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Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults

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Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults Clinical Therapeutics/Volume 37, Number 7, 2015 Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults Peter E. Haroldsen, PhD; Donald G. Musson, PhD; Boyd Hanson, PhD; Adrian Quartel, MD; and Charles A. O’Neill, PhD BioMarin Pharmaceutical Inc, Novato, California ABSTRACT in the fed state. The extent of exposure and plasma Purpose: Amifampridine (3,4-diaminopyridine) has elimination half-life of the major metabolite was been approved in the European Union for the treatment greater than those of amifampridine in the fed and of Lambert-Eaton myasthenic syndrome. Amifampridine fasted conditions. Mean AUCs in the fed and fasted has a narrow therapeutic index, and supratherapeutic states were slightly greater in women than men, with exposure has been associated with dose-dependent ad- no difference in mean Cmax. Orally administered verse events, including an increased risk for seizure. This amifampridine was renally eliminated (493%) as study assessed the effect of food on the relative bioavail- the parent compound and metabolite within 24 hours. ability of amifampridine in healthy subjects and informed Single oral doses of 20 mg of amifampridine phos- on conditions that can alter exposure. phate salt were considered well tolerated in both the Methods: This randomized, open-labeled, 2-treat- fed and fasted conditions. High intersubject variability ment, 2-period crossover study enrolled 47 healthy (%CVs, 430%) in amifampridine pharmacokinetic male and female subjects. Subjects were randomly parameter values was observed. assigned to receive 2 single oral doses of amifampri- Implications: At the intended dose under fasting dine phosphate salt (20 mg base equivalents per dose) conditions, amifampridine exposure may be increased. under fed or fasted conditions separated by a washout European Union Drug Regulating Authorities Clinical period. Blood and urine samples for pharmacokinetic Trials identifier: 2011-000596-13. (Clin Ther. 2015; analyses were taken before and after dosing. Plasma 37:1555–1563) & 2015 The Authors. Published by N concentrations of amifampridine and an inactive 3- - Elsevier HS Journals, Inc. acetyl metabolite were determined. The relative bio- Key words: amifampridine, food effects, pharma- availability values of amifampridine and metabolite cokinetics, 3,4-diaminopyridine, 3,4-DAP, Lambert- were assessed based on the plasma PK parameters Eaton Myasthenic Syndrome. AUC0–1, AUC0–t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic anal- ysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect INTRODUCTION 3,4-Diaminopyridine (3,4-DAP) has been used for on bioavailability would be established if the 90% CI 425 years for treating a variety of neurologic disor- of the ratio of population geometric mean value of ders of axonal or synaptic transmission, including AUC0–1, AUC0–t,orCmax between fed and fasted 1,2 administration was not within the bioequivalence Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis, congenital myasthenia, multiple range of 80% to 125%. Tolerability was assessed 3–5 based on adverse-event reporting, clinical laboratory sclerosis, and downbeat nystagmus. 3,4-DAP blocks assessments, physical examination including vital sign voltage-dependent potassium ion channels, thereby measurements, 12-lead ECG, and concurrent medica- prolonging the action potential and presynaptic cell tion use. Findings: Food slowed and somewhat decreased the Accepted for publication May 15, 2015. absorption of amifampridine. There was a decrease in http://dx.doi.org/10.1016/j.clinthera.2015.05.498 0149-2918/$ - see front matter exposure (Cmax, 44%; AUC, 20%) after oral admin- & 2015 The Authors. Published by Elsevier HS Journals, Inc. This is an istration of amifampridine phosphate salt in the open access article under the CC BY-NC-ND license presence of food, and mean Tmax was 2-fold longer (http://creativecommons.org/licenses/by-nc-nd/4.0/). July 2015 1555 Clinical Therapeutics membrane depolarization, enhancing influx or trans- narrow therapeutic index, and supratherapeutic expo- port of calcium into the nerve ending. The resulting sure has been associated with an increase in the risk for increase in intracellular calcium concentration facili- seizures.2 The purpose of this study was to evaluate the tates exocytosis of acetylcholine-containing vesicles, effects of food on the PK properties and relative leading to an increased concentration of acetylcholine bioavailability of amifampridine phosphate salt. at the motor end plate,6 which in turn results in improved neuromuscular transmission and SUBJECTS AND METHODS augmented muscle contraction and strength.7,8 Subjects Over the past 25 years, a considerable amount of This study enrolled healthy subjects, both men and clinical experience with 3,4-DAP has been gained, pro- women, aged 18 to 65 years and with a body mass index viding a strong body of evidence supporting its efficacy between 18.5 and 30 kg/m2, inclusive. Subjects under- and tolerability in the treatment of patients with LEMS.1,2 went screening to confirm eligibility within 28 days before 3,4-DAP is a standard of care for LEMS in the United the administration of the first dose of study drug. States and has been recommended by the European Screening included physical examination, clinical labora- Academy of Neurology (formerly, European Federation tory evaluations (hematology, chemistry, and urinalysis), of Neurological Societies) for first-line symptomatic treat- and ECG. Women of childbearing potential must have ment of patients with LEMS.9 For many years, the had a negative pregnancy test at screening. Sexually active absence of a product approved for the treatment of this subjects of childbearing potential must have been willing condition led physicians to prescribe ad hoc preparations to use 2 acceptable methods of contraception while of amifampridine base from compounding pharmacies or participating in the study, with 1 method spermicidal. independent small-scale manufacturers. The process of Subjects were excluded if they could not tolerate producing these products was associated with consider- the study-specific diet or were breast-feeding. Subjects able batch variability, lack of reliability in drug quality, were also excluded if they had received any prescribed safety concerns for the people manipulating the free base, systemic or topical medication; nonprescribed sys- and a risk for overdose due to compounding errors.10 temic or topical medication (including herbal rem- A new oral phosphate salt formulation of 3,4-DAP edies, but excluding vitamin/mineral supplements); (amifampridine) was approved by the European Med- any medication (including St. John’s wort or other icines Agency in 2009.11 Comparability of the base herbal remedy) known to chronically alter drug versus the phosphate salt formulation of 3,4-DAP was absorption or elimination processes; medication that demonstrated in a previously conducted double-blind, prolongs the QT interval or QT interval corrected for single-dose, crossover, bioavailability/bioequivalence heart rate; alcohol, caffeine, poppy seed, or grapefruit study conducted in 27 healthy male subjects.2 The containing products; or amifampridine (base or phos- pharmacokinetic (PK) profiles of both the 3,4-DAP phate salt) or fampridine (4-aminopyridine) within free base and phosphate salt forms in this study were defined time periods before planned administration of highly variable, with up to 10-fold differences in Cmax, the first dose of study drug. AUC, and t½ between subjects. The most probable Other exclusion criteria included a variety of signifi- explanation for this variability appears to be the single cant diseases, disorders, or illnesses; high or low blood metabolic disposition of 3,4-DAP via the activity of pressure; ECG abnormalities; a history of cardiac N-acetyl transferases (NATs) to form a single major disease; and current or history of alcohol abuse, drug 3-N-acetyl metabolite, which is inactive.12 NAT enzymes abuse, or smoking within defined time periods before are highly polymorphic in humans and vary consider- planned administration of the first dose of study drug. ably with ethnicity. Phenotypically, a patient’sNAT status can be classified, through a range of acetylation Study Design activities, from slow to rapid. Variations of polymorphic This was a randomized (1:1), open-labeled, NAT corresponding with fast and slow acetylator 2-treatment, 2-period crossover study to assess the phenotypes have been found to significantly affect the tolerability and effect of food on the relative bioavail- PK and tolerability profiles of amifampridine.12 ability of amifampridine phosphate salt in healthy Understanding the PK properties of amifampridine subjects after single-dose administration. Written in- is particularly important because amifampridine has a formed consent was obtained from each subject before 1556 Volume 37 Number 7 P.E. Haroldsen et al. any study-related activities were conducted. The study 3-N-acetyl amifampridine. During each collection period, protocol was approved by the institutional review the containers were stored in a refrigerator at 21Cto81C. board (Reading Independent Ethics Committee). The The weight of each urine sample was recorded before the study was conducted in accordance with the sections removal of 2 subsamples, which were stored, within 4 of the US Code of Federal Regulations relating to hours of the end
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