Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

2009 ◽  
Vol 27 (26) ◽  
pp. 4406-4412 ◽  
Author(s):  
Nielka P. van Erp ◽  
Karel Eechoute ◽  
Astrid A. van der Veldt ◽  
John B. Haanen ◽  
An K.L. Reyners ◽  
...  
Keyword(s):  
Drug Targets ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mucosal Inflammation ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Endothelial Growth Factor ◽  
T Haplotype

Purpose To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities: thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome, and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2. Patients and Methods A multicenter pharmacogenetic association study was performed in 219 patients treated with single-agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several nongenetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results The risk for leukopenia was increased when the G allele in CYP1A1 2455A/G (odds ratio [OR], 6.24; P = .029) or the T allele in FLT3 738T/C (OR, 2.8; P = .008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR, 1.74; P = .041) was absent. Any toxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T (OR, 2.39; P = .046) or a copy of TT in the ABCG2 (−15622C/T, 1143C/T) haplotype (OR, 2.63; P = .016) were present. The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G (OR, 4.03; P = .021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR, 2.56; P = .035) was present. Conclusion This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.

Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5006-5006
Author(s):  
N. van Erp ◽  
R. H. Mathijssen ◽  
A. A. van der Veldt ◽  
J. B. Haanen ◽  
A. K. Reyners ◽  
...  
Keyword(s):  
Drug Targets ◽  
Single Agent ◽  
Mucosal Inflammation ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
T Haplotype

5006 Background: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities; thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome and ‘any toxicity according to Common Terminology Criteria > grade 2.’ Methods: A multicenter pharmacogenetic association study was performed in 219 patients treated with single agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several non-genetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results: The risk for leukopenia was increased when the G-allele in CYP1A1 2455A/G (OR = 6.24; p = 0.029) or the T-allele in FLT3 738T/C (OR = 2.8; p = 0.008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR = 1.74; p = 0.041) was absent. ‘Any toxicity > grade 2’ prevalence was increased when the T-allele of VEGFR-2 1191C/T (OR = 2.39; p = 0.046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR = 2.63; p = 0.016) were present. The risk for mucosal inflammation was increased in the presence of the G-allele in CYP1A1 2455A/G (OR = 4.03; p = 0.021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR = 2.56; p = 0.035) was present. Conclusions: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters and drug targets are associated with sunitinib related toxicities. A better understanding of genetic and non-genetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients. [Table: see text]

ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 485-485
Author(s):  
Maria Bassanelli ◽  
Alessandra Felici ◽  
Michele Milella ◽  
Diana Giannarelli ◽  
Silvana Giacinti ◽  
...  
Keyword(s):  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Chi Square ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Chi Square Test ◽  
Grade 3 ◽  
The Individual

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

Evaluation of thyroid-stimulating hormone-increased, hypertriglyceridemia and proteinuria as markers of anlotinib efficacy in advanced soft tissue sarcoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23548-e23548
Author(s):  
Yihebali Chi ◽  
Yang Yao ◽  
Zhiwei Fang ◽  
Shusen Wang ◽  
Gang Huang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Thyroid Stimulating Hormone ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Hand Foot Syndrome ◽  
Endothelial Growth Factor ◽  
Stimulating Hormone

e23548 Background: ALTER0203 was a randomized phase IIB trial (NCT02449343) that demonstrated single-agent activity of anlotinib in advanced STS (aSTS). The primary endpoint progression-free survival (PFS) was met and presented as an oral presentation in 2018 ASCO. The most common adverse events with anlotinib were hypertension (62.66%), thyroid stimulating hormone (TSH) increased (56.33%), hypertriglyceridemia (50%), hand-foot syndrome (48.10%) and proteinuria (36.08%) similar to other vascular endothelial growth factor receptor pathway-targeted therapies. We had evaluated the anlotinib-induced hand-foot syndrome and hypertension with clinical outcome in aSTS patients previously. Here we investigated thyroid stimulating hormone increased, hypertriglyceridemia and proteinuria on clinical outcome in aSTS patients treated with anlotinib. Methods: We conducted a review of patients enrolled in ALTER0203. Median PFS was analyzed in patients with thyroid stimulating hormone increased, hypertriglyceridemia and proteinuria vs patients with no thyroid stimulating hormone increased, hypertriglyceridemia and proteinuria. All analyses were exploratory and required cautious interpretation. Results: A total of 158 patients received anlotinib in the ALTER0203 study. During the study, TSH increased was observed in 89 patients (56.33%). Hypertriglyceridemia was observed in 79 patients (50%). Proteinuria was observed in 57 patients (36.08%). Median PFS was longer in patients with TSH increased vs patients with no TSH increased (8.40 vs 4.23 months, p = 0.015). Patients with any grade TSH increased while on anlotinib had an adjusted hazard ratio for progression of 0.64 compared to those without TSH increased. Also, median PFS was longer in patients with hypertriglyceridemia and proteinuria vs patients with no hypertriglyceridemia and proteinuria (8.43 vs 4.13 months, p = 0.002; 8.40 vs 4.37, P = 0.048). Patients with any grade hypertriglyceridemia and proteinuria while on anlotinib had an adjusted hazard ratio for progression of 0.59 and 0.75 compared to those without hypertriglyceridemia and proteinuria respectively. Conclusions: In this retrospective analyses, TSH increased, hypertriglyceridemia and proteinuria can serve as biomarkers in aSTS patients treated with anlotinib. Clinical trial information: NCT02449343 .

Pharmacogenetics in oncology: Where we stand today?

2016 ◽  
Vol 1 (1) ◽  
pp. 2 ◽  
Author(s):  
Padmaj S. Kulkarni
Keyword(s):  
Drug Targets ◽  
Drug Response ◽  
Chemotherapeutic Drugs ◽  
Nucleotide Polymorphisms ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
A Genome ◽  
The Right ◽  
The Cost

<p>In a given population, there is considerable variation between individuals with regard to response to as well as toxicity of different drugs. The term “Pharmacogenetics” has largely been used in relation to genes determining drug metabolism, while “Pharmacogenomics” is a broader based term that encompasses all genes in a genome that may determine drug response. In oncology, efficacy and safety of many chemotherapeutic drugs show substantial individual and/or population variability. It can be explained, to a great extent, by gene polymorphism encoding drug-metabolizing enzymes, drug transporters, and drug targets which influence the pharmacokinetics and pharmacodynamics and affect clinical outcomes. Single nucleotide polymorphisms (SNPs) are the most studied genetic variants at present due to ease, accuracy, and reduced the cost of processing as well as due to public availability of online resources for SNPs. Candidate genes for a therapeutic and adverse response can be divided into three categories: Pharmacokinetic, receptor/target, and disease-modifying. Many anticancer drugs are evaluated for their variation in response according to germline variations. This information can be easily incorporated in day-to-day practice to improve efficacy and/or safety of these drugs. In the future, advances gained from pharmacogenetics research will provide information to guide doctors in advising just enough of the right medicine to a person – The practice of “personalized medicine.”</p>

Phase I and pharmacokinetic (PK) study of PTK787/ZK222584 (PTK/ZK) plus capecitabine (cape) in patients (Pts) with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3595-3595
Author(s):  
R. L. Schilsky ◽  
D. Geary ◽  
L. Skoog ◽  
A. Desai ◽  
J. Valickas ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Cancer ◽  
Standard Treatment ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Prior Chemotherapy ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Endothelial Growth Factor

3595 Background: PTK/ZK is a small molecule inhibitor of the vascular endothelial growth factor receptor family. Cape is a standard treatment for pts with breast and colon cancer, tumors for which angiogenesis inhibition is beneficial. Therefore, we conducted a phase I study of the combination to determine the maximally tolerated doses (MTD), toxicities and PK interactions. Methods: Eligible pts had advanced cancer with no standard treatment option, Karnofsky performance status (KPS) > 70, and normal organ function. Pts with bone marrow or CNS involvement or who had more than 4 prior chemotherapy regimens were excluded. A dose escalation (dosesc) phase was conducted to determine the MTD followed by a dose expansion (dosexp) phase to assess PK interactions. PTK/ZK was given as a single oral daily doser without interruption and cape was given orally twice daily for 14 of 21 days. Results to Date: 43 pts (30 male, 13 female), median age 61 y (34–78 y) and median KPS 95 (70–100) were enrolled in the dosesc phase. 37 had prior chemotherapy; 5 had radiation only. Diagnoses included colorectal cancer (10), head/neck (7), sarcoma (5), renal (4), stomach/pancreas (3 each) and others (11). 29/43 pts were evaluable for MTD determination and received a total of 145 cycles. Doses of PTK/ZK-cape (mg-mg/m2) were: 750/2,500; 1,000/2,500; 750/2,000; 1,000/2,000; 1,250/2,000. DLT occurred in 1/6 pts (gr 3 fatigue) at 750/2,500; 2/2 pts (≥gr 3 fatigue, hypertension [HTN]) at 1,000/2,500; 0/3 pts at 750/2,000; 2/12 pts (≥ gr 3 dizziness, HTN and seizure) at 1,000/2,000 and in 1/6 (gr 3 proteinuria) pts at 1,250/2,000. 1,250 mg was the highest PTK/ZK dose planned. Other common toxicities in the dosesc phase were hand-foot syndrome (HFS, 93%) and HTN (28%). In the dosexp phase 26 pts (14 M, 12 F) have thus far received 73 cycles at the MTD (1,250/2,000). Median age is 65 y (26–79 y) and median KPS is 80 (70–100). 28/73 cycles were delayed or interrupted for toxicity with gr ≥3 toxicities (# cycles): HFS (7), fatigue (5), increased LFTs (5), HTN (3), DVT/PE (4). 23 pts (17 in dosesc and 6 in dosexp) had response or stable disease longer than 12 weeks. Final results and PK data will be presented. Conclusion: PTK/ZK and cape can be combined without unexpected toxicities. No significant financial relationships to disclose.

scholarly journals Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

2021 ◽  
Vol 12 ◽  
Author(s):  
Gina Mejía-Abril ◽  
Pablo Zubiaur ◽  
Marcos Navares-Gómez ◽  
Gonzalo Villapalos-García ◽  
Manuel Román ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Genetic Polymorphism ◽  
Univariate Analysis ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Pharmacokinetic Variability ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
Individualization Of Therapy

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p &lt; 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p &lt; 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p &lt; 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p &lt; 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

scholarly journals REAL-LIFE CLINICAL UTILITY OF RAMUCIRUMAB FOR THE TREATMENT OF PATIENTS WITH DISSEMINATED GASTRIC ADENOCARCINOMA: PRELIMINARY REVIEW OF THE EXPERIENCE OF BLOKHIN RUSSIAN CANCER RESEARCH CENTRE

2017 ◽  
pp. 30-38 ◽  
Author(s):  
N. S. Besova ◽  
T. A. Titova ◽  
V. A. Gorbunova ◽  
O. O. Gordeeva ◽  
A. A. Tryakin ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Single Agent ◽  
Real Life ◽  
Growth Factor Receptor ◽  
Research Centre ◽  
Combination Group ◽  
Preliminary Review ◽  
National Medical ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Endothelial Growth Factor

Angiogenesis   has  become  an  important  target  in  the  treatment  of  solid  tumors  and  anti-angiogenic   agents   are a  promising  approach  to  cancer  therapy.  Ramucirumab, an  anti-angiogenic   agent   specifically  targeting  vascular endothelial  growth factor receptor-2  (VEGFR-2). In April 2014, the FDA approved ramucirumab as a single  agent  or in combination with paclitaxel  for treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC) that has progressed on or after prior fluoropyrimidine – or platinumcontaining chemotherapy based on data of REGARD and RAINBOW trials.We evaluated the progression free (PFS), overall survival (OS) and safety of ramucirumab in patients (pts) with advanced GC in routine clinical practice From June 2016  to 20 Sep 2017  40 pts with advanced GC were treated with ramucirumab in the second line treatment as single  agent (8 pts) or in combination with paclitaxel  (26 pts) in N.N.Blokhin National medical research center of oncology.Median PFS (MPFS) and median OS (MOS) was 1,8  and 7,6 mons for monotherapy group. For combination group MPFS was 5,02  mons, MOS was not reached. Ramucirumab had an acceptable safety profile Our data are similar to the data of REGARD and RAINBOW trials.

scholarly journals Results of the use of ramucirumab in combination with paclitaxel or ramucirumab monotherapy as the second line treatment in patients with disseminated HER2-negative gastric or cardioesophageal junction adenocarcinoma: experience of N.N. Blokhin russian cancer research center of the ministry of health of Russia

2018 ◽  
pp. 34-40
Author(s):  
N. S. Besova ◽  
T. A. Titova ◽  
E. V. Trusilova ◽  
V. A. Gorbunova ◽  
A. A. Tryakin ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Research Center ◽  
Combination Group ◽  
Line Treatment ◽  
Second Line ◽  
National Medical ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Endothelial Growth Factor

Background.Working out of the second line chemotherapy of advanced gastric adenocarcinoma is a promising approach to cancer therapy. Ramucirumab, an anti-angiogenic agent specifically targeting vascular endothelial growth factor receptor-2 (VEGFR-2). In April 2014, the FDA approved ramucirumab as a single agent or in combination with paclitaxel for treatment of advanced gastric or gastroesophageal junction adenocarcinoma that has progressed on or after prior fluoropyrimidineor platinum containing chemotherapy based on data of REGARD and RAINBOW trials.Materials and Methods: From June 2016 to 15Jan 201837 pts with advanced GC were treated with ramucirumabin the second line treatment as single agent (11 pts) or in combination with paclitaxel (26 pts) in N.N.Blokhin National medical research center of oncology.Results: edian PFS (MPFS) and median OS (MOS) was 1,8 and 7,6 mons for monotherapy group. For combination group MPFS was 4,0mons, MOS -10,6 mons. Ramucirumab had an acceptable safety profileConclusions:ur data are similar to the data of international randomized trials.

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