title: Pharmacokinetics and pharmacogenetics of 13-cis retinoic acid in Indian high-risk neuroblastoma patients.
abstract: To compare the pharmacokinetics of 13-cis retinoic acid (13-cisRA) between Indian and UK neuroblastoma patients receiving comparable treatment, alongside measures of toxicity and response.
  
  
  
  13-cisRA (160 mg/m(2)/day) was administered to 36 patients ≤16 years in two divided doses. Plasma 13-cisRA concentrations were determined on days 1 and 14 of cycles 1 and 4 of treatment. Area under the plasma concentration-time curve (AUC0-6h) was estimated using non-compartment modelling. Patients were genotyped for UGT2B7, CYP3A5*3, CYP3A7*2 and *2, *3 and *4 variants of CYP2C8.
  
  
  
  Marked inter-patient variability in 13-cisRA pharmacokinetics was observed. There was a trend towards a higher AUC0-6h on day 1 versus day 14 for both treatment cycles studied. Children who swallowed 13-cisRA capsules (n = 18) achieved higher AUC0-6h values compared to those who could not (n = 16) (Mean AUC 21.53 vs. 9.35 µM h, P < 0.05). Patients who were event free at 1 year tended to have higher AUC0-6h on C1D1 compared to those patients who progressed, although this did not reach significance with the number of patients studied (P = 0.08). Similarly, patients who achieved a 13-cisRA C max of ≥2 µM on C1D1 tended to have higher median EFS compared to those who did not (17.0 vs. 8.1 months). UGT2B7, CYP2C8*2/*3/*4 or CYP3A5*3 genotype did not have any effect on 13-cisRA pharmacokinetics.
  
  
  
  Method of administration markedly affects 13-cisRA pharmacokinetics in Indian neuroblastoma patients, supporting similar findings in UK patients. An appropriate oral liquid formulation of 13-cisRA that can be administered to all children with neuroblastoma is urgently needed on an international level.
authors.affiliation: Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Sector '22', Navi Mumbai, 410210, India. vgota76@gmail.com.
authors.forename: Vikram
authors.initials: V
authors.lastname: Gota
authors.affiliation: Department of Pediatric Oncology, Tata Memorial Hospital, Parel, Mumbai, 410210, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Chinnaswamy
authors.affiliation: Department of Pediatric Oncology, Tata Memorial Hospital, Parel, Mumbai, 410210, India.
authors.forename: Tushar
authors.initials: T
authors.lastname: Vora
authors.affiliation: Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Sector '22', Navi Mumbai, 410210, India.
authors.forename: Sanhita
authors.initials: S
authors.lastname: Rath
authors.affiliation: Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Sector '22', Navi Mumbai, 410210, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Department of Clinical Pharmacology, ACTREC, Tata Memorial Center, Kharghar, Sector '22', Navi Mumbai, 410210, India.
authors.forename: Murari
authors.initials: M
authors.lastname: Gurjar
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Veal
authors.affiliation: Department of Pediatric Oncology, Tata Memorial Hospital, Parel, Mumbai, 410210, India.
authors.forename: Purna
authors.initials: P
authors.lastname: Kurkure
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004339:Drug Compounding; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007194:India; D007223:Infant; D015474:Isotretinoin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000970:Antineoplastic Agents; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D015474:Isotretinoin
keywords: 13-cis retinoic acid; Drug formulation; Neuroblastoma; Pharmacogenetics; Pharmacokinetics