Pediatric melanoma—The whole (conflicts of interest) story

Rose, Klaus; Grant‐Kels, Jane M.

doi:10.1016/j.ijwd.2018.10.020

Cited by 27 publications

(70 citation statements)

References 67 publications

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“…Phenotyping measurement is available to assess CYP2D6 activity and allow a safe precision medicine approach. 4 However need for administration of a probe drug and invasive sampling limit its use. Our objective is to evaluate direct measurement of M1/tramadol ratio and pupillometry as phenotyping methods to identify CYP2D6 ultrarapid (UM) and poor (PM) metabolizers in children treated with tramadol.…”

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confidence: 99%

“…Our objective is to evaluate direct measurement of M1/tramadol ratio and pupillometry as phenotyping methods to identify CYP2D6 ultrarapid (UM) and poor (PM) metabolizers in children treated with tramadol. 1 4 and FDA/EMA pediatric reports. [5][6] Results FDA authors express two key assumptions: (1) children, defined as < 17y, need separate proof of efficacy; 1-3 (2) with the exception of chronic myelogenous leukema, the biology of cancer in children is different from adult cancer.…”

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confidence: 99%

“…10 Conclusion FDA representatives augmented the flawed 'therapeutic orphans' concept by additional wrong assumptions about 'paediatric' malignancies´biology. [1][2][3][4] The EMA further expanded the 'Paediatric Imperative'. Also PIPs do not advance treatment.…”

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P83 CYP2D6 phenotyping in children treated with tramadol at the Emergency Department

Rodieux¹,

Storelli²,

Manzano

et al. 2019

Arch Dis Child

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BackgroundPain management is essential and opioids side effects are of major concern. Tramadol safety and efficacy is influenced by CYP2D6 activity. Phenotyping measurement is available to assess CYP2D6 activity and allow a safe precision medicine approach.4 However need for administration of a probe drug and invasive sampling limit its use. Our objective is to evaluate direct measurement of M1/tramadol ratio and pupillometry as phenotyping methods to identify CYP2D6 ultrarapid (UM) and poor (PM) metabolizers in children treated with tramadol.1-6 MethodsWe plan to include 53 children receiving their 1st dose of tramadol at the Emergency Department (ED) of the Geneva Children’s Hospital. Children with concomitant inhibitors/inducers of CYP2D6 and CYP3A or drug with an impact on pupil size are exclude. Standard CYP2D6 phenotyping is performed by measuring blood dextrorphan/dextromethorphan (DOR/DEM) using dried blood spots (DBS) at least 90min after dextromethorphan and tramadol administration. Tramadol and its active metabolite, M1, concentrations are also performed using DBS at the same time. Pupillometry is performed at time of tramadol administration and 1 to twice per hour, during the stay in the ED.ResultsWe included 26 children, median age 10.7 years, of which 2 are UM (8%) and 3 PM (12%), corresponding to what is expected in the Caucasian population. We found a positive correlation between DOR/MED and M1/tramadol ratio (R2= 0.389, p = 0.0006). Pupillometry analyses are in progress. Tramadol 2 mg/kg orally was well tolerated in all children, including UM and PM.ConclusionOur study shows that it is possible to determine CYP2D6 activity in order to provide safe and effective tramadol prescription in children in a less invasive manner than by administering a probe drug, by directly determining the metabolic ratio between tramadol and its metabolite, M1 in children treated with tramadolReferencesFliegert, F., B. Kurth, and K. Gohler, The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status Eur J Clin Pharmacol, 2005. 61(4): p. 257–66.Slanar, O., et al., CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response Eur J Clin Pharmacol, 2006. 62(1): p. 75–6; author reply 77–8.Slanar, O., et al., Miotic action of tramadol is determined by CYP2D6 genotype Physiol Res, 2007. 56(1): p. 129–36.Kirchheiner, J., et al., Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol J Clin Psychopharmacol, 2008. 28(1): p. 78–83.Matouskova, O., et al., Pupillometry in healthy volunteers as a biomarker of tramadol efficacy J Clin Pharm Ther, 2011. 36(4): p. 513–7.Connelly, M.A., et al., Pupillometry: a non-invasive technique for pain assessment in paediatric patients Arch Dis Child, 2014. 99(12): p. 1125–31.Disclosure(s)Nothing to disclose

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P83 CYP2D6 phenotyping in children treated with tramadol at the Emergency Department

Rodieux¹,

Storelli²,

Manzano

et al. 2019

Arch Dis Child

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“…Do they advance pediatric cancer care? Methods We analysed publications of FDA representatives, 1-3 FDA-triggered pediatric oncology studies in the literature and in www.clinicaltrials.gov, 4 and FDA/EMA pediatric reports. [5][6] Results FDA authors express two key assumptions: (1) children, defined as < 17y, need separate proof of efficacy; [1][2][3] (2) with the exception of chronic myelogenous leukema, the biology of cancer in children is different from adult cancer.…”

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confidence: 99%

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P84 Pediatric oncology studies triggered by the united states (US) food and drug administration (FDA) and the european union (EU) european medicines agency (EMA) aim at labels, not at improved treatment. Some harm young patients by exposing them to substandard monotherapy instead of combination treatment

Rose¹

2019

Arch Dis Child

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BackgroundBoth FDA and EMA reward/demand pediatric oncology studies. Do they advance pediatric cancer care?MethodsWe analysed publications of FDA representatives,1–3 FDA-triggered pediatric oncology studies in the literature and in www.clinicaltrials.gov,4 and FDA/EMA pediatric reports.5–6 ResultsFDA authors express two key assumptions: (1) children, defined as < 17y, need separate proof of efficacy;1–3 (2) with the exception of chronic myelogenous leukema, the biology of cancer in children is different from adult cancer.1 FDA-triggered studies investigated single cytoxics agents in heavily pretreated refractory/relapsed patients < 21y.2 4 In these days, combination treatment with up to 13 cytotoxic agents was standard of care.7 Another round of treatment with a single chemotherapy agent did not increase survival, but rewarded companies with patent extension, researchers with publications, the FDA with labeled information. The EU expanded the definition of children to < 18y and demands ‘pediatric investigation plans’ (PIPs) also for rare diseases. One FDA-triggered package investigated ipilimumab in ‘pediatric’ melanoma; 13 EMA PIPs demand ‘pediatric’ studies in solid tumors including melanoma; two ‘pediatric’ monotherapy studies with ipilimumab and vemurafenib, respectively, were terminated in 2016, five others continue recruiting.3 4 8 DiscussionFDA/EMA-requested/demanded ‘paediatric’ oncology studies focus on labels in administratively defined ‘children’. FDA/EMA-used age limits are not physiological. FDA assumptions about different biology of ‘pediatric’ malignancies are incorrect.3 4 8 9 FDA/EMA reports list regulatory, not therapeutic achievements.5–6 Some EU researchers perform predominantly PIP-demanded oncology studies. In a cartel-like cooperation, the EMA demands such studies, threatening non-approval of life-saving drugs. Researchers and EMA representatives co-author lauding reports.10 ConclusionFDA representatives augmented the flawed ‘therapeutic orphans’ concept by additional wrong assumptions about ‘paediatric’ malignancies´ biology.1–4 The EMA further expanded the ‘Paediatric Imperative’. Also PIPs do not advance treatment. Ethics committees should be alerted to re-analyze ongoing ‘pediatric’ studies, suspend questionable ones, and reject new ones. US+EU pediatric laws need revision.ReferencesSnyder KM, et al. The impact of the written request process on drug development in childhood cancer Pediatr Blood Cancer. 2013;60:531–537.Wharton GT, et al. Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy Pediatrics. 2014;134(2):e512–e518.Roberts R, et al. Pediatric Drug Labeling. Improving the Safety and Efficacy of Pediatric Therapies JAMA. 2003;290(7):905–911.Rose K, Grant-Kels JM. Pediatric Melanoma - The Whole (Conflicts Of Interest) Story Int J Womens Dermatol 2018FDA. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. July 2016. Status Report to Congress Department of Health and Human Services.EMA. 10-year Report to the European Commission. General ...

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