Pharmacokinetics and pharmacogenetics of 13-cis retinoic acid in Indian high-risk neuroblastoma patients

Abstract

Purpose

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.

Methods

13-cisRA (160 mg/m2/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.

Results

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.

Conclusions

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.

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Acknowledgments

We thank the Terry Fox Foundation for providing financial support through the Tata Memorial Centre intramural grant. The authors are also grateful to UICC for the ICRETT fellowship offered to Dr. Vikram Gota which facilitated his training in HPLC at Northern Institute of Cancer Research. The authors are also thankful to Ms. Julie Errington for imparting this training.

Funding

The study was funded by the Terry Fox Foundation through the Tata Memorial Centre Intramural Grant (Grant No. 716 dated December 21, 2011).

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Correspondence to Vikram Gota.

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Gota, V., Chinnaswamy, G., Vora, T. et al. Pharmacokinetics and pharmacogenetics of 13-cis retinoic acid in Indian high-risk neuroblastoma patients. Cancer Chemother Pharmacol 78, 763–768 (2016). https://doi.org/10.1007/s00280-016-3126-3

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Keywords

  • 13-cis retinoic acid
  • Neuroblastoma
  • Pharmacokinetics
  • Pharmacogenetics
  • Drug formulation