Correspondence to:
Hua Shen, MD
International Medical Care Center
Shanghai General Hospital
Jiatong University Medical School
20080 Shanghai, China
Email: [email protected]
Bioavailability Section
Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors
Gerald S. Falchook, Karthik Venkatakrishnan, John Sarantopoulos, Razelle Kurzrock, Alain C. Mita, Siqing Fu, Monica M. Mita, Xiaofei Zhou, Jung Ah Jung, Claudio Dansky Ullmann, Catherine Milch, and Lee S. Rosen
Price
42.00 $
Page No. 563
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (563-572)
Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors
Gerald S. Falchook1*, Karthik Venkatakrishnan2*, John Sarantopoulos3, Razelle Kurzrock4, Alain C. Mita3, Siqing Fu1, Monica M. Mita3, Xiaofei Zhou2, Jung Ah Jung2, Claudio Dansky Ullmann2, Catherine Milch2, and Lee S. Rosen5
1Sarah Cannon Research Institute at HealthONE, Denver, CO, 2Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 3Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center San Antonio, San Antonio, TX, 4Center for Personalized Cancer Therapy and Clinical Trial Office, University of California, San Diego Moores Cancer Center, San Diego, and 5University of California, Los Angeles, Santa Monica, CA, USA
Objectives: Alisertib (MLN8237) is an investigational, oral, smallmolecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients. Materials and methods: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design. Results: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09 – 1.47 (OS, n = 17; PIC, n = 18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI ˃ 1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dosenormalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 – 2.37). Conclusions: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.
*These authors have contributed equally to this workCorrespondence to:
Karthik Venkatakrishnan, PhD
Millennium Pharmaceuticals, Inc.,
a wholly owned subsidiary of
Takeda Pharmaceutical Company Limited
35 Landsdowne Street, Cambridge, MA, 02139, USA
Email: [email protected]
Bioavailability Section
Pharmacokinetic properties and bioequivalence of two irbesartan/ hydrochlorothiazide fixed-dose combination tablets in healthy male Chinese volunteers
Jian Liu, Lihua Wu, Xingjiang Hu, Guolan Wu, Yunliang Zheng, Huili Zhou, You Zhai, Meixiang Zhu, and Jianzhong ShenTu
Price
42.00 $
Page No. 573
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (573-581)
Pharmacokinetic properties and bioequivalence of two irbesartan/ hydrochlorothiazide fixed-dose combination tablets in healthy male Chinese volunteers
Jian Liu, Lihua Wu, Xingjiang Hu, Guolan Wu, Yunliang Zheng, Huili Zhou, You Zhai, Meixiang Zhu, and Jianzhong ShenTu
Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Objectives: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and a branded reference formulation of irbesartan/ hydrochlorothiazide FDC tablets, and to assess the bioequivalence of the two products in healthy Chinese male volunteers. Materials and methods: 24 male healthy volunteers participated in the open-label, single-dose, randomized-sequence, 2-way crossover study. Eligible subjects were randomly assigned (1 : 1) to receive a single 300/12.5-mg dose of either the test or reference formulation followed by a 1-week washout. Blood samples were obtained before (0 hours) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours after dosing. Plasma concentrations of irbesartan and hydrochlorothiazide were analyzed by two separate validated liquid chromatography/tandem mass spectrometric (LC-MS/MS) methods. Results: For irbesartan, the 90% confidence intervals (CIs) of AUC0–t, AUC0–∞, and Cmax were 103.27 – 116.71%, 105.01 – 121.47%, and 84.15 – 96.88%, respectively. For hydrochlorothiazide, the 90% CIs of AUC0–t, AUC0–∞, and Cmax were 96.11 – 109.02%, 95.15 – 107.35%, and 91.66 – 101.40%, respectively. A total of 3 mild AEs were reported in 3 subjects (12.5%). Conclusion: In this study, a single dose (300/12.5-mg) of the test formulation of irbesartan and hydrochlorothiazide FDC tablet in fasting healthy Chinese male volunteers met WHO’s and China’s FDA regulatory criteria for assumption of bioequivalence to the reference formulation based on AUC and Cmax. Both formulations were well tolerated.Correspondence to:
Jianzhong ShenTu, MD
Research Center for Clinical Pharmacy
State Key Laboratory for Diagnosis and Treatment of Infectious Disease
The First Affiliated Hospital, College of Medicine
Zhejiang University
79 Qingchun Road, Hangzhou 310003, China
Email: [email protected]
Bioavailability Section
Online Supplemental material
Solen Pichereau, Xia Zhao, Yimin Cui, Shuai Zhao, Kathrin Hohl, Thomas Meinicke, and Christian Friedrich
Price
42.00 $
Page No. 582
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (582-592)
Online Supplemental material
Solen Pichereau1, Xia Zhao2, Yimin Cui2, Shuai Zhao3, Kathrin Hohl1, Thomas Meinicke1, and Christian Friedrich4
1Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, 2Peking University First Hospital, Beijing, China, 3Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd., Shanghai, China, and 4Bayer HealthCare Pharmaceuticals, Berlin, Germany
Online Supplemental materialCorrespondence to:
Solen Pichereau, PhD
Novartis Institutes for Biomedical Research
Novartis Campus, Fabrikstrasse 28, 4056 Basel, Switzerland
Email: [email protected]
Bioavailability Section
Bioequivalence of budesonide plus formoterol (BF) Spiromax® and BF Turbohaler® (with and without charcoal block) in healthy volunteers
Lori Weisfeld, Youyi Shu, and Tushar P. Shah
Price
42.00 $
Page No. 593
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 7/2015 (593-602)
Bioequivalence of budesonide plus formoterol (BF) Spiromax® and BF Turbohaler® (with and without charcoal block) in healthy volunteers
Lori Weisfeld1*, Youyi Shu2, and Tushar P. Shah2
1Teva Pharmaceuticals USA Inc, Miami, FL, and 1Teva Pharmaceutical Industries Ltd, Frazer, PA, USA
Objective: Budesonide formoterol (BF) Spiromax® is a breath-actuated dry-powder inhaler designed to deliver similar combinations of budesonide and formoterol as Symbicort® Turbohaler®. We performed two studies to demonstrate pharmacokinetic (PK) equivalence of BF Spiromax with BF Turbohaler. Materials and methods: Two single-center, open-label, randomized, 5-period crossover studies were performed. The first study compared BF Spiromax 160/4.5 μg with BF Turbohaler 200/6 μg, while the second study compared BF Spiromax 320/9 μg with BF Turbohaler 400/12 μg. All treatments were administered with and without charcoal. PK parameters were calculated by measuring plasma drug concentrations from blood samples taken pre-dose and up to 24 hours post-dose. Results: In each study, 90 healthy volunteers were randomized. Bioequivalence of BF Spiromax with BF Turbohaler was demonstrated for budesonide and formoterol (AUC0–t and Cmax (90% confidence intervals of the geometric mean between-device ratios for both parameters were within the predefined range of 0.80 – 1.25 in both studies)). Equivalence was observed without use of charcoal (overall absorption post-inhalation) and with charcoal (pulmonary absorption). There were no major differences between treatments in tmax for either budesonide or formoterol. All study treatments were well tolerated (one treatment-emergent adverse event (TEAE) in the medium-dose study and four TEAEs in the high-dose study). Conclusions: These studies indicate that BF Spiromax (± charcoal block) is bioequivalent to BF Turbohaler with respect to the PK parameters assessed. Single doses of BF Spiromax were well tolerated; the overall safety profile of BF Spiromax and BF Turbohaler was similar.
*former employee at the company during the study conductCorrespondence to:
Tushar P. Shah, PhD
Teva Pharmaceutical Industries Ltd
41 Moores Road, Frazer, PA, 19935, USA
Email: [email protected] and [email protected]
Book Review
Pediatric and Adolescent Medicine Series
Barry G. Woodcock and Matitiahu Berkovitch
Page No. 603
Abstract
Pediatric and Adolescent Medicine Series
Barry G. Woodcock and Matitiahu Berkovitch
