MORE THAN 180,000 PEOPLE in the United States and

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1 29 Pharmacokinetics and Safety of Multiple Oral Doses of Sustained-Release 4-Aminopyridine (Fampridine-SR) in Subjects With Chronic, Incomplete Spinal Cord Injury Keith C. Hayes, PhD, Patrick J. Potter, MD, Jane T. Hsieh, MSc, Mitchell A. Katz, PhD, Andrew R. Blight, PhD, Ron Cohen, MD From The University of Western Ontario and Parkwood Hospital, London, ON, Canada (Hayes, Potter); and Acorda Therapeutics Inc, Hawthorne, NY (Hsieh, Katz, Blight, Cohen). Supported by Acorda Therapeutics Inc. Hayes is a consultant to Acorda Therapeutics. Hsieh, Katz, Blight, and Cohen are employees of Acorda Therapeutics. Acorda Therapeutics has a financial interest in Fampridine-SR. A commercial party with a direct financial interest in the results of the research supporting this article has conferred or will confer a financial benefit on the author or 1 or more of the authors. Reprint requests to Keith C. Hayes, PhD, St Joseph s Health Care, Parkwood Hospital Site, 801 Commissioners Rd E, London, ON N6C 5J1, Canada, kchayes@uwo.ca /04/ $30.00/0 doi: /s (03) ABSTRACT. Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine- SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil 2004;85: Objective: To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). Design: Open-label. Setting: Clinical research unit in Ontario. Participants: Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). Intervention: Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily, each for 1wk). Main Outcome Measures: Steady-state pharmacokinetic parameters: maximum observed plasma concentration (C max ), minimum observed plasma concentration (C min ), average observed plasma concentration (C av ), area under the plasma concentration-time curve from 0 to 12 hours (AUC 0 12 ), time to C max (t max ), plasma half-life (t 1/2 ), apparent volume of distribution (V d /F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. Results: Mean steady-state C max,c min,c av, and AUC 0 12 increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50mg twice daily. Fampridine-SR had a mean t max of 2.2 to 3.0 hours and a mean t 1/2 of 5.7 to 6.9 hours. Mean V d /F ( L) and Cl/F ( L/h) were independent of dosage, as were mean t max and t 1/2 across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. Conclusion: In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twicedaily manner. Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily. Key Words: 4-Aminopyridine; Pharmacokinetics; Rehabilitation; Safety; Spinal cord injuries by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation MORE THAN 180,000 PEOPLE in the United States and approximately 36,000 people in Canada live with the consequences of spinal cord injury (SCI). Approximately 10,000 new SCI cases in the United States and 1000 new cases in Canada occur each year. 1,2 Pharmacologic management of chronic SCI has typically focused on treating the medical complications that arise (eg, pain, autonomic dysreflexia, urinary tract infection [UTI]), and to date, there are no approved pharmacologic therapies that specifically treat the underlying neurologic deficits. 4-Aminopyridine (Fampridine) is the first compound shown to restore some neurologic function in subjects with chronic SCI 3-8 and other demyelinating conditions such as multiple sclerosis (MS) It does this by blocking fast-acting potassium channels that are exposed in demyelinated axons. Potassium channel blockade prolongs the duration of nerve action current, thereby increasing the safety factor for conduction across demyelinated internodes It also increases neuroneuronal transmission in spared tracts. 16,19 Although Fampridine is not yet approved for use in North America, some physicians in the United States regularly prescribe it for patients with chronic SCI and MS. (Immediate-release formulations of Fampridine have been obtained through compounding pharmacies.) Orally administered immediate-release formulations of Fampridine have been shown to produce rapid peak plasma concentrations shortly after dosing (time to maximum concentration [t max ]is 1h) and have a plasma half-life of approximately 3.5 hours. 20,21 The subsequent peak in cerebrospinal fluid (CSF) level is delayed by 30 to 60 minutes. 22 Fampridine s window of therapeutic effect appears to correlate with its plasma half-life, lasting between 4 and 7 hours, 23 and this suggests that multiple daily doses ( 4) would be needed to maintain adequate plasma and CSF levels and to sustain its therapeutic effect. In response to this limitation, a sustained-release formulation of Fampridine (Fampridine-SR) has been developed that will allow for less frequent and more convenient dosing. This study examined the steady-state pharmacokinetics and the safety of Fampridine-SR at 6 ascending dosage levels in subjects with chronic, incomplete SCI. Steady-state plasma concentrations of Fampridine-SR are reached after 5 days of twice-daily dosing. 24 An important feature of this study was that it examined the response to doses that were higher than have been previously studied.

2 30 PHARMACOKINETICS OF FAMPRIDINE-SR IN SCI, Hayes METHODS Participants Subjects of either sex, aged 18 to 65 years, and within 20% of ideal body weight (as established in the 1983 Metropolitan Life Insurance height and weight tables 25 ) were eligible for study entry. All subjects provided informed consent to participate, and the study was approved by the University of Western Ontario Research Ethics Board for Health Sciences Research Involving Human Subjects. Inclusion criteria were the following: neurologic impairment secondary to chronic SCI that had been stable for at least 6 months; level of neurologic injury between C4 and T10; and American Spinal Injury Association Impairment Scale (AIS) neurologic grade B, C, or D (incomplete SCI). Subjects were to be in good health and receiving minimal concomitant medication(s), with no clinically significant laboratory abnormalities, and a negative urine drug screen and ethanol saliva test on study admission. Exclusion criteria were the following: women who were lactating, pregnant, or of childbearing potential and not using approved birth control methods; patients with a history of seizures (Fampridine in high doses has an excitatory effect on the nervous system, and can induce seizures in persons who are predisposed) 13 ; known allergy to pyridine-containing substances (pyridine, a molecule in Fampridine, is a chemical used to make many different products, eg, medicines, vitamins, and food flavorings) 26 ; history of drug or alcohol abuse in the previous year; evidence or history of diseases or conditions that might substantially affect the pharmacokinetics of Fampridine (eg, renal, hepatic, or gastrointestinal disease); use of any investigational drug in the previous 30 days; or considered by the investigator to be unlikely to complete the study for any reason. Design An open-label, 17-week, single-center study was conducted to investigate the pharmacokinetics and safety of multiple oral doses of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily) in 16 subjects with chronic, incomplete SCI. Dosing was conducted in 2 phases, with an interim period between the 2. During the first phase (weeks 1 5), subjects received 20 (initiation dose), 25, 30, 35, and 40mg of Fampridine-SR twice daily, each for 1 week (twice-daily dosing was defined as every 12h [8:00 AM and 8:00 PM]). Given the tolerability of the 40mg twice-daily dosage, it was determined that the protocol was to be amended to allow further dosage escalation to a maximum dosage of 60mg twice daily. While waiting for regulatory (Health Protection Branch [HPB], Canada) approval of the amendment, subjects were maintained on 20mg of Fampridine-SR twice daily under an HPB Special Access Program (weeks 6 11). At the beginning of week 6, patients were switched from 40mg twice daily to 20mg twice daily. Available study medication allowed for only 1 week of maintenance at 20mg twice daily (week 6). Thus, subjects received no medication during weeks 7, 8, and 9 and were restarted on 20mg twice daily at the beginning of week 10. They remained on 20mg twice daily during weeks 10 and 11 before initiation of the second dosing phase from weeks 12 to 17. During this interim period (weeks 6 11), pharmacokinetic sampling was not performed; however, subjects were contacted weekly by telephone to evaluate adverse events and safety. In the second dosing phase (weeks 12 17), subjects received Fampridine-SR in 30, 40, 50 (2 25mg), 60 (2 30mg), 40, and 20mg dose twice daily, each for 1 week, in an ascending and then descending manner. All dosages were administered as stated; there were no intermediate titration steps when moving from one dose to another. Fampridine-SR was provided as sustained-release tablets containing Fampridine equivalent to 5, 20, 25, 30, 35, and 40mg. Pharmacokinetic Sampling and Assessments Subjects attended the clinical research unit (CRU) at the Parkwood Hospital Site of St. Joseph s Health Care, London, ON, Canada, for approximately 24 hours on 6 different occasions for pharmacokinetic sampling. This occurred on the morning of the final dose at each target dosage level (days 15, 22, 29, 36, 99, 106), which corresponded to the last day of 1 week s administration of 25, 30, 35, 40, 50, and 60mg of Fampridine-SR twice daily. Subjects were instructed to fast overnight and not to take their morning doses before arriving at the CRU. The morning dose of Fampridine-SR was administered in the CRU at 8:00 AM with 240mL of water. (Water was allowed ad libitum except for 2-h predose and 2-h postdose.) A standard meal was provided 4 hours postdose. Subjects were not allowed to consume caffeine-containing foods and beverages from the time of admission until discharge from the CRU the following morning. Blood samples were collected at 0 (immediately preceding drug administration), 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose. The evening dose of Fampridine-SR was administered immediately after the final blood sampling (12h postdose). Subjects remained at the CRU overnight and were discharged the following morning after taking the first dose of their next dosage level. Blood samples (7mL; sufficient to provide 3-mL of plasma) were collected in heparinized tubes. Plasma was stored at 20 C. Plasma Fampridine concentrations were determined by using a validated liquid chromatographic mass spectrophotometric mass spectrophotometric assay. a Noncompartmental pharmacokinetic analysis was performed by using actual plasma Fampridine concentrations to determine steady-state pharmacokinetic parameters. The following pharmacokinetic parameters were determined: maximum and minimum observed plasma concentrations at steady state (C max, C min, respectively); area under the concentration-time curve from 0 to 12 hours (AUC 0 12 ); average plasma concentration, determined by AUC 0 12 /12 (C av ); time to C max (t max ); apparent plasma half-life (t 1/2 ); apparent total clearance (Cl/F); and apparent volume of distribution (V d /F). Safety Assessments At each clinical evaluation, subjects underwent a brief physical examination that included measuring vital signs (blood pressure, pulse, oral temperature, respiration). Clinical laboratory tests (hematology, blood chemistry, urinalysis, urine pregnancy testing for women of childbearing potential) and electrocardiograms (ECGs) were performed before study entry (screening) and repeated at the end of weeks 5 (end of dosing phase 1) and 15 (after last 60mg dose during dosing phase 2). Study staff conducted nonspecific questioning weekly to detect adverse events, speaking with subjects via telephone during weeks when there was no scheduled clinical visit. Adverse events were summarized by body system and preferred terms by using the Coding Symbol Thesaurus of Adverse Reaction Terms (COSTART). Adverse events were also graded by severity (mild, moderate, severe) and relationship to study drug (none, unlikely possible, probable). Other Measures Several other measures were evaluated for their potential use in future clinical trials. These included a baseline question-

3 PHARMACOKINETICS OF FAMPRIDINE-SR IN SCI, Hayes 31 Parameter Table 1: Subject Demographics naire, Clinical Global Impression, Ashworth Scale scores of spasticity, daily subject diaries, and bladder ultrasound. Statistical Analysis Standard descriptive statistics (eg, mean and coefficient of variation [expressed as a percentage, %CV]) were used to characterize the results. RESULTS N (%) or Mean (Range) No. of subjects 16 White 16 (100%) Male 13 (81%) Female 3 (19%) Age (y) 35.7 (18 60) Time since injury (y) 8.9 (1 25) Neurologic level of injury Cervical 14 (87.5%) Thoracic 2 (12.5%) AIS* grade B 2 (12.5%) C 6 (37.5%) D 8 (50.0%) *The AIS 33 uses the findings from neurologic examinations to categorize injury type into specific categories. AIS grade A (complete injury) is the most severe degree of impairment. Subjects with AIS grade B, C, or D (incomplete injury) have lesser degrees of sensory and/or motor function impairment. Subjects with AIS grade E have normal motor and sensory function. Subject Demographics and Disposition Sixteen subjects were enrolled in this study; their demographic characteristics are shown in table 1. Eleven subjects (68.8%) completed the entire study. Five subjects discontinued treatment before the end of the study; of these, 3 discontinued treatment during the first dosing phase (1 for reasons unrelated to the study medication, 2 because of adverse events) (see Safety section). Two subjects who completed the first dosing phase elected not to continue with the second phase. All of the 11 subjects who entered the second dosing phase of the study completed it. Pharmacokinetic parameters were calculated for the 15 subjects with sufficient data to adequately assess the full pharmacokinetic profile of Fampridine-SR for at least 1 dosage level. Complete data at all dosages were available for 11 subjects. All 16 subjects enrolled in the study were evaluated for safety. Pharmacokinetics All predose plasma samples had measurable Fampridine concentrations, except for 1 predose sample in a subject receiving the highest dosage (60mg twice daily). Mean predose plasma levels for the subset of 11 subjects completing both dosing phases of the study were 27.2, 35.6, 37.9, 40.5, 54.8, and 68.1ng/mL for Fampridine-SR dosages of 25, 30, 35, 40, 50, and 60mg twice daily, respectively. The principal Fampridine-SR steady-state pharmacokinetic parameters for the 11 subjects who completed both dosing phases are summarized in table 2. Figure 1 shows mean plasma concentrations by time and dosage level for these subjects. Across all dosage levels, Fampridine concentrations increased postdose and were still detectable at the final time point (12-h postdose). Mean C max, C min, and C av, as well as AUC 0 12 increased as Fampridine-SR dosages increased. These monotonic trends for both steady-state C max and AUC 0 12 are shown in figure 2. Fampridine-SR was slowly absorbed and eliminated, with mean t max occurring 2.2 to 3.0 hours postdose and with a mean t 1/2 of 5.7 to 6.9 hours (table 2). The %CV for postdose plasma concentrations was relatively low and constant across all dosage levels, except for that of C min (table 2). The %CV for C max ranged from 16.0% to 24.6% and for C min ranged from 22.1% to 49.2% (table 2). Mean C max for the lowest Fampridine-SR dosage (25mg twice daily) was 63.4ng/mL, whereas mean C max for the highest Fampridine-SR dosage (60mg twice daily) was 152.0ng/mL (table 2). Mean V d /F ( L) and Cl/F ( L/h) were independent of dosage, as were t max and t 1/2 across dosages. Safety Adverse events occurred in all 16 subjects after administration of Fampridine-SR during the 17-week study period. All adverse events were mild or moderate in severity. If an adverse event occurred more than once for a particular patient at a single dosage level, only the event with the greatest severity is shown. Adverse events occurring in 2 or more subjects after Fampridine-SR dosages during weeks 1 to 5 and 13 to 15 are Parameter Table 2: Fampridine-SR Steady-State Pharmacokinetic Parameters for 11 Subjects With Complete Data Fampridine-SR Dosage (mg twice daily) C max (ng/ml) (18.7%) (24.6%) (16.0%) (18.8%) (19.2%) (16.6%) C min (ng/ml) (22.1%) (49.2%) (36.5%) (26.7%) (45.8%) (35.4%) C av (ng/ml) (14.1%) (22.6%) (20.7%) (17.5%) (24.5%) (15.0%) t max (h) (40.1%) (60.6%) (51.0%) (50.8%) (63.3%) (66.7%) AUC (ng hr 1 ml 1 ) (13.8%) (21.3%) (20.9%) (17.5%) (24.7%) (15.2%) t 1/2 (h)* (21.4%) (56.1%) (49.2%) (32.4%) (33.6%) (40.3%) NOTE. Results are mean and %CV. *Calculated as.693/ z, where the group harmonic mean is defined as.693/mean z ( z elimination rate constant).

4 32 PHARMACOKINETICS OF FAMPRIDINE-SR IN SCI, Hayes Other Measures This was not a placebo-controlled, randomized study; therefore, these results cannot be interpreted as an efficacy analysis and we could not determine whether the response was drug related or a placebo effect. Fig 1. Mean plasma concentrations by time and dosage level for the 11 subjects completing the study. Abbreviation: bid, twice daily. listed in table 3. During the entire 17-week study, dizziness was the most frequently reported adverse event, with 19 episodes reported by 10 patients. Dizziness was followed in frequency by UTI (n 6), paresthesia (n 6), ataxia (n 4), and insomnia (n 4). The majority of these adverse events were considered at least possibly related to study drug. There was no apparent relationship between frequency of any individual adverse event, including dizziness, and dosage. There were no serious adverse events or deaths. Two subjects withdrew from the study because of adverse events. One subject (a 21-year-old man) withdrew while receiving 25mg of Fampridine-SR twice daily after experiencing light-headedness and a 20mmHg decrease in both systolic (SBP) and diastolic (DBP) blood pressure. The second subject (a 32-year-old man) withdrew while receiving 40mg of Fampridine-SR twice daily after experiencing dizziness, anxiety, and paresthesia. Two subjects accidentally took double doses of Fampridine-SR, and, in both instances, each dose was taken within a few minutes of the other. Each subject took a scheduled twice-daily dose as a single dose; 1 subject took 100mg and the other took 80mg. The subjects reported profuse sweating and numbness of the hands and forehead (100mg) and profuse sweating, tingling across the forehead, and tingling with a loss of sensation in the arms (80mg). Dosing was interrupted for blood work and monitoring. Both subjects recovered and continued the study. No clinically significant changes were detected among clinical laboratory tests (serum chemistry, hematology, urinary analyses) and ECGs. Generally, mean changes from baseline in DBP and SBP over the course of treatment were minimal, fluctuating from 1 to 3mmHg. Similarly, there was little effect on pulse, with an average fluctuation of less than 5bpm over the course of the study. Seven subjects had clinically significant changes from baseline in 1 or more vital sign or physical examination measurements during treatment with Fampridine- SR. Seven subjects had a decrease in body temperature ( F). One subject had a decrease in DBP (20mmHg), 1 subject had a decrease in SBP (30mmHg), and 2 subjects had a decrease in body weight (5.4kg and 12.6kg [12lb and 28lb]). There may have been 1 treatment-related effect evident on physical examination an increase in back pain unrelated to SCI. DISCUSSION Fampridine is a potassium channel blocking agent that has been shown to restore some neurologic function in subjects with chronic SCI 3-7,16,27-31 and MS. 9-11,13,23 Even though Fampridine has not been approved for use in the United States, it appears to have a place in therapy, because many physicians regularly prescribe immediate-release Fampridine (obtained through compounding pharmacies) to subjects with chronic SCI or MS. The relatively short half-life of Fampridine when delivered in its basic form, as a simple oral (gelatin) capsule and triturated with lactose, is approximately 3.5 hours and necessitates that subjects take 4 or more daily doses. 21 Fampridine-SR was developed with a longer plasma half-life to circumvent this problem, allowing for less frequent and more convenient dosing. In our study, Fampridine-SR was shown to be slowly absorbed (t max, h) and eliminated (t 1/2, h); these data are comparable with previously reported Fampridine-SR pharmacokinetic data. 24,32 These results confirm that Fampridine-SR can be administered in a convenient twice-daily manner. In addition to examining the pharmacokinetics of Fampridine-SR, this study also assessed safety. The results of our study confirm and extend those of previous studies that Fampridine is well tolerated. 24,28 All adverse events reported in our study were mild or moderate, with the most frequently reported adverse event being dizziness. No serious adverse events were reported. CONCLUSION Fampridine has been shown to restore some neurologic function in subjects with chronic SCI and MS. The efficacy and safety of a sustained-release formulation of Fampridine is currently being investigated in subjects with chronic SCI and MS. In our study, we showed that, in terms of the pharmacokinetics and safety, Fampridine-SR appears well suited for clinical use in subjects with chronic, incomplete SCI. Orally administered Fampridine-SR was slowly absorbed and eliminated, which will allow it to be administered in a convenient Fig 2. Mean C max and AUC 0 12 versus Fampridine-SR dosage level for the 11 subjects completing the study. Vertical bars represent standard deviation.

5 PHARMACOKINETICS OF FAMPRIDINE-SR IN SCI, Hayes 33 Adverse Event Week 1 20 (N 16) Week 2 25 Table 3: Adverse Events Occurring in 2 or More Subjects Week 3 30 Week 4 35 Fampridine-SR Dosage (mg twice daily) Week 5 40 Week 13* 40 (n 11) Week (n 11) Week (n 11) Total No. of Subjects Reporting Each Adverse Event Dizziness 2 (13%) 4 (29%) 2 (14%) 3 (21%) 2 (14%) 1 (9%) 3 (27%) 2 (18%) 10 UTI 0 1 (7%) 0 3 (21%) 2 (14%) Paresthesia 2 (13%) 0 1 (7%) (9%) 1 (9%) 1 (9%) 6 Ataxia (7%) 0 1 (9%) 2 (18%) 4 Pain 3 (19%) (7%) Sweating 0 1 (7%) 1 (7%) 1 (7%) (9%) 0 2 Headache 0 1 (7%) 0 1 (7%) 1 (7%) Hypertonia 1 (6%) (18%) 3 Hypesthesia (18%) 1 (9%) 3 Nausea 2 (13%) (9%) 2 Anxiety (7%) 0 1 (9%) 0 2 Back pain 0 2 (14%) Circumoral paresthesia 1 (6%) (9%) 0 2 Diarrhea 1 (6%) 0 1 (7%) Insomnia 1 (6%) 0 1 (7%) (18%) Rhinitis 2 (13%) Skin ulcer (7%) (9%) 2 Urine abnormality (7%) 1 (7%) NOTE. Values are n (%). *Week 13: patients were being titrated up to the higher dosages of 50 and 60mg twice daily after the interim period (weeks 6 11). twice-daily manner. Moreover, Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily in subjects with chronic SCI. These doses are higher than have been studied previously. 24,32 References 1. Spinal cord injury: facts and figures at a glance. J Spinal Cord Med 2000;23: Canadian Paraplegic Association. Workforce participation survey of Canadians with spinal cord injury. Available at: canparaplegic.org/pdf/1/wforce.pdf. Accessed March 21, Potter PJ, Hayes KC, Segal JL, et al. Randomized double-blind crossover trial of fampridine-sr (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury. J Neurotrauma 1998;15: Hansebout RR, Blight AR, Fawcett S, Reddy K. 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. J Neurotrauma 1993;10: Potter PJ, Hayes KC, Hsieh JT, Delaney GA, Segal JL. Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Spinal Cord 1998;36: Segal JL, Brunnemann SR. 4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury. Pharmacotherapy 1997;17: Segal JL, Brunnemann SR. 4-Aminopyridine alters gait characteristics and enhances locomotion in spinal cord injured humans. J Spinal Cord Med 1998;21: Segal JL, Pathak M, Himber PL, Hernandez JP, Brunnemann SR. 4-Aminopyridine long-term administration to spinal cord injured humans improves sensorimotor function and is not associated with toxicity [abstract]. Clin Invest Med 1998;21(Suppl): Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology 1997;48: Polman CH, Bertelsmann FW, de Waal R, et al. 4-Aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis. Arch Neurol 1994;51: Polman CH, Bertelsmann FW, van Loenen AC, Koetsier JC. 4-Aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. Arch Neurol 1994;51: Bever CT Jr. The current status of studies of aminopyridines in patients with multiple sclerosis. Ann Neurol 1994;36(Suppl): S Bever CT Jr, Young D, Anderson PA, et al. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. Neurology 1994;44: Blight AR. Effect of 4-aminopyridine on axonal conduction-block in chronic spinal cord injury. Brain Res Bull 1989;22: Bowe CM, Kocsis JD, Targ EF, Waxman SG. Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Ann Neurol 1987;22: Hayes KC. 4-Aminopyridine and spinal cord injury: a review. Restor Neurol Neurosci 1994;6: Qiao J, Hayes KC, Hsieh JT, Potter PJ, Delaney GA. Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury. J Neurotrauma 1997;14: Shi R, Blight AR. Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 1997;77: Smith KJ, Felts PA, John GR. Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain 2000; 123(Pt 1): Evenhuis J, Agoston S, Salt PJ, de Lange AR, Wouthuyzen W, Erdmann W. Pharmacokinetics of 4-aminopyridine in human volunteers. A preliminary study using a new GLC method for its estimation. Br J Anaesth 1981;53: Hayes KC, Katz MA, Devane JG, et al. Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury. J Clin Pharmacol 2003;43: Donovan WH, Halter JA, Graves DE, et al. Intravenous infusion of 4-AP in chronic spinal cord injured subjects. Spinal Cord 2000;38:7-15.

6 34 PHARMACOKINETICS OF FAMPRIDINE-SR IN SCI, Hayes 23. Davis FA, Stefoski D, Rush J. Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol 1990;27: Hayes KC, Potter PJ, Hansebout RR, et al. Pharmacokinetic studies of single and multiple oral doses of fampridine-sr (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury. Clin Neuropharmacol 2003;26: Metropolitan height and weight tables. Stat Bull Metrop Life Found 1983;64: Agency for Toxic Substances and Disease Registry (ATSDR). ToxFAQs for pyridine. Available at: tfacts52.html. Accessed March 21, Hayes KC, Blight AR, Potter PJ, et al. Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia 1993;31: Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA, Blight AR. 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J Neurotrauma 1994;11: Segal JL, Pathak MS, Hernandez JP, Himber PL, Brunnemann SR, Charter RS. Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Pharmacotherapy 1999;19: Hayes KC, Potter PJ, Segal JL, et al. Effects of oral 4-aminopyridine on neurological function in patients with spinal cord injury [abstract]. J Neurotrauma 1995;12: Waxman SG. Aminopyridines and the treatment of spinal cord injury [editorial]. J Neurotrauma 1993;10: Segal JL, Hayes KC, Brunnemann SR, et al. Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury. J Clin Pharmacol 2000; 40: Maynard FM, Bracken MB, Creasey G, et al. International standards for neurological and functional classification of spinal cord injury. Spinal Cord 1997;35: Supplier a. Analytical Division, Drug Studies Unit, Department of Biopharmaceutical Sciences, University of California, South San Francisco, CA.