Effects of Gastric Acid Suppression, Cytochrome P4503A Inhibition and Induction, and Food on the Pharmacokinetics of Tinlarebant in Healthy Adults

Tinlarebant is an oral retinol binding protein 4 antagonist in clinical development for geographic atrophy, an advanced stage of dry age-related macular degeneration, and Stargardt disease, an inherited juvenile-onset macular degeneration. A randomized, open-label, two-period, interaction study in healthy adults was conducted in four parts to determine the effects of gastric acid suppression (omeprazole 40 mg QD), cytochrome P4503A (CYP3A) inhibition (itraconazole 200 mg BD) and induction (rifampin 600 mg QD), and food on the pharmacokinetics of tinlarebant (5 mg single dose). The effects on tinlarebant exposure were quantified by geometric least squares (GLS) mean C_max and AUC_inf ratios, where GLS mean C_max or AUC_inf with potential perpetrator is divided by GLS mean C_max or AUC_inf without potential perpetrator. Steady-state dosing of omeprazole had no effect on tinlarebant exposure (C_max ratio = 1.16 and AUC_inf ratio = 1.03). The C_max and AUC_inf ratios of tinlarebant following itraconazole dosing were 1.29 and 2.42, respectively. Rifampin co-administration decreased tinlarebant C_max and AUC_inf ratios to 0.53 and 0.19, respectively. Compared with the fasting state, taking tinlarebant with food gave C_max and AUC_inf ratios in the range 1.08-1.22. No unexpected safety signals occurred and tinlarebant was well tolerated in all participants. These data show that the pharmacokinetics of tinlarebant is not significantly altered by gastric acid suppression or food. Dosing patients with tinlarebant and strong CYP3A inhibitors is unlikely to compromise safety based on its pharmacokinetic-pharmacodynamic relationships, but tinlarebant should be contraindicated with strong CYP3A inducers due to potential treatment failure.