Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma

Abstract

Purpose: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high-risk patients with neuroblastoma.

Experimental design: 13-cisRA (160 mg/m(2) or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13-cisRA C(max) of 2 μmol/L, with dose increases of 25% to 50% implemented for patients with C(max) values less than 2 μmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed.

Results: 13-cisRA C(max) values ranged from 0.42 to 11.2 μmol/L, with 34 of 103 (33%) patients failing to achieve a C(max) more than 2 μmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 μmol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a C(max) of 2 μmol/L or more. Significantly, lower C(max) values were observed for patients treated with 5.33 mg/kg versus 160 mg/m(2) (1.9 ± 1.2 vs. 3.1 ± 2.0 μmol/L; mean ± SD; P = 0.023). C(max) was higher in patients who swallowed 13-cisRA capsules as compared with receiving the drug extracted from capsules (4.0 ± 2.2 vs. 2.6 ± 1.8 μmol/L; P = 0.0012). The target C(max) was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 groups, respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters.

Conclusions: Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules.

Figure 1

Effect of CYP2C8*3 (A), CYP2C8*4 (B), CYP3A5*3 (C), CYP3A7*1C (D), CYP3A7*2 (E) and UGT2B7*2 (F) genotypes on peak plasma concentrations of 4-oxo-13-cisRA on day 14 of treatment with 13-cisRA in 73 patients with high-risk neuroblastoma

Figure 2

Peak plasma concentrations (C_max) of 13-cisRA observed with protocol-based dosing and following dose increases to identify an individualized dose for all patients with initial C_max values <2μM (n=20)

Figure 3

Peak plasma concentrations (C_max) of 13-cisRA achieved in patients >12kg treated on a 160mg/m² dosing regimen (n=92) as compared to those <12kg treated on a 5.33mg/kg dosing regimen (n=11) (A) and in patients who swallowed 13-cisRA capsules (n=27) as compared to those patients where the drug was extracted from capsules (n=76) (B)