The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants.

BACKGROUND AND OBJECTIVES: Palovarotene is under development for the treatment of fibrodysplasia ossificans progressiva (FOP). The objectives of this study were to evaluate palovarotene pharmacokinetics under fed versus fasted conditions and its induction potential towards cytochrome P450 3A4 (CYP3A4) substrate, midazolam. METHODS: In this phase I, open-label trial (NCT04829773), palovarotene pharmacokinetics were characterized after repeated once-daily dosing. In one cohort, healthy participants received three doses of palovarotene 20 mg on Days 1, 6, and 11, as whole capsules under fasted or fed conditions, or sprinkled on food under fed conditions. In another cohort, individuals received midazolam 2 mg on Days 1 and 15 and a daily dose of palovarotene 20 mg on Days 2-15. Palovarotene and midazolam pharmacokinetics, including area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and maximum observed plasma drug concentration (Cmax), were assessed. Adverse events (AEs) were recorded. RESULTS: Overall, 23 participants completed each part. Palovarotene Cmax and AUC(0-∞) increased by 16.5% and 39.7% under fed versus fasted conditions. Pharmacokinetics were comparable between the whole capsule and sprinkled on food, under fed conditions. Midazolam AUC(0-∞) and Cmax decreased by 13.3% and 9.7% upon palovarotene co-administration over 14 days, less than that required to be considered a weak CYP3A4 inducer. Plasma palovarotene exposures were comparable after single and multiple doses. No serious AEs were reported. CONCLUSIONS: These data support palovarotene administration after a meal, as a whole capsule or sprinkled on food. Palovarotene at 20 mg/day is a not a clinical inducer of CYP3A4. These results provide insights into palovarotene pharmacokinetics, aiding optimization of administration for patients with FOP. CLINICAL TRIALS REGISTRATION NUMBER: NCT04829773.

Fibrodysplasia ossificans progressiva, also known as FOP, is a very rare genetic condition where bone forms in places it is not usually found, such as in the muscles, tendons, and ligaments. Retinoids are molecules that the body produces from vitamin A to aid normal bone development. Palovarotene is a therapeutic retinoid that has been developed for the treatment of FOP. This article describes a clinical trial where people without FOP received oral palovarotene to determine how it is absorbed and broken down (metabolized) by the body when taken after a meal or after fasting (a period of not eating) as a whole capsule or when sprinkled on food. The trial also examined how palovarotene might interact with other treatments that are broken down by the body in the same way as palovarotene.The trial found that the amount of palovarotene that circulates in the blood increased more when taken after a meal compared with after fasting. Palovarotene was metabolized by the body in a similar way when taken as a whole capsule or when sprinkled on food. This finding is important as some people with FOP have difficulty swallowing. At a 20 mg dose, palovarotene was unlikely to interact with other treatments that are metabolized in the same way. No serious side effects were reported.These results show that palovarotene should be taken after a meal, either as a whole capsule or sprinkled on food.

A Pharmacokinetic, Safety, and Tolerability Trial of Palovarotene in Healthy Japanese and Non-Japanese Participants.

BACKGROUND AND OBJECTIVE: Palovarotene is an oral, selective retinoic acid receptor gamma agonist under investigation for fibrodysplasia ossificans progressiva (FOP). Palovarotene is primarily metabolized by cytochrome P450 (CYP) 3A4. Differences in CYP-mediated metabolism of CYP substrates have been observed between Japanese and non-Japanese individuals. This phase I trial (NCT04829786) compared the pharmacokinetic profile of palovarotene in healthy Japanese and non-Japanese participants and evaluated the safety of single doses. METHODS: Healthy Japanese and non-Japanese participants were matched individually (1:1) and randomized to receive a single oral dose of palovarotene 5 or 10 mg, followed by the alternate dose after a 5-day washout period. Maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were assessed. Estimates of the geometric mean difference between dose and Japanese and non-Japanese groups were calculated for natural log-transformed Cmax and AUC parameters. Adverse events (AEs), serious AEs, and treatment-emergent AEs were recorded. RESULTS: Eight pairs of matched non-Japanese and Japanese individuals and two unmatched Japanese individuals participated. Mean plasma concentration-time profiles were similar between the two cohorts at both dose levels, demonstrating that palovarotene absorption and elimination are similar irrespective of dose level. The pharmacokinetic parameters of palovarotene were similar between groups at both dose levels. Cmax and AUC values were dose-proportional between doses in each group. Palovarotene was well tolerated; there were no deaths or AEs leading to treatment discontinuation. CONCLUSIONS: Japanese and non-Japanese groups had similar pharmacokinetic profiles, indicating that palovarotene dose adjustments are not necessary for Japanese patients with FOP.

Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study.

BACKGROUND: A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. OBJECTIVE: To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. METHODS: Patients with moderate asthma treated with short-acting beta-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n = 206); placebo CR, twice daily (n = 203); zileuton immediate-release (IR), 600 mg 4 times daily (n = 101); or placebo IR, 4 times daily (n = 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). RESULTS: Improvement in trough FEV1 was observed after 2 weeks of treatment (P = .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P = .02). A significant decline in beta-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR-treated patients (2.5%) vs 1 placebo CR-treated patient (0.5%). CONCLUSIONS: Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo).

Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma.

OBJECTIVE: Zileuton is a 5-lipoxygenase inhibitor approved by the US FDA in 1996 for the treatment of asthma in adults and children. During phase II/III clinical trials, zileuton was generally well tolerated, although elevations in ALT and AST levels were noted in some patients, and a single treated patient developed hepatocellular jaundice. To more fully characterise the hepatic effects of zileuton, and to establish appropriate monitoring guidelines, a 12-month open-label, safety surveillance study was conducted prior to FDA approval. PATIENTS AND METHODS: In this study, 2458 patients with asthma received zileuton 600mg four times daily in addition to usual asthma care, and 489 patients were treated with usual asthma care only. All patients had their liver biochemistry checked monthly for the first 5 months, and at months 7, 10 and 12 thereafter. RESULTS: A total of 109 patients (4.4%) receiving zileuton treatment had elevations in ALT levels to > or =3 x the upper limit of normal (ULN), including 31 patients (1.3%) who had levels elevated to > or =8 x ULN, compared with 5 of 480 patients in the usual care alone group (1.0%) who had levels elevated to > or =3 x ULN, of whom 1 (0.2%) had levels elevated to > or =8 x ULN. Elevations in ALT levels were generally not associated with increases in alkaline phosphatase and/or total bilirubin levels. Therefore, the hepatic injury was predominantly hepatocellular. The majority of elevations in ALT level to > or =3 x ULN (64.2%) in the zileuton-treated group occurred within the first 3 months of treatment. There was no correlation between the time of onset of ALT level elevation and the height of the peak ALT level observed. There was no overall difference in the occurrence of elevations in ALT level to > or =3 x ULN between men (4.5%) and women (4.7%), but more women than men experienced an ALT level > or =8 x ULN (1.8% vs 0.5%). Women aged > or =65 years appeared to be at higher risk of elevated ALT levels than those aged <65 years (a rate of 10.1% compared with 4.1%). Patients who experienced ALT levels of > or =3 x ULN but <5 x ULN were allowed to remain on treatment and 52.5% of these patients were able to continue zileuton therapy and experienced resolution of the elevation (a reduction in level to <2 x ULN). In each of the patients who discontinued treatment because of elevated ALT levels, the ALT level returned towards baseline, with a mean time to resolution (defined as a reduction in levels to <2 x ULN) of 4 weeks. No patient in this study developed clinically apparent jaundice or liver failure. Two patients (0.1%) experienced total bilirubin levels > or =1.5 x ULN in association with serum ALT levels exceeding 3 x ULN. CONCLUSIONS: This study established that liver chemistry monitoring is most effective in detecting elevation of ALT levels during the first 3 months of zileuton therapy and that with appropriate monitoring the risk of irreversible liver injury appears to be low.

A unique iontophoretic patch for optimal transdermal delivery of sumatriptan.

PURPOSE: Migraines affect approximately 10% of the adult population worldwide. The purpose of this study was to assess the pharmacokinetic and safety profile of a novel iontophoretic sumatriptan delivery system, NP101, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue. Four unique prototype iontophoretic sumatriptan patch conditions were compared to a 6 mg subcutaneous injection and an oral 50 mg tablet of sumatriptan succinate. MATERIALS AND METHODS: This was a randomized, single-center, single-dose, six-period Phase I study. RESULTS: Patches were well tolerated with fewer adverse events than the subcutaneous injection. Adverse events that were more prevalent for NP101 than other formulations included localized sensations and reactions at the patch site. A linear relationship was observed between total applied current and sumatriptan delivery. Patches delivering 6 and 12 mA per h yielded favorable sumatriptan systemic profiles, delivering drug at a rate that maintained plasma levels above the target level (> or = 10 ng/ml) for greater than 7 h. CONCLUSIONS: This study met the initial objective to define the dose-current relationship in humans as well as delimiting specific current and current density targets for a well tolerated patch design that can deliver therapeutic drug levels for longer periods than currently possible.

The safety and efficacy of zileuton controlled-release tablets as adjunctive therapy to usual care in the treatment of moderate persistent asthma: a 6-month randomized controlled study.

This study was conducted to assess the safety and efficacy of zileuton controlled release [CR] 1,200 mg BID added to usual care (UC) in 926 patients with moderate asthma (619 patients randomized to zileuton CR and 307 to placebo). Sustained improvements in AM and PM peak expiratory flow (PEF) were observed in the zileuton CR group compared to placebo. The adverse event profile was similar in the two treatment groups. Eleven patients (1.8%) receiving zileuton CR and 2 (0.7%) receiving placebo experienced elevations of alanine aminotransferase (ALT) >or= 3X the upper limit of normal (ULN). These elevations typically occurred (81.8%) during the first 3 months of exposure and most resolved within 21 days after discontinuation.