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

Gareth J Veal, Deborah A Tweddle, Johannes Visser, Julie Errington, Helen Buck, Josephine Marange, Jon Moss, Shiju Joseph, Hussain Mulla, Gareth J Veal, Deborah A Tweddle, Johannes Visser, Julie Errington, Helen Buck, Josephine Marange, Jon Moss, Shiju Joseph, Hussain Mulla

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/m2, reduced to 160 mg/m2 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.

Keywords: 13-CRA; liquid; neuroblastoma; pharmacokinetics.

Conflict of interest statement

Hussain Mulla and Josephine Marange are employees of Nova Laboratories Limited. The other authors declare no competing interests.

Figures

Figure 1
Figure 1
Schematic of study design.
Figure 2
Figure 2
Mean (SE) plasma concentration versus time profiles for 13-cis-retinoic acid (13-CRA) (upper panel) and 4-oxo-13-CRA (lower panel). Blue lines are oral liquid, red lines are extracted capsule. Continuous lines are Day 1, interrupted lines are Day 14.
Figure 3
Figure 3
The plots above compare the individual model-predicted AUC(0-12)ss, Cmaxss and Tmaxss (left-to-right) of 13-CRA (upper panel) and 4-oxo-13-CRA (lower panel). Individual values are summarized as vertical box-and-whisker plots, with the box covering the interquartile range (IQR), the median shown by the thick black line and with whiskers extending to 1.5 times the IQR.

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