Non randomized study on the potential of nitisinone to inhibit cytochrome P450 2C9, 2D6, 2E1 and the organic anion transporters OAT1 and OAT3 in healthy volunteers

• Published in: European journal of clinical pharmacology 2019-03, Vol.75 (3), p.313-320
• Main Authors: Huledal, Gunilla, Olsson, Birgitta, Önnestam, Kristin, Dalén, Per, Lindqvist, Daniel, Kruse, Matthias, Bröijersén, Anders
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Chlorzoxazone; Clinical Trial; Cyclohexanones - adverse effects; Cyclohexanones - pharmacokinetics; Cyclohexanones - pharmacology; CYP2D6 protein; Cytochrome; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2E1 - metabolism; Cytochrome P450; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Female; Furosemide; Healthy Volunteers; Humans; Isoforms; Male; Metoprolol; Middle Aged; Nitrobenzoates - adverse effects; Nitrobenzoates - pharmacokinetics; Nitrobenzoates - pharmacology; Oats; Organic Anion Transport Protein 1 - antagonists & inhibitors; Organic Anion Transporters, Sodium-Independent - antagonists & inhibitors; Pharmacokinetics; Pharmacology/Toxicology; Substrate Specificity; Substrates; Tolbutamide; Urine; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-018-2581-7

Purpose Nitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro . Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms. Methods This was an open-label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUC ∞ ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC-MS/MS. Results Thirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUC ∞ was 2.31 (2.11–2.53) for tolbutamide, 0.95 (0.88–1.03) for metoprolol, 0.73 (0.67–0.80) for chlorzoxazone, and 1.72 (1.63–1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean C av,ss of 94.08 μM. All treatments were well tolerated, and no safety concerns were identified. Conclusions Nitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme. Clinical trial registry identification EudraCT 2016-004297-17.