T0930-13-88 - A Drug-Drug Interaction Study: The Effect of Multiple Doses of Vatiquinone on the Single Dose Pharmacokinetics of Tolbutamide and Omeprazole

Purpose: Vatiquinone (EPI-743, alpha tocotrienol quinone) is an orally bioavailable small molecule being developed for the treatment of mitochondrial diseases and other disorders characterized by high levels of oxidative stress and dysregulation of energy metabolism. Vatiquinone is the quinone oxidation product of alpha-tocotrienol, one of the eight naturally occurring forms of vitamin E, and is a member of the para-benzoquinone class of drugs. Vatiquinone is administered orally, passes into the brain, and works by targeting 15-lipoxygenase, a key enzyme driving the processes of cellular ferroptosis and inflammation. The potential for vatiquinone to inhibit the common CYPs involved with drug metabolism was examined in vitro using human liver microsomes and model substrates for the individual cytochromes of interest. To confirm the relevance of in vitro findings (vatiquinone exhibited direct inhibition of CYP2C9 and CYP2C19), a study to investigate the effect of vatiquinone on the pharmacokinetics (PK) of substrates for CYP2C9 and CYP2C19 in healthy volunteers was conducted.

Methods: An open label, fixed sequence, 2-period, single and multiple dose study was conducted to evaluate the effect of multiple doses of vatiquinone on the PK profile of a combined single dose of tolbutamide (CYP2C9 substrate) and omeprazole (CYP2C19 substrate) in 18 healthy subjects. Subjects who met all entry criteria were enrolled in the study to receive each of the following 2 treatments in a fixed sequence fashion in Periods 1 and 2 under the following fed conditions:

Treatment A: On Day 1, subjects received a single oral dose of 500 mg tolbutamide and 40 mg omeprazole 30 minutes after consuming a medium-fat breakfast on Day 1.

Treatment B: Day 8-13, subjects received multiple oral dosings of 400 mg vatiquinone (tid) from Day 8 to Day 13, 30 minutes after consuming a medium-fat meal, with co-administration of a single oral dose of 500 mg tolbutamide and 40 mg omeprazole on Day 12.

The primary plasma PK parameters of tolbutamide, 4-hydroxy-tolbutamide, omeprazole, and 5-hydroxy-omeprazole (C_max, AUC0_-t, and AUC0_-∞) were calculated for each treatment by non-compartmental methods using Phoenix WinNonlin (version 6.3). Analysis of Variance (ANOVA) was performed to determine the least square geometric means for C_max, AUC0_-t, and AUC0_-∞ for each treatment. For comparison of treatments (ie, with versus without vatiquinone), 90% confidence intervals (CIs) were constructed.

Results: The results of the effect of multiple doses of vatiquinone on the single dose pharmacokinetics of tolbutamide and omeprazole are presented in Table 1 (JPG format file attached).

The 90% CIs of GMR of C_max, AUC_0-t, and AUC0_-∞ for tolbutamide and 4-hydroxy tolbutamide are all within 80.00 – 125.00%, which indicate there is no effect with co-administrated vatiquinone.

The 90% CIs of GMR of AUC_0-t and AUC0_-∞ for omeprazole are within 80.00 – 125.00% with C_max slightly below 80% (78.70 – 112.50%), which indicate there is no significant effect with co-administrated vatiquinone on omeprazole. However, effect is observed for 5-hydroxy omeprazole, as 90% CIs of GMR are all below 80%.

Conclusion: Tolbutamide and 4-Hydroxy Tolbutamide – Co-administration with 400 mg vatiquinone (tid) resulted in no effect on the peak concentration (C_max) and systemic exposures (AUC_0-t and AUC0_-∞) of tolbutamide (a CYP2C9 substrate) and its metabolite, 4-hydroxy tolbutamide.

Omeprazole and 5-Hydroxy Omeprazole – Co-administration with 400 mg vatiquinone (tid) resulted in no significant effect on the peak concentration (C_max) and systemic exposures (AUC0_-t and AUC0_-∞) of omeprazole (a CYP2C19 substrate). However, co-administration with 400 mg vatiquinone (tid) resulted in an approximate 20% decrease on the peak concentration (C_max) and systemic exposures (AUC_0-t and AUC_0-∞) of 5-hydroxy omeprazole.