Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma - a study of the United Kingdom Children's Cancer Study Group

Abstract

The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m(-2) b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h(-1), apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (P<0.02), with 2.44- and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (mean+/-s.d. 4.67+/-3.17 microM) higher than those of 13-cisRA (2.83+/-1.44 microM) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA.

Figure 1

13-cis-retinoic acid data; study day 1 for all patients shown by course; separate graphs shown by method of administration. Patient 26 received 13cisRA via an NG tube.

Figure 2

13-cis-retinoic acid data; course 2 for all patients shown by study day; separate graphs shown by method of administration. Patient 26 received 13cisRA via an NG tube.

Figure 3

Area under the curve of 13-cisRA observed on day 1 of course 2 of treatment in patients who swallowed 13-cisRA capsules vs those patients for whom the capsules were opened and the contents mixed with food before administration. Median values are identified with a cross.

Figure 4

4-oxo-13-cisRA data; course 2 for all patients shown by study day; separate graphs shown by method of administration. Patient 26 received 13cisRA via and NG tube.