Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1

Background: Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing. Methods: This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well-controlled patients of <2, 2 to <12, 12 to <18, and ≥18 years of age who were on twice-daily dosing were eligible for participation. Nitisinone and succinylacetone levels were determined from dry blood spots by tandem mass spectrometry. The primary endpoint was C(min) of nitisinone after ≥4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen. Results: In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone C(min) decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) μmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of C(min) decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone. Conclusion: The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1.