PharmGKB summary

Thorn, Caroline F.; Sharma, Manish; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000292

Cited by 11 publications

(4 citation statements)

References 40 publications

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“…Sunitinib and pazopanib are frequently prescribed tyrosine kinase inhibitors (TKIs) with established exposure-response relationships for renal cell carcinoma ( Houk et al, 2010 ; Suttle et al, 2014 ). Both drugs are predominantly metabolized by CYP3A4 into less active metabolites ( Sugiyama et al, 2011 ; Thorn et al, 2017 ). CYP3A4 ∗ 22 status was associated with a significantly decreased clearance of pazopanib (35%) ( Bins et al, 2019 ) and a decreased clearance of sunitinib (22.5%) ( Diekstra et al, 2014 ) ( Supplementary Table 6 ).…”

Section: Anticancer Agentsmentioning

confidence: 99%

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

et al. 2021

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Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

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Section: Anticancer Agentsmentioning

confidence: 99%

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

et al. 2021

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“…Although several herbs have shown in vitro inhibition of CYP3A4, grapefruit juice and St. John's Wort have proven clinically relevant in vivo interactions with CYP3A4( 18 ). Pazopanib is metabolized in the liver primarily through the CYP3A4 enzyme with a minor contribution from CYP1A2 and CYP2C8( 19 ). Strong inhibitors of CYP3A4 are to be avoided for concurrent use with pazopanib.…”

Section: Discussionmentioning

confidence: 99%

Elderberry interaction with pazopanib in a patient with soft‑tissue sarcoma: A case report and literature review

Agarwal,

Mangla

2024

Mol Clin Oncol

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Elderberry flower extract is marketed as an herbal supplement with purported benefits in boosting the immune system. The use of elderberry increased during the coronavirus pandemic. However, the interaction of elderberry with cytotoxic medicines has remained elusive. Pazopanib is a multikinase inhibitor approved for patients diagnosed with soft-tissue sarcoma. The present study reported on the case of a middle-aged woman diagnosed with localized intermediate-grade sarcoma of the left sartorius muscle who received neoadjuvant pazopanib with radiation therapy. The patient had no other medical comorbidities and only took over-the-counter (OTC) elderberry supplements for numerous years to ‘boost’ her immune system. She started pazopanib at 400 mg per os (PO) daily, which was increased to 800 mg PO daily after a week. By week three on pazopanib, the patient reported intense nausea and a number of loose stools, requiring anti-nausea medication. By the fourth week on pazopanib, laboratory tests showed grade 3 liver injury, as demonstrated by a fivefold rise in liver enzymes along with severe nausea and loose stools. All medications, including elderberry supplement, were stopped. Within two weeks of stopping all medicines, the liver enzymes started normalizing within two weeks and were normal by the end of four weeks. Pazopanib treatment was resumed without the recurrence of side effect. Pazopanib is metabolized in the liver via the cytochrome P 450 (CYP)3A4 enzyme pathway. Hence, potent inhibitors of CYP3A4 are avoided for concurrent use with pazopanib. Small in vitro studies on elderberry extracts have shown weak inhibition of CYP3A4. However, considering the wide usage of elderberry and the availability of mixed supplements OTC, it is essential to pursue clinical studies in cancer patients to understand the interactions of elderberry extracts with cytotoxic medicines. In this report, the scientific evidence behind the use of elderberry was reviewed and a hypothesis of its interaction with pazopanib was proposed.

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“…Furthermore, sorafenib has also been approved for treatment in advanced renal cell carcinoma, imatinib-resistant/-intolerant gastrointestinal stromal tumors and also for certain patients with progressive, well-differentiated pancreatic neuroendocrine tumors. Sorafenib and sunitinib are relatively well-tolerated ( 22 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical observation of apatinib‑related hypothyroidism in patients with advanced malignancies

et al. 2020

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Thyroid dysfunction has been previously reported during treatment with certain small-molecule multi-tyrosine kinase inhibitors, including sunitinib and sorafenib. Apatinib, which has a similar mechanism of action to these inhibitors, has reportedly induced hypothyroidism during treatment. Fully elucidating drug-associated adverse events could aid in patient monitoring and recommendations of suitable management strategies. The current 2-year observational study monitored patients with solid tumors who were prescribed apatinib. A total of 149 patients treated with apatinib from February 2015 to January 2016 were included. Their thyroid function and thyroid ultrastructure was evaluated for at least 24 months or until death. The primary objective of the current study was evaluating accepted thyroid replacement treatment. Secondary objective was ultrastructural changes in the thyroid gland. The current study was approved by the Medical Ethics Committee of Qianfoshan Hospital, affiliated with Shandong University and written informed consent was obtained from all patients prior to commencing the clinical trial. A total of 53 (35.57%) patients developed hypothyroidism, which varied from subclinical (12 cases; 8.05%) to clinical (41 cases; 27.52%). Thyroid nodules were noted in 15 cases (10.07%). Furthermore, 3 cases (2.01%) had thyroid imaging reporting and data system scores of 4a/4b/4c and 12 cases (8.05%) had scores of 1, 2 and 3. A total of 25 patients (16.78%) experienced 1-2 grade fatigue and 2 patients (1.34%) reported 3-4 grade fatigue. There was no reported association between disease control rate and hypothyroidism. Apatinib significantly increased the risk of clinically relevant hypothyroidism and altered thyroid gland structure.

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PharmGKB summary

Cited by 11 publications

References 40 publications

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

Elderberry interaction with pazopanib in a patient with soft‑tissue sarcoma: A case report and literature review

Clinical observation of apatinib‑related hypothyroidism in patients with advanced malignancies

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