ABSTRACT
Vatiquinone, a 15‐lipoxygenase (LO) inhibitor, is an orally bioavailable small molecule being developed for the treatment of Friedreich's ataxia, a disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism. This investigation discusses the results of the food effect and three times a day (TID) dosing schedule studies data. The food effect study showed that absorption is significantly enhanced when vatiquinone was administered with fatty meals, either solid or liquid. Mean vatiquinone area under the concentration‐time curve (AUC) values were 22‐fold and 3‐fold higher in subjects who consumed fatty meals and liquid meals, respectively, compared with subjects who fasted. With fatty meals, the intersubject variabilities appeared lower for AUC. The TID dosing study showed that the typical individual pharmacokinetic concentration profile exhibited 3 peaks on both Day 1 and after multiple dosing on Day 6. Vatiquinone exposures, AUC, and maximum concentration (Cmax) appeared to increase from 200 to 400 mg in a dose‐proportional manner with moderate variabilities, ranging from approximately 35% to 65%. The mean Day 6 accumulation ratio (ARAUC) suggested an accumulation ratio of 1.61 and 1.73 for 200 and 400 mg, respectively. The results of both studies support the recommendation of administering vatiquinone TID with fatty meals taken on a convenient dosing regimen.
Keywords: bioavailability, dosing regimen, food effect, rare disease
This investigation discusses two clinical studies. One investigated the effect of fatty meals (≥ 25% fat) on vatiquinone PK exposures, and the other one characterized vatiquinone PK profiles when administered on a TID dosing regimen corresponding to mealtimes. The data support the recommendation of administering vatiquinone with fatty meals (≥ 25% fat) taken conveniently at times corresponding to breakfast, lunch, and dinner.
1. Introduction
Vatiquinone (PTC743, EPI‐743, alpha‐tocotrienol quinone) is an orally bioavailable small molecule being developed by PTC Therapeutics for the treatment of Friedreich's ataxia, a disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism (Enns et al. 2012). High levels of oxygen free radicals can cause an accumulation of lipid peroxides and the depletion of reduced glutathione (GSH; Riederer et al. 1989; Piemonte et al. 2001), triggering a feed‐forward cycle that promotes proinflammatory signaling, additional increases in oxidative stress, and, ultimately, cell death through ferroptosis (Guiney et al. 2017). Vatiquinone is a potent inhibitor of 15‐lipoxygenase (15‐LO), a key enzyme responsible for the formation of lipid peroxides. Inhibition of 15‐LO blocks the accumulation of lipid peroxides and prevents the depletion of GSH, which, in turn, prevents proinflammatory signals, preserves cellular function, and promotes cell survival. In clinical studies, vatiquinone has been found to increase GSH levels and decrease the ratio of oxidized GSH to reduced GSH (OX/GSH), correlating with clinical improvement in disease symptoms and the arrest or reversal of disease progression (Blankenberg et al. 2012; Pastore et al. 2013). The critical role of 15‐LO as a key enzyme in the biological process of ferroptosis has been implicated in central nervous system diseases (Joshi et al. 2015; Guiney et al. 2017).
Vatiquinone crosses the blood–brain barrier and promotes its pharmacological activities by inhibiting 15‐LO (Pastore et al. 2013; Guiney et al. 2017). Data from clinical studies demonstrated long‐term improvement in neurological and neuromuscular function with vatiquinone (TID dosing) in patients with Friedreich’s ataxia. Clinical safety data suggest that vatiquinone is well tolerated, with no dose‐limiting toxicities reported (Zesiewicz et al. 2018). The pharmacokinetics (PK) and pharmacodynamics (PD) of vatiquinone have been evaluated in healthy volunteers and in Phase 2/2b studies in pediatric and adult patients. As mentioned earlier, clinical studies have utilized an increase in GSH and a decrease in OX/GSH as a “redox signature” and surrogate PD marker of 15‐LO inhibition (Pastore et al. 2013). At target PK exposures, a reduction of 96% of the baseline OX/GSH ratio was achieved. A body weight‐based band dosing regimen was developed to allow patients across a broad age range to achieve consistent vatiquinone PK exposures. Patients with 13–25 kg body weight receive 200 mg TID, whereas patients with > 25 kg body weight receive 400 mg TID (Murase et al. 2022).
A human mass balance and metabolite identification study demonstrated that hepatic elimination is the main route of drug elimination. No major metabolite was identified (Ma et al. 2023). As a perpetrator, clinical studies demonstrated a lack of clinically relevant effects of vatiquinone on CYP2C9 (IC50: 3.7 μM), CYP2C19 (IC50: 5.4 μM), and breast cancer resistance protein (BCRP) (IC50: 3.8 μM) substrates (Murase et al. 2022; Lee et al. 2023). As a victim of itraconazole, a CYP3A4 inhibitor, vatiquinone Cmax and AUC0–inf increased by 3.5‐ and 2.9‐fold, respectively. As a victim of rifampin, a strong CYP3A4 inducer, vatiquinone Cmax and AUC0–inf decreased by 0.64‐ and 0.54‐fold, respectively (Lee, Thoolen, et al. 2024). Furthermore, PBPK modeling demonstrated that moderate CYP3A4 inhibitors and inducers have negligible impact on vatiquinone exposures (Lee, Okudaira, et al. 2024).
Vatiquinone is orally administered either in capsule form or as a solution. Fatty food intake is required to enhance the absorption of such lipophilic molecules with low bioavailability. To enhance oral bioavailability, vatiquinone should be administered with food. It is recommended that patients take vatiquinone with fatty meals that consist of at least 25% fat of the total caloric content. With an estimated effective half‐life (T1/2,eff) of approximately 9 hr, a three times a day (TID) dosing regimen is required to maintain therapeutic drug exposures (Lee et al. 2022). It is recommended to administer vatiquinone on TID schedules that coincide with mealtimes (breakfast, lunch, and dinner). This investigation discusses the clinical study data that support the recommendation of administering vatiquinone with fatty meals taken at times corresponding to breakfast, lunch, and dinner. The supportive clinical studies include a vatiquinone food effect study and a 6–6–12‐hr interval TID dosing schedule study.
2. Material and Methods
2.1. Food Effect and TID Scheduling Studies
2.1.1. Ethics
The food effect study was conducted at QPS Bio‐Kinetic (Springfield, MO) in compliance with the Declaration of Helsinki, ICH Guideline for Good Clinical Practice (GCP), and regulatory requirements. Subjects signed the Institutional Review Board (IRB)‐approved informed consent at least 48 hr prior to the start of this study.
The TID scheduling study was conducted in accordance with the protocol and with the consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, and applicable laws and regulations. Prior to patient participation in this study, written informed consent was obtained according to ICH GCP and the regulatory and legal requirements of the participating country.
2.1.2. Study Participants
This food effect study enrolled male and female subjects who were between 18 and 55 years of age, inclusive, with a body mass index (BMI) of 18–32 kg/m2. Subjects were determined to be healthy based on medical history, physical examination, laboratory assessments, a 12‐lead electrocardiogram (ECG), and vital signs at screening. Strong CYP3A4 inhibitors/inducers were prohibited during this study. Other key exclusion criteria included subjects with any current condition or a history of significant endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, immunological, or neurological disorders.
The TID scheduling study enrolled male and female subjects who were between 18 and 55 years of age, inclusive, with a BMI of 18–32 kg/m2. Subjects were determined to be healthy based on medical history, physical examination, laboratory assessments, a 12‐lead ECG, and vital signs at screening. All subjects agreed to the use of contraceptives for the duration of this study and for at least 1 month after the last dose. Subjects must not have participated in any other investigational trial within 28 days prior to study drug administration or have known hypersensitivity to the study drugs or any of their excipients. Strong CYP3A4 inhibitors/inducers were prohibited 30 days prior to check‐in and during this study. Other key exclusion criteria included subjects with any current condition or a history of significant endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, urological, immunological, or neurological disorders with clinical manifestations or a history of gastrointestinal surgery.
2.1.3. Study Design
The food effect study was an open‐label, randomized, 3‐treatment, 3‐way crossover study that aimed to evaluate vatiquinone pharmacokinetics when administered as a single dose of 300 mg (3 × 100 mg capsules) under fasted and fed (with liquid food [PediaSure] or with a fatty meal) conditions. Subjects received the assigned treatment at each visit according to the randomization scheme. A minimum of a 7‐day washout period was included between treatments. Subjects in the fasted treatment group were required to fast for at least 10 hr prior to dosing. Subjects in the fatty meal treatment group ingested their meals within a 30‐min period, followed by study medication, which was taken with 240 mL of water within 15 min after completion of the full meal. Subjects in the liquid meal treatment group ingested the liquid food at the same time as dosing. All subjects fasted for 4 hr after receiving their dose of study medication. Water restriction was implemented 1 hr before and 1 hr after dosing. Subjects in the fatty meal group consumed meals that consisted of approximately 30%–35% of calories from fat and approximately 45%–55% of calories from carbohydrates. Total calories per day were 1890–2420 kcal. Subjects in the liquid meal group consumed one bottle of PediaSure (8 fl oz), which consisted of 240 kcal with 9 kcal that came from fat (12%). PediaSure was tested to provide a meal option for pediatric patients who could not take solid formulations or solid food.
The TID scheduling study was a Phase 1, open‐label, nonrandomized, multiple‐dose study in healthy male and female subjects (Part 1), followed by a single‐dose study in healthy male subjects (Part 2). Part 1 of this study consisted of 2 groups; 8 subjects were enrolled into each group for a total of up to 16 subjects. Four males and 4 females were allocated to each group. Subjects were admitted to the study site on Day 1. From Days 1 to 6, all subjects in Group 1 received a 200‐mg oral dose of vatiquinone administered TID, whereas all subjects in Group 2 received a 400‐mg oral dose of vatiquinone administered TID. The TID dosing schedule was based on a 6‐hr interval that corresponded to the timing of breakfast, lunch, and dinner. The drug was administered within 30 min after consuming fatty meals. Breakfast, lunch, and dinner consisted of meals that had at least 25% fat of the total caloric content. Each fatty meal consisted of 400–500 calories, with 100–125 calories that came from fat.
2.1.4. Pharmacokinetic Sample Collection and Noncompartmental (NCA) Pharmacokinetic Analysis
In the food effect study, blood samples for vatiquinone PK analysis were taken starting on Days 1 and 6 for all treatment groups (fasted, liquid meal, and fatty meal). The collection timepoints were 0 (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hr postdose. Subjects completing at least one period of the study and having at least 5 samples above BQL were included in the analysis. Vatiquinone PK parameters were computed with noncompartmental analysis (NCA) using Phoenix WinNonlin 5.2. PK parameters included Cmax, time to peak concentration (Tmax), terminal elimination rate constant (λz), terminal elimination half‐life (T1/2), and area under the concentration‐time curve from time 0 to time t (AUC0–t ) and from time 0 to infinity (AUC0–∞).
In the TID scheduling study, blood samples for vatiquinone PK analysis were taken after the morning dose on Days 1 and 6 for both treatment groups (200 and 400 mg). The collection timepoints were 0 (predose) and 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 24 hr postdose. Vatiquinone PK parameters were computed using Phoenix WinNonlin 6.3 and employing an NCA of plasma concentration‐time profiles based on actual blood sampling times. PK parameters derived from the analysis included, but were not limited to, Cmax, Tmax, T1/2, AUC0–t , and AUC0–∞. A regression analysis was performed on the terminal linear phase of the semilogarithmic plots of individual concentration‐time data. During the analysis, regressions using at least the last 3 points with nonzero concentrations, then the last 4 points, the last 5 points, and so forth, were repeated. Points prior to Cmax (including Cmax) were not used.
2.1.5. Safety Assessments
In the food effect study, the safety dataset included subjects who received the study drug and had at least one safety assessment postbaseline, was employed in the analysis of tolerability and safety variables. Drug safety was evaluated by predose and postdose assessments, including vital signs (blood pressure, respiratory rate, and heart rate), ECGs, clinical laboratory values (chemistry, hematology, and urinalysis), physical examinations, and monitoring of adverse events (incidence, severity, and relationship). A follow‐up visit occurred 7 days after the last clinic day.
In the TID scheduling study, the safety dataset included subjects who received the study drug and had at least one safety assessment postbaseline, was employed in the analysis of tolerability and safety variables. Drug safety was evaluated by predose and postdose assessments, including vital signs (blood pressure, respiratory rate, and heart rate), ECGs, clinical laboratory values (chemistry, hematology, and urinalysis), physical examinations, and monitoring of adverse events (incidence, severity, and relationship). A follow‐up visit occurred 7 days after the last clinic day.
2.1.6. Statistical Consideration
For both studies, no formal statistics were used to determine the sample size.
2.1.7. Bioanalytical Method
Sample collection: 3 mL human blood specimens for vatiquinone were collected in 3 mL lithium heparin vacutainers under protection from white light. Upon collection, blood vacutainers were covered with amber‐colored bags and harvested to plasma by spinning the blood samples at 1600 g for 10 min at 4°C or at ambient temperature. All drawn blood samples were processed and centrifuged within 45 min of blood collection based on established stability in blood. At least 0.8 mL of plasma from each centrifuged blood sample tube was transferred, using a clean disposable pipette (1 new pipette per sample), into two appropriately labeled plasma amber‐colored cryovials and stored in a freezer maintained at < −70°C in an upright position until analysis.
Bioanalysis: The method involved extraction of 50 μL of lithium heparin human plasma and 50 μL of the internal standard (IS), vatiquinone‐d4, by a protein‐precipitation extraction procedure using cold methanol across a quantitation range of 5.00–1000 ng/mL. The mixture was vortexed and centrifuged, and the supernatant layer was transferred to a clean 1‐mL 96‐well plate where 100 μL of methanol:water (50:50; v/v) was added to all wells and the plate vortexed and centrifuged. A 5‐μL sample of the final extract was injected into an HPLC system and quantified using tandem mass spectrometers. The chromatographic separation was performed using an Acquity UPLC BEH Phenyl Column (1.7 μm, 2.1 mm × 50 mm, Waters Corporation, MA) with water:acetonitrile:1M ammonium acetate:acetic acid (95:5:0.2:0.2 (v:v:v:v)) as mobile Phase A and acetonitrile:1M ammonium acetate:acetic acid (100:0.2:0.2 (v:v:v)) as mobile Phase B under gradients.
The multiple reaction monitoring transition ions were monitored as m/z 423.4→165.1 and m/z 427.4→169.1 for vatiquinone and the IS (vatiquinone‐d4), respectively. Analyte‐to‐IS peak area ratios for the standards were used to obtain a linear calibration curve using 1/x 2‐weighted least squares regression analysis. Owing to the photolabile nature of vatiquinone, the method was validated under yellow light conditions (in the absence of white light). Specimens were stored deep frozen (≤ −70°C) until analysis. The validation study demonstrated that the procedures for the determination of vatiquinone in human lithium heparin plasma were specific, accurate, precise, and reproducible.
3. Results
3.1. Demographics
Subject demographics for both studies are listed in Table 1.
TABLE 1.
Subject demographics for food effect and TID dosing schedule studies.
| Demographic | Statistics | |
|---|---|---|
| Food effect study | ||
| Age (years) | N | 18 |
| Mean (SD) | 34.9 (12.1) | |
| Sex (n, %) | Female | 9 (50%) |
| Male | 9 (50%) | |
| Race (n, %) | White | 16 (88.9%) |
| Black or African American | 2 (11.1%) | |
| Ethnicity (n, %) | Hispanic or Latino | 0 (0.00%) |
| Non‐Hispanic or Latino | 18 (100%) | |
| Height (cm) | N | 18 |
| Mean (SD) | 171.5 (8.7) | |
| Weight (kg) | N | 18 |
| Mean (SD) | 72.4 (14.3) | |
| 6–6–12 hr interval TID dosing schedule study | ||
| Age (years) | N | 16 |
| Mean (SD) | 37.1 (11.8) | |
| Sex (n, %) | Female | 8 (50.0%) |
| Male | 8 (50.0%) | |
| Race (n, %) | Black or African American | 7 (43.8%) |
| White | 6 (37.5%) | |
| Asian | 2 (12.5%) | |
| American Indian or Alaska Native | 1 (6.30%) | |
| Ethnicity (n, %) | Hispanic or Latino | 4 (25.0%) |
| Non‐Hispanic or Latino | 12 (75.0%) | |
| Height (cm) | N | 18 |
| Mean (SD) | 170 (9.34) | |
| Weight (kg) | N | 18 |
| Mean (SD) | 74.2 (12.7) | |
3.2. Food Effect Study
3.2.1. Pharmacokinetic Evaluation
Vatiquinone plasma concentration profiles for each treatment group are shown in Figure 1, and the pharmacokinetic parameters are listed in Table 2.
FIGURE 1.
Mean (SD) vatiquinone plasma concentration versus time profile after a single 300‐mg dose by meal status; top: linear scale, bottom: log scale.
TABLE 2.
Mean (CV%) vatiquinone pharmacokinetic parameters after a single 300‐mg dose by meal status.
| Treatment (N) | Pharmacokinetic parameters | Mean (CV%) |
|---|---|---|
| Fasted (15) | Cmax (ng/mL) | 7.65 (102) |
| Tmax (hr) | 4.00 (2,12) | |
| AUC0–24 (ng·hr/mL) | 42.1 (91) | |
| AUC0‐t (ng·hr/mL) | 55.2 (89) | |
| T1/2 (hr) | 11.5 (10) | |
| CL/F (L/hr/kg) | 515 (16) | |
| Vd/F (L/kg) | 31.6 (26) | |
| Liquid food (18) | Cmax (ng/mL) | 31.2 (150) |
| Tmax (hr) | 5.00 (2, 8) | |
| AUC0–24 (ng·hr/mL) | 144 (170) | |
| AUC0‐t (ng·hr/mL) | 167 (164) | |
| T1/2 (hr) | 13 (54) | |
| CL/F (L/hr/kg) | 304 (84) | |
| Vd/F (L/kg) | 15.8 (79) | |
| Fatty meal (17) | Cmax (ng/mL) | 274 (74) |
| Tmax (hr) | 4.00 (4,12) | |
| AUC0–24 (ng·hr/mL) | 1070 (72) | |
| AUC0‐t (ng·hr/mL) | 1200 (69) | |
| T1/2 (hr) | 13.3 (23) | |
| CL/F (L/hr/kg) | 95.5 (60) | |
| Vd/F (L/kg) | 5.29 (87) |
After a single 300‐mg dose, vatiquinone exhibited an absorption phase followed by multiphasic disposition phases regardless of meal status. Absorption appeared enhanced when vatiquinone was administered with fatty meals, either solid or liquid. After a single 300‐mg dose, vatiquinone absorption was rapid with a median Tmax of 4–5 hr regardless of meal status. The T1/2 also appeared similar among all treatment groups. However, vatiquinone exposures were significantly enhanced when taken with fatty meals, either solid or liquid.
Compared with subjects who fasted, mean vatiquinone Cmax and AUC0–t were 36‐fold and 22‐fold higher, respectively, in subjects who consumed fatty meals, and 4.1‐fold and 3.0‐fold higher, respectively (Table 3), in subjects who consumed liquid meals. The intersubject variabilities of Cmax and AUC0–t were lower with fatty meals.
TABLE 3.
Mean (CV%) vatiquinone pharmacokinetic parameters after a single 300‐mg dose by meal status.
| Pharmacokinetic parameters | N | Mean (CV%) | Fold change from fasted | Fold change from liquid food | |
|---|---|---|---|---|---|
| Fasted | Cmax (ng/mL) | 15 | 7.65 (102) | na | na |
| Tmax (hr) | 15 | 4.00 (2,12) | na | na | |
| AUC0–t (ng·hr/mL) | 15 | 55.2 (89) | na | na | |
| Liquid food | Cmax (ng/mL) | 18 | 31.2 (150) | 4.1 | na |
| Tmax (hr) | 18 | 5.00 (2,8) | 1.3 | na | |
| AUC0–t (ng·hr/mL) | 18 | 167 (164) | 3.0 | na | |
| Fatty meal | Cmax (ng/mL) | 17 | 274 (74) | 36 | 8.8 |
| Tmax (hr) | 17 | 4.00 (4, 12) | 1.0 | 0.8 | |
| AUC0–t (ng·hr/mL) | 17 | 1200 (69) | 22 | 7.2 |
Note: Parameters are presented as arithmetic mean (CV%), except Tmax, which is presented as median (range).
3.2.2. Safety Evaluation
As seen in this study, a single dose of vatiquinone was safe and well tolerated for all treatment groups. Five subjects reported a total of 6 adverse experiences. In the fasted group, one subject (5.9%) reported at least one treatment‐emergent adverse event (TEAE). In the liquid meal group, 5 subjects (27.8%) reported at least one TEAE. In the fatty meal group, 3 subjects (17.6%) reported at least one TEAE. There were no deaths and no serious adverse experiences. All adverse experiences were of mild intensity and resolved during this study. There were no clinically significant findings for laboratory safety values, vital signs, or ECG data.
3.3. 6–6–12 hr Interval TID Dosing Schedule Study Taken With Fatty Meals
3.3.1. Pharmacokinetic Evaluation
Vatiquinone plasma concentration profiles are shown in Figure 2, and the pharmacokinetic parameters are listed in Table 4.
FIGURE 2.
Steady‐state vatiquinone plasma concentration versus time profile after daily TID dosing on a 6–6–12‐hr interval schedule. Top: typical individual (200 mg) vatiquinone concentration on Days 1 and 6; bottom: mean (± SD) vatiquinone concentration by dose groups on Day 6 (log scale).
TABLE 4.
Mean (CV%) vatiquinone pharmacokinetic parameters after a daily 200 or 400‐mg 6–6–12‐hr interval TID dosing schedule for 7 days.
| Parameters | 200 mg (n = 8) | 400 mg (n = 8) |
|---|---|---|
| AUC0–24, hr.ng/mL | 4220 (55.6) | 9820 (35.7) |
| Cavg,24, ng/mL | 176 (55.6) | 409 (35.7) |
| Cmax,24, ng/mL | 768 (63.5) | 1370 (53.6) |
| Tmax,24, hr | 4.99 (3.00–9.00) | 6.47 (4.00–15.0) |
| Tlag, hr | 0 (0–0) | 0 (0–0) |
| ARAUC | 1.61 (37.2) | 1.73 (39.3) |
Abbreviations: ARAUC, accumulation ratio; AUC0–24, area under the concentration‐time curve over the time interval 0–24 hr postdose; Cavg,24, average concentration over 24 hr; CV, coefficient of variation; Tlag, time immediately prior to the first quantifiable concentration.
TID dosing on a 6–6–12‐hr interval schedule exhibited 3 peaks over the course of 24 hr in all subjects. The typical individual PK profile clearly demonstrated 3 peaks that corresponded to the timing of vatiquinone administration during meals (breakfast, lunch, and dinner). The 3 peaks were consistently observed on both Day 1 and after multiple dosing on Day 6. Delayed absorption was observed after the first morning dose in all subjects. The PK profile at steady state (Day 6) suggested that all subjects exhibited multiple peaks over the 24‐hr period. The multiple peaks in the mean PK concentration profile compared to the individual profile on Day 1 appeared flatter (Figure 2, top) due to the variabilities in the timing of the 3 peaks, which became more consistent after dosing for 7 days (Figure 2, bottom).
Vatiquinone exposures, AUC0–24, Cavg,24, and Cmax, appeared to increase from 200 to 400 mg in a dose‐proportional manner. The exposure variabilities were moderate, ranging from approximately 36%–64%. Mean Day 6 ARAUC suggested an accumulation ratio of 1.61 and 1.73 for 200 and 400 mg, respectively.
3.3.2. Safety Evaluation
As seen in this study, a single dose of vatiquinone was safe and well tolerated for all treatment groups. A total of 6 subjects experienced 17 TEAEs. There were 2 subjects in the 200‐mg dose group and 4 subjects in the 400‐mg dose group. There were no serious TEAEs or TEAEs leading to discontinuation or death in this study. All TEAEs were mild in severity. There were no clinically meaningful trends observed in hematology parameters, biochemistry parameters, 12‐lead ECG, vital signs, physical examinations, and other observations related to safety.
4. Discussion
Vatiquinone is an alpha‐tocotrienol quinone that is the molecule derived from the oxidation of alpha‐tocotrienol. The absorption of lipophilic molecules is significantly enhanced in the presence of fatty meals. The lipophilic derivatives are initially incorporated into micelles of dietary lipids, whereas bile acid and salt production are stimulated by fatty foods to aid the emulsification process. The micelles are absorbed at the brush border of the mucosa into the enterocyte and then secreted from the enterocytes into the lymphatic system in the form of chylomicrons. Thereafter, chylomicrons containing the absorbed lipid products enter the lymphatic system rather than the portal blood system and thus avoid first‐pass metabolism by the liver (Reboul 2017).
Vatiquinone is highly lipophilic. The partition coefficient (clogP) is approximately 7.8 and is classified as Biopharmaceutical Class System (BCS) Class 4, one with low solubility and low permeability (Lee et al. 2023). Consistently, the bioavailability of BCS Class 4 drugs is highly enhanced with fatty meals (Singh 1999).
As observed for the fatty and liquid meal treatment groups, meals with fat content reduced the intersubject variability, likely due to the increased solubility provided by the emulsification process. The effect of a liquid nutrition drink such as PediaSure was included in the food effect study because the target patient population may, in the future, include younger patients. Both meals demonstrated significant enhancement in drug bioavailability and, therefore, all subsequent clinical studies were conducted under fed conditions, either with fatty meals or liquid meals for patients who cannot take solid food or capsule formulations.
The dosing frequency of TID dosing schedule was selected based on the vatiquinone drug T1/2 estimated from PK results taken from single‐ and multiple‐dose healthy volunteer and patient studies to target a minimum steady‐state concentration above in vitro EC50. It was determined that the optimal dosing regimen maintains a minimum plasma concentration, Cmin, above the EC50 that corresponds to rescue of fibroblasts derived from FA patients with disorders of oxidative stress. The EC50 is approximately 11 ng/mL (EC50: 24 nM). Population PK simulations demonstrated that TID dosing maintains Cmin above the target EC50 for the duration of the dosing intervals.
The dosing schedule study evaluated vatiquinone PK on Day 1 and at Day 6 after continuous TID dosing. Specifically, this study evaluated a TID dosing schedule of 6–6–12 hr intervals, where the drug administration schedule conveniently corresponded to the timing of breakfast, lunch, and dinner. Meals, rather than snacks, have higher caloric content and, therefore, it is critical to take vatiquinone during mealtimes to maximize drug bioavailability. Because ingesting a fatty meal (≥ 25% fat) is a critical part of enhancing drug bioavailability and achieving therapeutic drug exposures, an optimal TID dosing schedule that further helps to reinforce convenience and compliance should be considered as an integral part of the vatiquinone dosing regimen.
Disclosure
No medical writing support was provided.
Conflicts of Interest
All authors are stockholders of PTC Therapeutics.
Lee, Lucy , Murase Katsuyuki, Thoolen Martin, et al. 2025. Enhanced Vatiquinone Bioavailability With Fatty Meals and Optimal Dosing Schedule Biopharmaceutics & Drug Disposition: 46. no. 5-6), 175–182. 10.1002/bdd.70015.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data used to support the findings of this study are included within the article.
References
- Blankenberg, F. G. , Kinsman S. L., Cohen B. H., et al. 2012. “Brain Uptake of Tc99m‐HMPAO Correlates With Clinical Response to the Novel Redox Modulating Agent EPI‐743 in Patients With Mitochondrial Disease.” Molecular Genetics and Metabolism 107, no. 4 (December): 690–699: Epub ahead of print. PMID: 23084792. 10.1016/j.ymgme.2012.09.023. [DOI] [PubMed] [Google Scholar]
- Enns, G. M. , Kinsman S. L., Perlman S. L., et al. 2012. “Initial Experience in the Treatment of Inherited Mitochondrial Disease With EPI‐743.” Molecular Genetics and Metabolism 105, no. 1 (January): 91–102: Epub ahead of print. PMID: 22115768. 10.1016/j.ymgme.2011.10.009. [DOI] [PubMed] [Google Scholar]
- Guiney, S. J. , Adlard P. A., Bush A. I., Finkelstein D. I., and Ayton S.. 2017. “Ferroptosis and Cell Death Mechanisms in Parkinson’s Disease.” Neurochemistry International 104: 34–48. 10.1016/j.neuint.2017.01.004. [DOI] [PubMed] [Google Scholar]
- Joshi, Y. B. , Giannopoulos P. F., and Praticò D.. 2015. “The 12/15‐Lipoxygenase as an Emerging Therapeutic Target for Alzheimer’s Disease.” Trends in Pharmacological Sciences 36, no. 3: 181–186. 10.1016/j.tips.2015.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee, L. , Ma M., Murase K., Kong R., and Thoolen M.. 2022. “The Clinical Pharmacology of Vatiquinone, a 15‐Lipoxygenase Inhibitor Targeting Inflammation and Oxidative Stress.” Poster presented at Behind the Exhibit Hall (virtual). American Epilepsy Society. [Google Scholar]
- Lee, L. , Murase K., Ma J., and Thoolen M.. 2023. “Clinical Drug‐Drug Interaction Between Vatiquinone, a 15‐Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate.” Clinical Pharmacology in Drug Development 12, no. 3 (March): 279–286. 10.1002/cpdd.1199. [DOI] [PubMed] [Google Scholar]
- Lee, L. , Okudaira N., Murase K., Kong R., and Jones H. M.. 2025. “Determination of Vatiquinone Drug‐Drug Interactions, as CYP450 Perpetrator and Victim, Using Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation.” Journal of Clinical Pharmacology 65, no. 2 (February): 160–169: Epub ahead of print. PMID: 39308341. 10.1002/jcph.6133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee, L. , Thoolen M., Ma J., Kaushik D., Golden L., and Kong R.. 2024. “Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone.” Clinical Pharmacology in Drug Development 13, no. 12 (August): 1283–1290. 10.1002/cpdd.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ma, J. , Lee L., Yao B., et al. 2023. “Absorption, Distribution, Metabolism and Excretion of 14C‐Vatiquinone in Rats, Dogs, and Human Subjects.” Xenobiotica 53, no. 5 (May): 396–411: Epub ahead of print. PMID: 37552765. 10.1080/00498254.2023.2245459. [DOI] [PubMed] [Google Scholar]
- Murase, K. , Lee L., Ma J., Barrett R., and Thoolen M.. 2022. “Evaluation of Vatiquinone Drug‐Drug Interaction Potential In Vitro and in a Phase 1 Clinical Study With Tolbutamide, a CYP2C9 Substrate, and Omeprazole, a CYP2C19 Substrate, in Healthy Subjects.” European Journal of Clinical Pharmacology 78, no. 11 (November): 1823–1831. 10.1007/s00228-022-03393-0. [DOI] [PubMed] [Google Scholar]
- Pastore, A. , Petrillo S., Tozzi G., et al. 2013. “Glutathione: A Redox Signature in Monitoring EPI‐743 Therapy in Children With Mitochondrial Encephalomyopathies.” Molecular Genetics and Metabolism 109, no. 2 (June): 208–214: Epub ahead of print. PMID: 23583222. 10.1016/j.ymgme.2013.03.011. [DOI] [PubMed] [Google Scholar]
- Piemonte, F. , Pastore A., Tozzi G., et al. 2001. “Glutathione in Blood of Patients With Friedreich’s Ataxia.” European Journal of Clinical Investigation 31, no. 11 (November): 1007–1011: Epub ahead of print. PMID: 11737244. 10.1046/j.1365-2362.2001.00922.x. [DOI] [PubMed] [Google Scholar]
- Reboul, E. 2017. “Vitamin E Bioavailability: Mechanisms of Intestinal Absorption in the Spotlight.” Antioxidants (Basel) 6, no. 4 (November): 95. 10.3390/antiox6040095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Riederer, P. , Sofic E., Rausch W. D., et al. 1989. “Transition Metals, Ferritin, Glutathione, and Ascorbic Acid in Parkinsonian Brains.” Journal of Neurochemistry 52, no. 2: 515–520. 10.1111/j.1471-4159.1989.tb09150.x. [DOI] [PubMed] [Google Scholar]
- Singh, B. N. 1999. “Effects of Food on Clinical Pharmacokinetics.” Clinical Pharmacokinetics 37, no. 3 (September): 213–255. 10.2165/00003088-199937030-00003. [DOI] [PubMed] [Google Scholar]
- Zesiewicz, T. , Salemi J. L., Perlman S., et al. 2018. “Double‐Blind, Randomized, and Controlled Trial of EPI‐743 in Friedreich’s Ataxia.” Neurodegenerative Disease Management 8, no. 4 (August): 233–242: Epub ahead of print. PMID: 30051753. 10.2217/nmt-2018-0013. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
The data used to support the findings of this study are included within the article.