Pharmacokinetics and Safety of a Novel Oral Liquid Formulation of 13-cis Retinoic Acid in Children with Neuroblastoma: A Randomized Crossover Clinical Trial

SIMPLE SUMMARY: The availability of a child-friendly drug formulation can be an important determinant of therapeutic success. 13-cis-retinoic acid (13-CRA) is a key component of high-risk neuroblastoma treatment protocols, and yet there is no such formulation available in any country worldwide. Typically, parents have an onerous and potentially hazardous daily task of extracting 13-CRA from capsules. We have developed a novel oral liquid formulation, which is stable and permits accurate daily dosing. This study compared the pharmacokinetics (PK), safety and palatability of the liquid formulation to the current capsule extraction approach to dosing. The liquid formulation demonstrated superior bioavailability, increasing the likelihood of achieving therapeutic levels, which in previous studies had proven difficult with 13-CRA extracted from capsules. The adverse effect profile was as expected for 13-CRA and was similar between the two formulations. Feedback on palatability was good with both dosing approaches, but parents found daily dosing much easier with the liquid formulation. ABSTRACT: (1) Background: 13-cis-retinoic acid (13-CRA) is a key component of neuroblastoma treatment protocols. This randomized crossover study compares the pharmacokinetics (PK), safety and palatability of a novel oral liquid formulation to the current method of extracting 13-CRA from capsules. (2) Methods: Pharmacokinetics was evaluated in two consecutive treatment cycles. Patients were randomized to receive either liquid or capsule formulation on cycle 1 and then crossed over to the alternative formulation on cycle 2. The daily dose was 200 mg/m(2), reduced to 160 mg/m(2) in patients with weight ≤ 12 kg. (3) Results: A total of 20 children, median (range) age 4.3 (1–11.6) y were recruited. Pharmacokinetic data were pooled and a population model describing the disposition of 13-CRA and 4-oxo-13-CRA was developed. Bioavailability of the liquid formulation was estimated to be 65% higher (95% CI; 51–79%) than the extracted capsule. CmaxSS and AUC(0-12)SS estimates were also significantly higher; mean (95% CI) differences were 489 (144–835) ng/mL and 3933 (2020–5846) ng/mL·h, respectively (p < 0.01). There were no significant differences in reported adverse effects. Parents found dosing considerably easier with liquid formulation. (4) Conclusions: The pharmacokinetics, safety and palatability of a new liquid formulation of 13-CRA compares favorably to 13-CRA extracted from capsules. Clinical Trial Registration: clinicaltrial.gov NCT03291080.