Is vinorelbine pharmacokinetics modified in Asian patients when compared to caucasian patients?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13036-e13036
Author(s):  
Pierre Ferre ◽  
Zhimin Shao ◽  
Zefei Jiang ◽  
Dafang Zhong ◽  
Chen Xiaoyan ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Single Agent ◽  
Asian Population ◽  
Two Phase ◽  
Asian Patients ◽  
Phase Ii Studies ◽  
Population Pk ◽  
Caucasian Patients

e13036 Background: Pharmacokinetics (PK) of vinorelbine (VRL) has been extensively studied through a series of clinical studies, mainly conducted in Caucasian patients. Interethnic differences in drug disposition may however induce interethnic variation in drug exposure. Consequently, the PK of VRL was assessed in Asian patients during two clinical studies conducted in China, and compared to previous knowledge from non-Asian patients. Methods: Two phase II studies were conducted in China using VRL on Day 1 and 8 in combination on Day 1 with iv cisplatin for lung cancer (NSCLC) or with epirubicin for breast cancer (ABC). Patients were randomized within each study to receive either iv VRL (25 mg/m2 on cycle 1) or oral VRL. PK samples were obtained from subgroups of patients, and blood VRL and its active metabolite DVRL were quantified through LC-MS/MS. Bayesian PK parameters were calculated and VRL monotherapy results (iv 25 mg/m²; oral 60 mg/m²) were compared to historical single agent data from Caucasian patients. A population PK analysis (Variol P. et al. Eur J Clin Pharmacol, 2002: 58) was conducted to investigate for a potential effect of ethnicity. Results: VRL PK was evaluated in 38 NSCLC and 43 ABC Asian patients. Blood VRL and DVRL concentrations profiles were consistent with those from European studies. In Asian patients, mean Cltot/F (oral VRL) was 138 ± 56.5 and 179 ± 87.3 L/h for NSCLC and ABC, and mean Cltot (iv VRL) was 34.6 ± 8.82 and 41.2 ± 13.5 L/h for NSCLC and ABC. Those results did not differ from a reference European study (Bourgeois H. et al. Cancer Chemother Pharmacol, 2007: 60) (n = 48), for which mean clearance was 144 ± 66.6 and 42.8 ± 12.2 L/h for oral and iv VRL. The population PK analysis (n = 222 and 111 patients for oral and iv route) did not evidence ethnicity as a significant covariate on both clearance and oral bioavailability. Conclusions: The PK results reported from 81 Asian patients having received iv or oral monotherapy VRL treatment are consistent with previous data from European PK studies. This is in line with the metabolism knowledge of VRL, mainly involving esterase and CYP3A4 enzymes, which are not described as highly functionally polymorphic in Caucasian and Asian population.

A Review of Recent Data in the Treatment of Gallbladder Cancer: What We Know, What We Do, and What Should Be Done

2014 ◽  
pp. e165-e170 ◽  
Author(s):  
Bettina G. Müller ◽  
Xabier De Aretxabala ◽  
Manuel González Domingo
Keyword(s):  
Gallbladder Cancer ◽  
Abdominal Mass ◽  
Multidisciplinary Treatment ◽  
Single Agent ◽  
Biliary Tree ◽  
Clinical Entity ◽  
Phase Iii ◽  
Separate Analysis ◽  
Two Phase ◽  
Phase Ii Studies

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.

scholarly journals Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Laura L. Kovanda ◽  
Francisco M. Marty ◽  
Johan Maertens ◽  
Amit V. Desai ◽  
Christopher Lademacher ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Invasive Fungal Disease ◽  
Oral Formulation ◽  
Water Soluble ◽  
Parameter Estimates ◽  
Two Phase ◽  
Population Pk ◽  
The Impact

ABSTRACT Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.

Phase II Trials of Clofarabine in Relapsed or Refractory Pediatric Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 684-684 ◽  
Author(s):  
Sima Jeha ◽  
Bassem I. Razzouk ◽  
Michael E. Rytting ◽  
Paul S. Gaynon ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Median Duration ◽  
Single Agent ◽  
Median Number ◽  
Phase Ii Trials ◽  
Open Label ◽  
Two Phase ◽  
Pediatric Leukemia ◽  
Phase Ii Studies

Abstract Background: Clofarabine, a next generation nucleoside analogue, was well tolerated and demonstrated activity in adult and pediatric Phase I trials conducted in heavily pretreated leukemia patients. Multicenter Phase II studies in pediatric leukemia have completed accrual in the US and are reported here. Methods: Two Phase 2, multicenter, open-label studies were conducted with clofarabine in children with refractory or relapsed ALL or AML. Clofarabine was administered intravenously over 2 hours at 52 mg/m2/day for 5 consecutive days. Cycles were repeated every 2 to 6 weeks based on response and toxicity. Results: The studies enrolled 100 patients (60 ALL and 40 AML). Currently, data are available for 84 patients (49 ALL, 35 AML). Median age is 12 years (range 1 to 22 years) and median number of prior regimens is 3 (range 1 to 6). Thirty-nine percent had received prior bone marrow transplant (BMT). As determined by independent review, preliminary data indicate overall response rates of 31% in ALL (6 CR, 4 CRp, and 5 PR) and 26% in AML (1 CRp and 8 PR). Median duration of remission for ALL is 9.7 weeks (range 1.0 to 28.6) and for AML is 16.2 weeks (range 1.7 to 56.6+). Thirteen of 24 responding patients (54%) proceeded to BMT. Median survival was 42 weeks (range 7.0 to 63.1+) for responding ALL patients (CR+CRp+PR) and 39 weeks (range 7.7 to 93.6+) for responding AML patients (CRp+PR). Patients who failed treatment or were non-evaluable had shorter median survival; 7.4 weeks (range 0.9 to 40.1+) and 12.4 weeks (range 1.6 to 84.9+) for ALL and AML, respectively. Among the patients who were refractory to the last prior chemotherapy, 7/30 (23%) with ALL and 4/22 (18%) with AML achieved a response with clofarabine. Median duration of remission in these patients is 4.6 weeks (range 2.3 to 24.4+) for ALL and 20 weeks (range 1.7 to 56.6+) for AML. Most drug-related adverse events were transient including febrile neutropenia, diarrhea, nausea/vomiting, fever, skin rash, headache, elevation in liver enzymes and bilirubin, and infusion-related flushing and anxiety. Conclusions: Clofarabine is active as a single agent in pediatric ALL and AML that are refractory to intensive salvage regimens. The overall safety profile is similar to that reported in other pediatric salvage studies. Clofarabine in combination with standard chemotherapy is currently under investigation in children.

Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5045-5045 ◽  
Author(s):  
O. Rixe ◽  
J. Dutcher ◽  
R. Motzer ◽  
G. Wilding ◽  
W. M. Stadler ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Efficacy ◽  
Strong Predictor ◽  
Cell Cancer ◽  
Phase Iii ◽  
Dose Titration ◽  
Two Phase ◽  
Pivotal Phase ◽  
Phase Ii Studies ◽  
Population Pk

5045 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, 3. An association between dBP elevation and clinical outcome has been previously reported (Rini, ASCO. 2008). The objective of this pooled analysis of two phase II mRCC studies was to explore the relationship between PK, dBP, and clinical efficacy. Methods: PK data from two phase II studies in cytokine-refractory mRCC patients (pts) and 8 single-dose healthy volunteer (HV) studies were included (n = 109 mRCC pts and 240 HV) in the population PK analysis; the efficacy analysis included mRCC pts only. PK data was analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability). Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and the dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier analyses. Results: The median overall survival (mOS) for mRCC pts with at least 1 dBP measurement ≥90 mmHg (n = 59) during axitinib therapy was 130 weeks vs. 42 weeks (p < 0.01) for pts without any dBP ≥90 mmHg (n = 50). The mOS of pts with an AUC below the median (605 ng.hr/ml; n = 54) was 69 weeks vs. 88 weeks (p > 0.05) for pts with an AUC above the median (n = 55). Among pts with dBP ≥90 mmHg, mOS was 120 weeks and 131 weeks (p > 0.05) for pts with AUC below and above the median (n = 23 and 36), respectively. Among pts without dBP ≥90 mmHg, mOS was 42 weeks and 43 weeks (p > 0.05) for pts with AUC below and above the median (n = 31 and 19), respectively. An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy. There was no apparent correlation between the AUC and maximum dBP during axitinib therapy. Conclusions: dBP ≥90 mmHg during axitinib therapy is a strong predictor of clinical efficacy in patients with mRCC, and is not merely a reflection of higher axitinib drug levels. These data support an ongoing pivotal phase III trial in previously treated mRCC that incorporates a dose-titration scheme based on patient tolerance and BP. [Table: see text]

scholarly journals Population Pharmacokinetics of Ropeginterferon Alfa-2b: A Comparison Between Healthy Caucasian and Chinese Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Zhu ◽  
Mei-xia Wang ◽  
Zi-ran Li ◽  
Wei Wang ◽  
Xia Su ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Relative Standard Error ◽  
Quasi Equilibrium ◽  
Phase I Clinical Trials ◽  
Two Phase ◽  
Relative Standard ◽  
Population Pk ◽  
Chinese Subjects

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations.Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b.Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations.Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

scholarly journals A Review of Recent Data in the Treatment of Gallbladder Cancer

2016 ◽  
Vol 15 (3) ◽  
pp. 320-325
Author(s):  
Shah Naveed ◽  
Hasina Qari ◽  
Asma Altaf ◽  
Mah Para
Keyword(s):  
Gallbladder Cancer ◽  
Abdominal Mass ◽  
Multidisciplinary Treatment ◽  
Single Agent ◽  
Medical Science ◽  
Clinical Entity ◽  
Phase Iii ◽  
Separate Analysis ◽  
Two Phase ◽  
Phase Ii Studies

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.Bangladesh Journal of Medical Science Vol.15(3) 2016 p.320-325

Identification of High-risk Patients for Implantable Cardioverter–Defibrillator Therapy in Asia

2011 ◽  
Vol 3 (1) ◽  
pp. 77
Author(s):  
Cyril YK Ko ◽  
Jeffrey WH Fung ◽  
◽  
Keyword(s):  
Heart Disease ◽  
Implantable Cardioverter Defibrillator ◽  
Asian Population ◽  
Structural Heart Disease ◽  
Medical Problem ◽  
Western World ◽  
Asian Countries ◽  
Cardioverter Defibrillator ◽  
Asian Patients ◽  
Risk Patients

Sudden cardiac death (SCD) is a serious medical problem worldwide. Multiple landmark studies have demonstrated the benefit of implantable cardioverter–defibrillator (ICD) therapy in preventing SCD in at-risk patients. Although the data available in Asia are limited, the disease pattern seems to be different from that in the western world. The Asian population seems to have a lower incidence of SCD. Coronary heart disease, which is the major underlying cause of SCD in the west, may play a less important role in Asian countries. In addition, non-structural heart disease seems to be a more prevalent cause of SCD in Asia. It is thus questionable whether the results of ICD trials can be applied directly to Asian countries, as most of these trials seldom recruited Asian patients. This article will review SCD in Asia, focusing on the epidemiology and risk factors for SCD in Asia and highlighting some unique features that may be different from those seen in the western world.

scholarly journals A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 204
Author(s):  
Erik Sjögren ◽  
Joel Tarning ◽  
Karen I. Barnes ◽  
E. Niclas Jonsson
Keyword(s):  
Body Composition ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Pediatric Population ◽  
Model Performance ◽  
Vulnerable Population ◽  
Pbpk Modeling ◽  
Malnourished Children ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically-based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on (a) the differences in body composition between healthy and malnourished adults and (b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

The Influence of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor on Stroke Recovery Outcome: A Systematic Review and Meta-analysis

2021 ◽  
pp. 154596832110141
Author(s):  
Xuan Liu ◽  
Jun-Chao Fang ◽  
Xin-Yue Zhi ◽  
Qiu-Yu Yan ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Genetic Model ◽  
Meta Analysis ◽  
Brain Derived Neurotrophic Factor ◽  
Recessive Model ◽  
Stroke Recovery ◽  
Stroke Severity ◽  
Val66met Polymorphism ◽  
Asian Patients ◽  
Caucasian Patients

Background and purpose. A single nucleotide polymorphism at nucleotide 196 (G/A) in the human brain-derived neurotrophic factor ( BDNF) gene produces an amino acid substitution (valine to methionine) at codon 66(Val66Met). It is unclear whether carriers of this substitution may have worse functional outcomes after stroke. We aimed to explore the distribution of Val66Met polymorphism and evaluate the effect of different genotypes on stroke functional recovery. Methods. Several databases were searched using the keywords BDNF or brain-derived neurotrophic factor, codon66, G196A, rs6265, or Val66Met, and stroke. Results. A total of 25 articles were relevant to estimate the distribution of alleles; 5 reports were applied in the meta-analysis to assess genetic differences on recovery outcomes. The genetic model analysis showed that the recessive model should be used; we combined data for AA versus GA+GG (GG—Val/Val, GA—Val/Met, AA—Met/Met). The results showed that stroke patients with AA might have worse recovery outcomes than those with GA+GG (odds ratio = 1.90; 95% CI: 1.17-3.10; P = .010; I2 = 69.2%). Overall, the A allele may be more common in Asian patients (48.6%; 95% CI: 45.8%-51.4%, I2 = 54.2%) than Caucasian patients (29.8%; 95% CI: 7.5%-52.1%; I2 = 99.1%). However, in Caucasian patients, the frequency of the A allele in Iranians (87.9%; 95% CI: 83.4%-92.3%) was quite higher than that in other Caucasians (18.7%; 95% CI: 16.6%-20.9%; I2 = 0.00%). Conclusion. Val66Met AA carriers may have worse rehabilitation outcomes than GA+GG carriers. Further studies are needed to determine the effect of Val66Met polymorphism on stroke recovery and to evaluate this relationship with ethnicity, sex, age, stroke type, observe duration, stroke severity, injury location, and therapies.

scholarly journals Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

2018 ◽  
pp. 1-13 ◽  
Author(s):  
Masayuki Nagahashi ◽  
YiWei Ling ◽  
Tetsu Hayashida ◽  
Yuko Kitagawa ◽  
Manabu Futamura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Ethnic Diversity ◽  
Triple Negative ◽  
Asian Population ◽  
Japanese Patients ◽  
The United States ◽  
The Cancer Genome Atlas ◽  
Cancer Genes ◽  
Asian Patients

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

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