Drug absorption and elimination vs time. Mean levels (±SEM) of total plasma idebenone after the first oral dose (A) and last oral dose (B) in adults (18 years or older), adolescents (12-17 years old), and children (5-11 years old) with Friedreich ataxia receiving 60 mg/kg per day.
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Di Prospero NA, Sumner CJ, Penzak SR, Ravina B, Fischbeck KH, Taylor JP. Safety, Tolerability, and Pharmacokinetics of High-Dose Idebenone in Patients With Friedreich Ataxia. Arch Neurol. 2007;64(6):803–808. doi:10.1001/archneur.64.6.803
Friedreich ataxia (FA) is a progressive, multisystem degenerative disorder in which oxidative stress is believed to have a role. Recent clinical studies indicate that the antioxidant idebenone, administered at 5 mg/kg per day, reduces the cardiac hypertrophy that occurs in FA, but improvement in neurologic measures is unclear. Some studies suggest that higher doses of idebenone may be more effective, but pharmacology and toxicology at higher doses have not been investigated in human beings.
To determine the safety, tolerability, and pharmacokinetics of increasing doses of idebenone in subjects with FA.
Open-label, phase 1A dose-escalation trial followed by an open-label, 1-month phase 1B trial.
National Institutes of Health Clinical Center, Bethesda, Md.
Phase 1A included 78 subjects with FA (24 adults, 27 adolescents, and 27 children), and phase 1B included 15 subjects with FA (5 adults, 5 adolescents, and 5 children).
Oral idebenone was administered to groups of 3 subjects in each age cohort during day 1. In phase 1A, the dose was increased in 10-mg/kg increments in each successive dose group to a maximum of 75 mg/kg. In phase 1B, oral idebenone was administered at 60 mg/kg divided in 3 doses per day for 1 month.
Main Outcome Measures
We studied the type, number, and frequency of adverse events, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, area under the curve, and half-life.
In the first phase of the study, no dose-limiting toxicity was observed and the maximum allowed dose of 75 mg/kg was achieved in all cohorts. Plasma levels of total idebenone were found to increase proportional to drug dose up to 55 mg/kg. Variability in absorption of the drug was observed, but drug half-life was relatively consistent across dose levels. In the second phase of the study, 14 of 15 subjects with FA tolerated idebenone at a dose of 60 mg/kg per day for 1 month. All adverse events were mild, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, and half-life did not differ significantly across age cohorts.
These findings indicate that higher doses of idebenone lead to a proportional increase in plasma levels up to 55 mg/kg per day and that high-dose idebenone is well-tolerated in patients with FA. These findings are essential to planning efficacy trials of high-dose idebenone in FA and other degenerative diseases in which oxidative damage has been implicated.
Clinical Trial Registry
http://clinicaltrials.gov Identifiers: NCT00015808 and NCT00078481.
Friedreich ataxia (FA) is an autosomal recessive, multisystem disorder characterized by progressive gait and limb ataxia caused by degeneration of the posterior columns and spinocerebellar tracts of the spinal cord. Additional features include hypertrophic cardiomyopathy, scoliosis, and diabetes.1 The causative mutation is expansion of a GAA repeat within the first intron of the frataxin gene, leading to decreased levels of the corresponding messenger RNA transcript and protein.2 The deficiency of cellular frataxin results in decreased iron-sulfur cluster synthesis and reduced oxidative phosphorylation, as well as accumulation of iron in mitochondria and increased production of free radicals.3 Thus, mitochondrial dysfunction and oxidative tissue damage may each contribute to FA pathogenesis. In subjects with FA, blood and urine samples show elevated levels of markers of oxidative damage and cells show increased sensitivity to oxidative stress.4,5
Idebenone, a short-chain benzoquinone structurally similar to coenzyme Q10, is a potent antioxidant and electron carrier.6 Clinical studies consistently have shown that treatment with idebenone at a dose of 5 mg/kg per day reduces cardiac hypertrophy in patients with FA.7-9 While most of these trials included neurologic end points, only 1 small, open-label trial found a significant improvement in overall neurologic function,10 which was directly related to idebenone plasma concentrations. In 2 other trials, patients who failed to respond to the initial dose of idebenone (5 mg/kg per day) subsequently responded to higher doses (10 mg/kg per day).7,8 These studies suggest that greater benefit from idebenone in FA may be achieved at higher doses. A trial of idebenone in an animal model of FA found that efficacy was dose-responsive, with 10 mg/kg having no effect, 30 mg/kg having a trend toward efficacy that was not statistically significant, and 90 mg/kg significantly delaying disease onset, slowing progression, and prolonging life.11,12 However, the safety and pharmacokinetics of higher doses of idebenone have not been assessed in human beings, precluding efficacy trials of high-dose idebenone therapy. The goal of this study was to determine the safety and tolerability of high-dose idebenone therapy in patients with FA to allow high-dose efficacy trials of this promising drug.
Subjects with genetically confirmed FA were recruited and stratified into 3 age cohorts, as follows: children, 5 to 11 years; adolescents, 12 to 17 years; and adults, 18 years or older. Informed consent was obtained before enrollment. The study was conducted with the approval of the National Institute of Neurological Diseases and Stroke Institutional Review Board and the Food and Drug Administration (investigational new drug 62 926).
Idebenone was provided by Takeda Pharmaceuticals, Osaka, Japan. For the phase 1A study, 120-mg tablets were crushed, weighed, and encapsulated in appropriate doses by the National Institutes of Health Clinical Center Pharmacy Department. For the phase 1B study, whole 120-mg tablets were dispensed.
This was an unblinded, dose-escalation study. Within each age cohort, 3 subjects were given the initial dose of idebenone: 5 mg/kg in 3 divided doses in adults and 2.5 mg/kg in 3 divided doses in adolescents and children. If none of the 3 subjects experienced dose-limiting toxicity, 3 different subjects were given the next higher dose in 10-mg/kg increments (except that the second dose in adolescents and children was 5 mg/kg) to a maximum of 75 mg/kg. Dose-limiting toxicity was defined as any adverse event graded as 2 or greater, as described in the Common Toxicity Criteria Manual, version 2.0 (http://ctep.cancer.gov/reporting/ctc_archive.html), occurring in 2 of 3 subjects at a given dose level. For pharmacokinetic analysis, plasma samples were collected before dosing and 30 minutes and 1, 2, and 4 hours after the first dose and 30 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the final dose.
Subjects received 60 mg/kg per day of idebenone, divided into 3 doses, for 72 hours, followed by a 48-hour drug washout. For pharmacokinetic analysis, plasma samples were collected before dosing and 30 minutes and 1, 2, 4, and 6 hours after the first dose, then just before the first dose and 1 hour after the third dose on subsequent days. In addition, plasma levels were collected 1, 2, 4, 8, 12, 24, 36, and 48 hours after the final dose for analysis of elimination kinetics. Patients were then given a supply of idebenone and instructed to take the drug at a dose of 60 mg/kg per day for 1 month at home. During the outpatient phase, scripted telephone interviews and routine blood tests were conducted every 2 weeks for 6 weeks to evaluate safety, tolerability, and compliance. The scripted interview included the open-ended question, “Have you noticed any changes in your health or the way that you normally feel?”
Plasma samples were frozen at −20°C and shipped frozen to MDS Pharma Services (Lincoln, Neb) for liquid chromatography–mass spectroscopy analysis of levels of free and total idebenone and the idebenone metabolite QS10. Idebenone pharmacokinetic values were determined using noncompartmental methods with the WinNonlin Professional computer program (version 5.0; Pharsight Corp, Mountain View, Calif). Maximum plasma concentrations and time to reach maximum plasma concentrations were determined by visual inspection of the concentration-time profiles. The elimination rate constant, λZ, was estimated as the absolute value of the slope of a linear regression of the natural logarithm of concentration vs time. Half-life was calculated as natural logarithm 2/λZ. Values for area under the curve (AUC) of concentration vs time from zero hours to the last quantifiable concentration (AUC0-last) were determined using the linear trapezoidal rule.
Seventy-eight subjects were divided into adult, adolescent, and child cohorts (Table 1). All cohorts completed dose escalation to the maximum dose of 75 mg/kg without the occurrence of dose-limiting toxicity. Twenty-two adverse events were reported (Table 2): 13 occurred in 9 of 24 adults, 4 occurred in 3 of 27 adolescents, and 5 occurred in 4 of 27 children. All adverse events were mild (common toxicity criteria, grade 1) except for 1 transient episode of hyperglycemia reported as grade 3 (severe and undesirable adverse event). This occurred with the 5-mg/kg dose in a patient with diabetes mellitus who had a history of poor glycemic control that was deemed unrelated to the study medication. No serious adverse events occurred, and there were no significant changes in vital signs, findings at physical examination, hematology or chemistry blood values, or electrocardiograms.
Pharmacokinetic data are reported for alternate dose levels (Table 3). The mean ± SEM time to maximal drug concentration across dose levels and age cohorts was 2.2 ± 0.2 hours (adults, 2.1 ± 0.3 hours; adolescents, 2.3 ± 0.3 hours; and children, 2.3 ± 0.3 hours). The maximum drug concentration increased with increasing idebenone dose, although there was marked variability between patients within dose levels. Idebenone elimination showed a biphasic decline with a mean ± SEM terminal elimination half-life of 14.9 ± 0.7 hours in adults, 13.4 ± 2.1 hours in adolescents, and 9.8 ± 0.5 hours in children. The half-life did not differ significantly across dosing levels. Total drug exposure is indicated by the AUC of the concentration vs time plot. Despite some variation likely owing to the relatively small sample size, the AUC consistently increased with increasing dose up to 55 mg/kg. Beyond this dose level, there was a further increase in drug exposure, but it was not proportional to the increase in dose. Free idebenone mimicked the pharmacokinetics of total idebenone, but the free levels were in the range of only 0.25% to 0.5% of total levels, indicating that the drug is more than 99% protein bound (data not shown). The pharmacokinetics of total and free QS10 also followed that of total idebenone, with levels of approximately 50% and 2% of total idebenone, respectively (data not shown).
Fifteen subjects were divided into adult, adolescent, and child cohorts (Table 1) and given idebenone at 60 mg/kg per day for 1 month. The 4 reported self-limited adverse events were mild (grade 1) gastrointestinal complaints including dyspepsia, loose stool, nausea, and vomiting. One child experienced grade 1 nausea and 2 episodes of diarrhea during the second day of idebenone administration. The medication was stopped, with resolution of symptoms. Two weeks later, the subject was rechallenged with idebenone; the symptoms recurred and the medication was discontinued. No serious adverse events occurred, and there were no significant changes in vital signs, findings at physical examination, hematology or chemistry blood values, or electrocardiograms. Urine discoloration, a known phenomenon caused by idebenone metabolites,13 was reported in 6 subjects, but hematuria and other urinary abnormalities were not observed.
Time to reach maximum plasma concentration (Figure, A) across age cohorts averaged 2.1 ± 0.2 hours (2.4 ± 0.4 hours in adults, 2.2 ± 0.5 hours in adolescents, and 1.8 ± 0.3 hours in children). The mean ± SEM maximum plasma concentration (Figure, A) across age cohorts was 7220 ± 620 ng/mL (6560 ± 1480 ng/mL in adults, 7850 ± 500 ng/mL in adolescents, and 7260 ± 1160 ng/mL in children). The mean terminal half-life (Figure, B) of total idebenone was not significantly different among the age cohorts at 12.7 ± 2.0 hours in adults, 10.4 ± 1.0 hours in adolescents, and 9.4 ± 0.5 hours in children. The mean AUC across the age cohorts (Figure, B) for terminal elimination after the last dose was approximately 137 000 ng*h/mL. The trough level of the drug, that is, the predose serum level before the first daily dose after achieving steady state, was consistent across cohorts, with a mean ± SEM of 3590 ng/mL (3760 ± 870 in adults; 3750 ± 690 in adolescents, and 3270 ± 240 in children). Therefore, the levels of total drug exposure ranged from 10 to 32 μmol/L.
Scripted telephone interviews were conducted every 2 weeks to assess compliance and overall patient well-being. In response to an open-ended question about their well-being, 10 of 14 subjects reported subjective improvement after 1 month of treatment. Self-reported observations included decreased fatigue (7 of 10 subjects), improved balance and stability (5 of 10 subjects), improved fine motor tasks such as handwriting (4 of 10 subjects), and improved peripheral sensation (2 of 10 subjects).
The antioxidant idebenone is a short-chain benzoquinone derivative with a structure similar to coenzyme Q10 but with a more favorable pharmacokinetic profile. The oxidized form of idebenone reduces mitochondrial production of superoxide, and the reduced form is an effective scavenger of hydroxy radicals. In animals, idebenone reduces lipid peroxidation and neuronal toxicity in response to oxidative stress.14,15 In addition, idebenone can act as an electron carrier in the respiratory chain and stimulate formation of adenosine triphosphate.16 In theory, this class of drug has wide application in various neurologic disorders, but investigational drug studies have been limited by lack of safety and toxicity data at higher doses in human beings.
In this study, we showed that high doses of the antioxidant idebenone are safe and well-tolerated in patients with FA. In the 1-day dose-escalation study, no dose-limiting toxicity was noted up to a dose of 75 mg/kg, which is 15 times the dose used in most previous studies. The most common adverse event in the 1-day study was transient, mild nausea. In the 4-week treatment study, 1 child experienced nausea and diarrhea on the second inpatient day and again when rechallenged, suggesting that these symptoms may be related to drug at this dose level. Overall, however, 93% of subjects completed the phase 1B study with no toxicity.
In general, the pharmacokinetic profile across dose levels and cohorts in both phase 1A and phase 1B was similar and in agreement with previous low-dose studies of idebenone.17,18 The idebenone half-life was relatively consistent across dose levels and consistent with previous phase 1 studies in which half-life ranged from 2.6 to 21.7 hours.17-19 The insignificantly increased half-life observed in the adolescent and adult cohorts is likely explained by larger distribution volumes in these individuals (data not shown). The dose proportionality of exposure up to 55 mg/kg observed in phase 1A indicates that higher drug dosing may be explored for greater biologic effects. The lowest drug concentration (trough) observed under steady-state conditions in the phase 1B study would suggest that, at higher dose levels, tissues would have a relatively constant drug exposure, which may be necessary for effective therapy. It is likely that these increased plasma levels correlate with increased central nervous system concentrations because previous animal studies with radiolabeled idebenone demonstrated that it quickly crosses the blood-brain barrier and can be found in central nervous system tissues.13 Idebenone's lipophilic structure, small molecular size, and large volume of distribution support its ability to penetrate central nervous system tissues. While examination of cerebrospinal fluid may have been helpful to document this, previous studies have suggested that cerebrospinal fluid may not be an appropriate medium for idebenone monitoring.20
Idebenone is a promising drug for treatment of FA. The drug is cytoprotective in fibroblasts from patients with FA, with a median effective concentration of approximately 0.5 μmol/L,21 which is well below the peak (approximately 30 μmol/L) and trough (approximately 10 μmol/L) concentrations achieved in our phase 1B study. A dose-escalation trial found that idebenone was efficacious in a mouse model of FA.11 In this study, low-dose idebenone (10 and 30 mg/kg per day) showed no benefit, but high-dose idebenone (90 mg/kg per day) delayed disease onset, slowed progression, and prolonged survival, although serum idebenone levels were not reported.11,12 Most promising, clinical studies have consistently shown that treatment with low-dose idebenone (5 mg/kg per day) reduces cardiac hypertrophy in patients with FA.7-9
Objective clinical trials are required to determine whether high-dose idebenone will provide efficacy for neurologic features of FA. Nevertheless, it is encouraging that most subjects in our phase 1B trial reported subjective improvement after 1 month of treatment. Idebenone is also a promising therapeutic candidate for other neurodegenerative diseases in which mitochondrial dysfunction and oxidative damage are implicated, including Huntington disease, Parkinson disease, and Alzheimer disease.22 This dose is more than 10 times higher than the dose found to reduce cardiac hypertrophy in patients with FA and more than 5 to 20 times the dose used in previous efficacy trials for Huntington disease and Alzheimer disease.23,24
In summary, the data from these trials provide evidence that idebenone is safe and well tolerated at doses up to at least 60 mg/kg per day. To our knowledge, the full-dose range of idebenone has not been examined in previous clinical trials, and our study lays the foundation for further studies of high-dose efficacy in FA and other neurodegenerative diseases.
Correspondence: Nicholas A. Di Prospero, MD, PhD, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Dr, Room 2A-1008, Bethesda, MD 20892-3705 (firstname.lastname@example.org).
Accepted for Publication: September 28, 2006.
Author Contributions: All of the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Di Prospero, Ravina, Fischbeck, and Taylor. Acquisition of data: Di Prospero, Sumner, and Taylor. Analysis and interpretation of data: Di Prospero, Penzak, Ravina, Fischbeck, and Taylor. Drafting of the manuscript: Di Prospero, Sumner, Ravina, and Taylor. Critical revision of the manuscript for important intellectual content: Penzak, Ravina, Fischbeck, and Taylor. Statistical analysis: Penzak and Ravina. Obtained funding: Fischbeck. Study supervision: Di Prospero, Sumner, Ravina, Fischbeck, and Taylor.
Financial Disclosure: None reported.
Funding/Support: This study was supported by intramural research funds from the National Institutes of Health (Dr Fischbeck). Takeda Pharmaceuticals provided idebenone and safety data from previous preclinical and clinical studies.
Role of the Sponsor: Takeda Pharmaceuticals had no role in study design, data collection, data analysis, or writing of the manuscript.
Acknowledgment: We thank the patients, their families, and the members of the Friedreich's Ataxia Research Alliance for their generous time and commitment to this study; genetic counselors Jennifer Lieb, Amy Jewel, and Alison La Pean, and patient care coordinators Anthony Crawley and Tasha White for assistance; and G. Martin, MD, D. Escolar, MD, A. Wichman, MD, and N. Jeffries, PhD, for serving as members of the data and safety monitoring board.