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 (AUC_0–6h) 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 AUC_0–6h on day 1 versus day 14 for both treatment cycles studied. Children who swallowed 13-cisRA capsules (n = 18) achieved higher AUC_0–6h 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 AUC_0–6h 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.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDHf0O
via IFTTT