Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials.

BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). METHODS: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. RESULTS: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.

OBJECTIVE: To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic-clonic seizure or in the postictal period following a tonic-clonic or other seizure type, to assess pharmacokinetics and to assess tolerability. METHODS: An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax ); time to maximum concentration (Tmax ); and the area under the plasma concentration-time curve for time zero to last sampling time (AUC0-12 ) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed. RESULTS: Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic-clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period ≥ 5 min after a tonic-clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose. SIGNIFICANCE: Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic-clonic seizures or in the postictal periods following tonic-clonic or other seizure types.

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease.

PURPOSE: Levodopa (LD) is the most effective oral pharmacotherapy for the management of motor symptoms in Parkinson's disease. However, LD use is complicated by a progressive shortening of the duration of efficacy of a dose, resulting in episodes of inadequate responsiveness, or OFF periods. OFF periods may also occur unpredictably, partly due to the pharmacokinetic (PK) variability of oral LD, resulting from gastrointestinal dysfunction and from the effects of food on absorption. CVT-301 is a levodopa inhalation powder for the treatment of OFF period symptoms in patients on oral dopa-decarboxylase inhibitor/LD. PK and safety profiles of single dose CVT-301, administered with oral carbidopa (CD) and oral CD/LD, were examined in patients with Parkinson's disease in the fed state. METHODS: Eligible patients were aged 30-85 years, with a clinical diagnosis of Parkinson's disease and a body mass index of 18-32 kg/m2, and were receiving treatment with a stable regimen that included oral CD/LD (25/100 mg) (total LD, ≤800 mg/d). A high-fat/protein meal was eaten 4-5 h after the administration of the morning oral CD/LD dose. Blood samples for predose PK analysis were obtained after the meal, followed by a single inhaled dose of CVT-301 84 mg (+25 mg of oral CD) or oral CD/LD (25/100 mg) or vice versa in 2 dosing periods in a crossover design. Blood was sampled at 0, 5, 10, 15, 30, and 45 min and at 1, 1.5, 2, 3, and 4 h postdose. Tolerability assessments included treatment-emergent adverse events. FINDINGS: Twenty-three patients were enrolled (65.2% male; 87.0% white; mean age, 69.3 years; mean body mass index, 26.9 kg/m2; mean Parkinson's disease duration, 8.2 years; mean baseline LD dosage, 460.9 mg/d; 73.9% at Hoehn and Yahr stage <2.5). PK analyses were based on LD concentrations without baseline adjustment. Median Tmax values with CVT-301 and oral CD/LD were 15 and 120 min (P < 0.001). Cmax with CVT-301 was lower than with oral CD/LD (590.3 vs 844.3 ng/mL). C10min and C30min values with CVT-301 were approximately twice those with CD/LD (522.9 and 531.5 ng/mL vs 247.3 and 300.9 ng/mL, respectively). %CV for C5min to Cmax with CVT-301 was lower than that with oral CD/LD. The most common treatment-emergent adverse event was cough (CVT-301, 7 patients [30.4%]; oral CD/LD, 1 patient [4.5%]). IMPLICATIONS: PK properties showed that CVT-301 was more rapidly absorbed, with higher plasma LD concentrations in the first 45 min, and demonstrated lower interpatient variability, than was oral CD/LD in the fed condition. The study findings suggest that CVT-301 can be used without regard to food intake. ClinicalTrials.gov identifier: NCT03887884.

Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers.

BACKGROUND: Fampridine (4-aminopyridine) is a potassium channel blocker that has been evaluated as a treatment for patients with spinal cord injury and multiple sclerosis. OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of a single dose of an orally administered solution of (14)C-labeled fampridine in healthy volunteers. METHODS: In this open-label, single-dose study conducted in an inpatient setting, healthy adult men were administered an oral solution containing 15 mg of (14)C-labeled fampridine (100 microCi) in a fasted state. In addition to blood sampling for analysis of plasma (14)C-radioactivity at prescribed intervals over 7 days, all urine and feces were collected for analysis of drug recovery and disposition. Urine samples were also analyzed for metabolic profiling. Plasma pharmacokinetic parameters of the (14)C-radiolabeled drug were determined using standard liquid-scintillation techniques. Recovery was calculated to provide the total amount of radioactivity excreted as a proportion of the original dose. Nonhydrolyzed and hydrolyzed urine extracts were analyzed for radioactivity and metabolites using reverse-phase, isocratic high-performance liquid chromatography with spectrophotometric and radioactive detection. Tolerability was assessed through evaluation of vital signs, hematologic and other laboratory parameters, and electrocardiography. RESULTS: The 4 white male subjects had a mean (SD) age of 21 (2) years. No clinically significant abnormalities in vital signs, clinical chemistry, hematology, urinalysis, or electrocardiography were observed either before or during the study. Peak plasma radioactivity was reached at 1 hour after dosing, with a median concentration of 72.9 ng x mL(-1). There was complete disappearance of radioactivity by 24 hours (limit of quantitation, 400 disintegrations/min per peak), and the calculated median t(1/2) was 3.14 hours. Total cumulative recovery of (14)C-radioactivity was 96.36%, with only 0.51% of drug recovered in feces. On chromatography, 2 metabolites accounted for a low proportion of total urinary radioactivity (3% and 6% of total radioactivity in the interval from 0 to 4 hours after dosing; 17% and 9% in the interval from 8 to 12 hours after dosing). Three subjects reported mild and transient dizziness occurring 1 half-hour after dosing; this was considered possibly related to the study drug. CONCLUSION: Fampridine administered as an oral solution was rapidly absorbed and was nearly completely and rapidly eliminated as unchanged drug via urinary excretion, suggesting that it is unlikely to undergo substantial metabolic transformation.

Relative bioavailability of tizanidine hydrochloride capsule formulation compared with capsule contents administered in applesauce: a single-dose, open-label, randomized, two-way, crossover study in fasted healthy adult subjects.

BACKGROUND: The alpha2-adrenergic agonist tizanidine has been reported to have a narrow therapeutic index. A multiparticulate capsule formulation of tizanidine has been developed in an attempt to improve patient tolerability. OBJECTIVE: This study assessed bioequivalence between a single, intact, 6-mg capsule of tizanidine and the capsule contents sprinkled in applesauce in fasted healthy subjects. METHODS: Healthy male and female subjects aged 18 to 45 years completed 2 treatment periods: one with a tizanidine 6-mg capsule administered intact and the other with capsule contents sprinkled in applesauce. The 2 treatment periods had a 6-day washout period between administrations. Plasma tizanidine concentrations were determined for blood samples collected over 24 hours after administration. All treatment-emergent adverse events were recorded and graded by intensity and relationship to the study drug (not, improbable, possible, probable, definite) by the attending physician based on his or her clinical impression. RESULTS: A total of 19 men and 9 women (mean age, 26 years) completed the trial. Geometric mean natural logarithm-transformed AUC values (AUC(0-infinity) [AUC to infinity] and AUC(0-t) [AUC to the last measurable time point]) and C(max) ratios were significantly (P

Relative bioavailability of tizanidine 4-mg capsule and tablet formulations after a standardized high-fat meal: a single-dose, randomized, open-label, crossover study in healthy subjects.

BACKGROUND: An immediate-release, multiparticulate capsule formulation of tizanidine has been developed to modify tizanidine pharmacokinetic characteristics in an attempt to decrease adverse events (AEs) while maintaining effectiveness in the management of spasticity. OBJECTIVE: This study was designed to compare the pharmacokinetic properties and tolerability of a single dose (4 mg) of an immediate-release, multiparticulate tizanidine capsule versus a commercially available tablet (reference) administered after a standardized high-fat meal. METHODS: This single-dose, randomized, open-label, 2-way crossover study in healthy, nonsmoking adult subjects was conducted at MDS Pharma Services, Belfast, United Kingdom. Subjects were randomly assigned to receive the capsule-tablet or tablet-capsule treatment. The 2 treatment periods were separated by a 6-day washout period. All treatments were administered after a standardized high-fat meal. To determine plasma tizanidine pharmacokinetic properties, blood samples were collected over 24 hours after administration. The predetermined bioequivalence range for the test drug (capsule) was 80% to 125% of the reference drug (tablet). Drug tolerability was assessed using routine physical examination, including vital-sign measurements; laboratory analysis (hematology, biochemistry, and urinalysis); 12-lead electrocardiography; direct observation; spontaneous reporting; and non specific questioning. RESULTS: This study included 18 subjects (12 men, 6 women; mean [SD] age, 26 [7] years). The mean height and body weight of the subjects were 176 (8) cm and 70.1 (9.6) kg, respectively. The peak exposure, as measured by mean natural logarithm-transformed C(max) values, was significantly lower with the capsule compared with the tablet (2.7 vs 4.0 ng/mL; P < 0.019), and mean TmaX was significantly longer (2.6 vs 1.2 hours; P < 0.001). The 90% CIs for the capsule:tablet treatment ratios were 70.55 to 121.94 for AUC(0-lat) and 70.12 to 118.75 for AUC(0-infinity). The capsule did not achieve the protocol-defined definition of bioequivalence when given after a high-fat meal. All AEs were transient and mild in intensity, with asthenia being the most common event with the capsule and tablet formulations, occurring in 5 (28%) and 8 (44%) subjects, respectively. CONCLUSIONS: In this small study in healthy volunteers, after a single oral dose was administered following a high-fat meal, the mean C(max) was significantly lower and mean T(max) was significantly longer with the capsule formulation of tizanidine compared with the tablet. The capsule formulation was found not to be bioequivalent to the tablet when given with food. Based on these findings, caution is needed when a patient is switched between the capsule and tablet formulations of tizanidine, or when the timing of administration of either formulation is changed in relation to food ingestion.

Effects of food on the single-dose pharmacokinetics/pharmacodynamics of tizanidine capsules and tablets in healthy volunteers.

BACKGROUND: A multiparticulate capsule formulation of the alpha2-adrenergic agonist tizanidine has been developed to decrease C(max), AUC, and associated somnolence, while maintaining efficacy. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics and impact of somnolence on cognitive function after single doses of the tablet and capsule formulations of tizanidine under fed and fasted conditions in healthy volunteers. METHODS: This Phase I, single-dose, randomized, open-label, 4-way crossover study was conducted at MDS Pharma Services, Belfast, United Kingdom. Healthy male and female adult subjects received tizanidine (8 mg) as tablets and capsules under fasting and nonfasting conditions. Blood samples were collected to determine plasma tizanidine pharmacokinetic profiles, and computerized cognitive function tests were performed that yielded a validated composite score, Power of Attention, an index of sedation. RESULTS: Ninety-six patients were enrolled in the study (54 men, 42 women; mean [SD] age, 27 [8] years [range, 18-52 years]; mean [SD] body weight, 71.7 [12.4] kg [range, 46-102 kg]). Tizanidine tablets and capsules were found to be bioequivalent after fasting. In the fed state, mean C(max) and AUC(0-t) were substantially decreased, by 33.8% and 15.4%, comparing the capsules and tablets, respectively. The median T(max) increased significantly from 1.41 to 3.0 hours (P < 0.001). Administration of the capsules with food resulted in <20% difference in mean C(max) and AUC(0-t) compared with the fasting state, whereas mean C(max) and AUC(0-t) were 22.6% and 45.2% higher when the tablet formulation was administered with food. The onset of impairment in Power of Attention was significantly delayed from 0.75 to 1.5 hours postdose when capsules were administered with food compared with the other conditions (P < 0.001). The most commonly reported adverse events were asthenia, somnolence, and orthostatic hypotension. A significantly lower adverse event rate was observed in the combined capsules group compared with the tablets, suggesting that differences in tolerability may exist. CONCLUSIONS: The results of this study in healthy volunteers suggest that the capsule and tablet formulations of tizanidine were bioequivalent only in the fasted state. The capsule formulation exhibited a food effect that reduced C(max) and AUC(0-t), and significantly increased T(max), which was associated with a delay in cognitive impairment. The large interpatient variability in plasma profiles most likely dampened the ability to fully elucidate the differences between the 2 formulations.

Prescriber utilization of dalfampridine extended release tablets in multiple sclerosis: a retrospective pharmacy and medical claims analysis.

PURPOSE: This study aimed to characterize the prescribing of dalfampridine extended release (D-ER) 10 mg tablet treatment in people with multiple sclerosis (MS). METHODS: A retrospective cohort study was performed using Medco pharmacy and medical claims. Medical claims were used to identify MS patients with more than one prescription for D-ER with 1 year of prior continuous enrollment (n=704). These patients were matched 2:1 on age, sex, and health insurance source with a comparison group of MS patients who were treatment naïve for D-ER (n=1,403). Categorical data were analyzed by χ (2) test; ordinal data by Wilcoxon rank sum test; and continuous data by Student's t-test. RESULTS: Most patients were women aged 45-64 years. In the year preceding D-ER initiation, the prevalence of seizure and renal impairment was numerically lower in the D-ER cohort relative to those who were D-ER naïve (seizure: 3.1% versus 4.7%, respectively; renal impairment: 4.3% versus 5.1%, respectively); however, prescriptions for antiepileptic drugs in the two cohorts were comparable. In the year preceding treatment initiation, 62% of the D-ER cohort was prescribed MS-specific disease-modifying therapies relative to 45% who were D-ER naïve. CONCLUSION: Seizure and renal impairment rates among D-ER-naïve patients were consistent with published literature, yet rates among those prescribed D-ER during the year preceding treatment initiation were slightly lower than rates among D-ER-naïve patients. Given that D-ER is contraindicated in patients with history of seizure or moderate or severe renal impairment, lower rates may indicate that risk-minimization strategies contributed to the lower prevalence.

Dalfampridine Effects Beyond Walking Speed in Multiple Sclerosis.

BACKGROUND: Dalfampridine extended release (ER) improves walking in people with multiple sclerosis (MS), as demonstrated by walking speed improvement. This exploratory study evaluated treatment effects of dalfampridine-ER on gait, balance, and walking through treatment withdrawal and reinitiation. METHODS: Dalfampridine-ER responders, based on Timed 25-Foot Walk (T25FW) assessment before study entry, were included in this open-label, three-period, single-center study. Period 1: on-drug evaluations performed at screening and 1 week after screening. Period 2: dalfampridine-ER withdrawal and off-drug evaluations (days 5 and 11). Period 3: dalfampridine-ER reinitiation/final on-drug evaluation (day 15). PRIMARY OUTCOME VARIABLES: NeuroCom composite scores for gait and balance; balance was evaluated if gait changes were significant. Secondary variables: individual NeuroCom scores, walking speed (T25FW) and distance (2-Minute Walk Test [2MWT]), and balance (Berg Balance Scale [BBS]). RESULTS: All 20 patients completed the study: mean age, 53.1 years; mean MS duration, 11.3 years; mean time taking dalfampridine-ER, 315.3 days. NeuroCom gait composite scores worsened during period 2 relative to period 1 and improved during period 3; the mean ± SD difference in gait composite scores on drug was 4.03 ± 1.51 points (P = .015). Balance composite scores did not change significantly. Improvements were observed for off-drug versus on-drug for T25FW (0.36 ft/sec, P < .001), 2MWT (25.4 ft, P = .006), and BBS (1.7 points, P = .003). Safety profile was consistent with previous studies. CONCLUSIONS: Significant improvements in gait, walking speed, distance, and balance were demonstrated by dalfampridine-ER reinitiation after a 10-day withdrawal period.

Assessment of confirmed urinary tract infection in patients treated with dalfampridine for multiple sclerosis.

Urinary tract infections (UTIs) were reported frequently with dalfampridine extended-release (dalfampridine-ER) 10 mg relative to placebo in previous multiple sclerosis (MS) studies. The objective of this study was to determine whether dalfampridine-ER is associated with increased incidence of confirmed UTIs in MS patients. This post hoc analysis used UTI data from a study comparing the 4-week safety and efficacy of 5 mg (n = 144) and 10 mg (n = 142) twice-daily dalfampridine-ER versus placebo (n = 143). To confirm UTIs, three clinical assessments were used: standard urinalysis (leukocytes > 5/high-power field); urine culture (≥ 100,000 and ≥ 10,000 colony-forming units [CFUs]/mL) for those who reported UTIs as adverse events (AEs) or had positive urinalysis; and UTI symptomatology. Fisher's exact test assessed statistical significance. The proportion of patients who reported UTIs as AEs in the placebo and dalfampridine-ER 5 mg and 10 mg groups were 5.6%, 6.3%, and 9.9%, respectively. In comparison, those with laboratory-confirmed UTIs were lower: ≥ 100,000 CFUs/mL: 4.2%, 2.8%, and 2.8%; and ≥ 10,000 CFUs/mL: 4.2%, 3.5%, and 4.9%, respectively (no significant statistical difference across treatments). The proportion of patients with confirmed UTI was similar between dalfampridine-ER and placebo, thus suggesting that the treatment does not increase the risk of UTIs.

Dalfampridine in chronic sensorimotor deficits after ischemic stroke: A proof of concept study.

OBJECTIVE: To evaluate the safety and tolerability of dalfampridine extended release (D-ER) in participants with chronic post-ischemic stroke deficits, and to assess for potential drug activity on sensorimotor function. METHODS: Using a double-blind, placebo-controlled, cross-over design, participants were randomized to placebo/D-ER or D-ER/placebo sequences and given D-ER 10 mg or placebo twice daily. Key inclusion criteria were: ischemic stroke ≥ 6 months, Fugl-Meyer Assessment lower extremity motor score ≤ 28, ability to complete Timed 25-Foot Walk (T25FW). The primary outcome was safety and tolerability. The key exploratory measure was walking speed (T25FW). Other assessments were: Box and Block, and Grip and Pinch tests; Functional Independence Measure. Full-crossover data were analyzed using mixed-effects model. RESULTS: A total of 83 participants were randomized: 70 completed and 13 discontinued the study. Adverse events were consistent with previous D-ER trials; no new safety signals were observed. Four participants experienced serious adverse events: 3 seizures (1 placebo, 2 D-ER), 1 was secondary to intentional overdose. Most common treatment-emergent adverse events were: dizziness, nausea, arthralgia and fatigue. Mixed-effects analysis showed an effect for D-ER vs. placebo in improving walking speed (0.21 vs. 0.10 ft/s; p = 0.027). CONCLUSIONS: D-ER was generally well tolerated in participants with chronic stroke deficits. Potential drug activity on lower extremity sensorimotor function, with an improvement in walking speed, was seen.

Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial.

BACKGROUND: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

Development of dalfampridine, a novel pharmacologic approach for treating walking impairment in multiple sclerosis.

Walking impairment is a clinical hallmark of multiple sclerosis (MS). Dalfampridine-ER, an extended-release formulation of dalfampridine (also known by its chemical name, 4-aminopyridine, and its international nonproprietary name, fampridine), was developed to maintain drug plasma levels within a narrow therapeutic window, and assessed for its ability to improve walking in MS. The putative mechanism of action of dalfampridine-ER is restoration of axonal conduction via blockade of the potassium channels that become exposed during axonal demyelination. Two pivotal phase III clinical trials demonstrated that dalfampridine-ER 10-mg tablets administered twice daily improved walking speed and patient-reported perceptions of walking in some patients. Dalfampridine-ER was generally well tolerated, and, at the approved dose, risk of seizure was neither elevated relative to placebo nor higher than the rate in the MS population. Dalfampridine-ER (AMPYRA®) was approved in the United States for the treatment of walking in patients with MS as demonstrated by an increase in walking speed. The use of the dalfampridine-ER is contraindicated in patients with a history of seizure. It is the first pharmacologic therapy for this indication and has been incorporated into clinical management of MS.

Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.

Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.

Pharmacokinetics of dalfampridine extended release 7.5-mg tablets in healthy subjects and individuals with mild and moderate renal impairment: an open-label study.

Dalfampridine extended release tablets (D-ER; prolonged-release fampridine in Europe) are available to improve walking in patients with multiple sclerosis (MS). D-ER is mainly renally eliminated; the approved 10-mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. This study evaluated single-dose and steady-state pharmacokinetics of a 7.5-mg dose of D-ER in healthy subjects (n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. D-ER plasma concentrations were consistently higher in subjects with renal impairment relative to healthy individuals with a significant (P < .0001) inverse linear relationship between creatinine clearance and drug exposure. Steady-state AUC0-12 among healthy subjects, 167.0 ± 55.3 ng h/mL, increased 74% and 151% with mild and moderate renal impairment, respectively. The overall incidence of adverse events was 61.5%, 47.1%, and 33.3% in healthy subjects, and subjects with mild and moderate renal impairment, respectively, and for treatment-related adverse events the rates were 0%, 17.6%, and 8.3%, respectively. The most common adverse events were headache, dizziness, and arthralgia. The pharmacokinetics of D-ER 7.5-mg twice daily in subjects with mild renal impairment was comparable to 10-mg twice daily in patients with MS who had normal renal function. Exposure was significantly higher in moderate renal impairment.

Population pharmacokinetics and pharmacodynamics of dalfampridine-ER in healthy volunteers and in patients with multiple sclerosis.

OBJECTIVE: Using data pooled from several studies of dalfampridine extended release (ER), a population pharmacokinetic model was developed for the purposes of characterizing the population pharmacokinetics and pharmacodynamics of dalfampridine-ER with respect to variability in pharmacokinetics, covariates affecting the pharmacokinetics, and whether the current therapeutic dosage represents an optimal dosage. Studies were conducted in healthy volunteers and multiple sclerosis (MS) patients over the course of development and registration of dalfampridine extended release tablets (dalfampridine-ER [Ampyra *]; prolonged-, modified- or sustained-release fampridine [Fampyra †] in some countries). METHODS: The model used to best describe the population pharmacokinetics of dalfampridine-ER was an open, one-compartment model with first-order absorption, first-order elimination and an absorption lag time. RESULTS: The population median estimated oral clearance was 36 L/h for a 50-year-old woman with a creatinine clearance of 105 mL/min and 42 L/h for a comparable man. The typical volume of distribution was 304 L for women and 403 L for men. The estimated absorption rate constant was 1.22 hours(-1) in the fasted state and 2.22 hours(-1) when given with food. The covariates identified as having a significant effect (p < 0.01) on model fit were food and gender on absorption rate, and gender, age and creatinine clearance on oral clearance. Only creatinine clearance and age are of clinical relevance. Concomitant medications did not affect any of the parameters in the model. Exposure-response relationships for both efficacy and safety were consistent with what has been observed in clinical trials. Limitations of this study include some reliance on unpublished data, and the limited effectiveness of the model for determining the likelihood of the efficacy and safety of dalfampridine-ER in clinical practice. CONCLUSIONS: The approved therapeutic dosage regimen of dalfampridine-ER 10 mg twice daily was identified as the optimum dosing regimen based on model-predicted exposure response relationships for efficacy and adverse events. A limitation of this study is the limited effectiveness of the models used to predict long-term efficacy and safety of dalfampridine-ER in clinical use.

Pharmacokinetic profile of dalfampridine extended release: clinical relevance in patients with multiple sclerosis.

BACKGROUND: In January 2010, dalfampridine extended release tablets (dalfampridine-ER [Ampyra *]; prolonged-, modified- or sustained-release fampridine [Fampyra †] in some countries), 10 mg to be administered twice daily approximately 12 hours apart, were approved by the US Food and Drug Administration. This was the first drug indicated to improve walking in patients with MS. SCOPE: Publications describing the pharmacokinetics of dalfampridine-ER or the immediate release formulation were identified from a search of PubMed through June 2012 using the search terms 'dalfampridine OR fampridine OR 4-aminopyridine' AND 'pharmacokinetics' and were supplemented with unpublished studies made available by Acorda Therapeutics Inc. FINDINGS: Pharmacokinetic studies show dose proportionality, with dalfampridine-ER having a more favorable profile than immediate-release dalfampridine. With twice-daily dosing of dalfampridine-ER, time to peak plasma concentration (3.2-3.9 hours) and apparent terminal plasma half-life (5.6-6.4 hours) are approximately twice those of immediate-release formulations, with comparable overall exposure and peak plasma concentrations (21.6 ng/mL) that were maintained at levels approximately 50% lower than immediate release. Steady state is achieved within 39 hours; pharmacokinetics are predictable based on single dosing. Trough plasma concentrations of 13-15 ng/mL are required to maintain efficacy. Renal excretion is predominantly as unchanged compound, and renal clearance in healthy individuals exceeds the glomerular filtration rate. Since dalfampridine-ER exposure increases with renal impairment, it is contraindicated in patients with moderate or severe impairment in the US, and in patients with any renal impairment in the European Union. CONCLUSIONS: Dalfampridine-ER has low protein binding, is not a substrate for p-glycoprotein and does not affect CYP450 enzymes, suggesting a low potential for drug-drug interactions. Because of the narrow therapeutic range and risk of adverse events, including seizure, with increasing plasma concentrations, the recommended dose and regimen of dalfampridine-ER should not be exceeded and not be used with other dalfampridine formulations. A limitation of this review is that it includes some data that have not yet been published.

Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US.

BACKGROUND: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. OBJECTIVE: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. METHODS: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. RESULTS: THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (∼5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (∼5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. CONCLUSION: Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold.

Walking impairment in patients with multiple sclerosis - a new therapeutic approach and clinical potential of dalfampridine extended release tablets.

Walking impairment is a clinical hallmark of multiple sclerosis (MS) that has been under-recognized as a therapeutic target for pharmacologic intervention. The development and approval of dalfampridine extended release tablets (dalfampridine-ER; known as prolonged-, modified, or sustained-release fampridine outside the USA), 10 mg taken twice daily, to improve walking in patients with MS, fills a previously unmet need. In three randomized, double-blind, placebo-controlled trials, dalfampridine-ER improved walking speed in approximately one-third (37%) of treated patients, and average walking speed on therapy among these responders improved by approximately 25% relative to baseline. Walking-speed improvement among responders was clinically significant, as determined by a statistically significant improvement in the patient-reported 12-item Multiple Sclerosis Walking Scale. Long-term extension studies indicate that responders were able to maintain benefits, compared with nonresponders over prolonged periods of treatment. Dalfampridine-ER was generally well tolerated. Dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, and asthenia were the most common adverse events. Although the incidence of seizures appeared to be dose related, among patients treated with dalfampridine-ER in the three trials, the rate of seizures was 0.25%. These efficacy and safety data suggest that dalfampridine-ER can be a useful and clinically relevant addition to the pharmacologic armamentarium for the management of MS symptoms and disabilities. Because of its narrow therapeutic index and potential for seizures, it is especially important in the clinical setting to adhere to the dosing recommended in the approved labels.

Effect of food on the single-dose pharmacokinetics and tolerability of dalfampridine extended-release tablets in healthy volunteers.

PURPOSE: The pharmacokinetics, bioavailability, and tolerability of dalfampridine extended-release tablets in healthy adults under fed and fasted conditions were evaluated. METHODS: The study participants (n = 30) were randomly assigned to receive one 10-mg dalfampridine tablet in a fasted condition (no food for 10-12 hours) or a fed condition (after a high-fat meal); after a seven-day washout period, participants received the same dalfampridine dosage under the converse condition. The endpoints were the maximum plasma drug concentration (C(max)) and areas under the plasma-concentration curve (AUC) for 24-hour exposure (AUC(0-24)) and total exposure (AUC(0-∞)). A 90% two-sided confidence interval (CI) within predefined limits for the fed:fasted ratio of the geometric mean values was used as the standard for determining the absence of a significant food effect. RESULTS: Among the participants who received both treatments (n = 28), food intake was associated with a 23% increase in the log-transformed geometric mean C(max) of dalfampridine (p ≤ 0.10) but no significant change in mean AUC values. Eight (26.7%) of the study participants reported a total of 13 adverse events (AEs), of which only dizziness and upper abdominal pain occurred in more than one participant; all AEs were of mild-to-moderate severity. CONCLUSION: When a single 10-mg dose of dalfampridine was given to healthy volunteers after a high-fat meal, a significant increase in C(max) was observed. However, overall differences in dalfampridine pharmacokinetics when the drug was administered to participants under fasting and fed conditions did not exceed predefined limits, indicating that the extended-release formulation may be taken without regard to meals.