Herbert R. Henney

A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury

ABSTRACT Objective: Tizanidine is an imidazoline central α2-adrenoceptor agonist widely used to manage spasticity secondary to conditions such as multiple sclerosis (MS), stroke, and spinal cord injury (SCI). While there is widespread use of tizanidine in clinical practice, little practical information is available to assist prescribers with the effective use of tizanidine for spasticity management. The aim of this review is to provide an up-to-date overview of tizanidine and its use in the management of spasticity associated with acquired (SCI), static (stroke), and progressive neurological (MS) diseases. Scope: An unfiltered literature search of the term ‘tizanidine’ was undertaken on the Medline database resulting in 311 papers. As the review focused on tizanidine clinical pharmacokinetics, efficacy, and tolerability, with comparisons limited to the oral antispastic agents baclofen, diazepam, and dantrolene, 53 articles were selected for detailed assessment. Findings: Tizanidine, an α2-adrenoceptor agonist, is a short-acting drug with larger interpatient variability, and linear pharmacokinetics that is dosage form-dependent. Clinical trials have demonstrated that the efficacy of tizanidine is comparable to that of baclofen or diazepam with global tolerability data favoring tizanidine. A clinical case presentation demonstrated the effective use of tizanidine in combination with baclofen as a logical avenue for improved spasticity control. Conclusions: There is a large body of evidence for the effective use of tizanidine monotherapy in the management of spasticity. A case study demonstrates that combination therapy can effectively control spasticity while better managing dose-dependant adverse events, although additional studies need to be performed to confirm these results.

Single-Dose Pharmacokinetics of Sustained-Release Fampridine (Fampridine-SR) in Healthy Volunteers and Adults With Renal Impairment

Fampridine‐SR is a sustained‐release formulation of fampridine (4‐aminopyridine), a potassium channel blocker demonstrated to improve walking ability in patients with multiple sclerosis. This study evaluated the pharmacokinetics of fampridine and its metabolites after administration of fampridine‐SR 10 mg in healthy volunteers and in subjects with mild, moderate, or severe renal impairment (5 per group). Analysis of variance was used to calculate 90% confidence intervals (CIs) for the ratios (impaired/healthy) of least squares mean in maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC). Clearance was primarily through urinary excretion. In renally impaired subjects, fampridine plasma concentrations were consistently higher than in healthy individuals: ratios for Cmax ranged from 166.5% to 199.9% for mild and severe renal impairment, respectively. AUC0–∞ ratios ranged from 175.3% to 398.7%, respectively, for mild and severe renal impairment. Mean terminal disposition half‐life was 6.4 hours in healthy individuals, compared with 7.4, 8.1, and 14.3 hours in patients with mild, moderate, and severe renal impairment, respectively. Regression analysis confirmed the significant relationship between creatinine clearance and extent of exposure as quantified by AUC for fampridine and its metabolites, suggesting cautious use in patients with mild renal impairment and avoidance in cases of moderate or severe renal impairment.

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.

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

Abstract 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.

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

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.

Pediatric safety of tizanidine: clinical adverse event database and retrospective chart assessment.

AbstractBackground: Tizanidine is an imidazoline with central α2-adrenoceptor agonist activity at both spinal and supraspinal levels, which is indicated as a short-acting drug for the management of spasticity. Despite being used in pediatric populations, there is no adequate information or well controlled studies to document the safety and efficacy of tizanidine in this group. Objective: To evaluate the safety of tizanidine in the pediatric population. Methods: We compared spontaneous adverse event reports in the Acorda Therapeutics worldwide clinical adverse event database for children (≤16 years; n = 99) and adults (>16 years; n= 1153) who had received tizanidine and for whom at least one adverse event was reported, and performed a retrospective chart review of the safety of tizanidine in children (≤16 years; n = 76) at a large US pediatric neurology practice. Causality of adverse events in our worldwide clinical adverse event database were neither assessed nor assigned by the company. Results: When adverse events from the clinical adverse event database were collapsed into the 25 Medical Dictionary for Regulatory Activities (MedDRA; version 9.0) organ system classes, five classes were more frequent in adults (general disorders and administration site conditions [p = 0.0006], hepatobiliary disorders [p = 0.0031], nervous system disorders [p = 0.0108], skin and subcutaneous disorders [p = 0.0063], and vascular disorders [p = 0.0029]), while one class was more frequent in children (psychiatric disorders [p < 0.0001]). The most common adverse event classes in children were psychiatric disorders (52.5%) followed by nervous system disorders (29.3%), and gastrointestinal disorders (16.2%), whereas the most common adverse event classes in adults were nervous system disorders (42.4%), general disorders and administration site conditions (28.6%), and gastrointestinal disorders (21.3%). Serious adverse events were substantially less frequent in children than adults (19.2% vs 45.9%) in the clinical adverse event database. In the pediatric practice chart review, the incidence of adverse events in the MedDRA psychiatric disorders class was very similar (52.6%) to that for children in the clinical adverse event database, while the next most common classes were gastrointestinal disorders (14.5%), and nervous system disorders (13.2%). There were three deaths in children across the databases, including one from accidental exposure and two from cardiac events; the relationship of cardiac events in relation to tizanidine or other causes was difficult to assess with the limited available information. The major causes of death in adults were related to suicide or overdose. Minor, transient liver transaminase increases were occasionally reported; the effect of tizanidine could not be ruled out. Conclusion: The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.

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 <or= 0.035) increased to 1.14 (90% CI, 105.47%-127.01%), 1.16 (90% CI, 106.80%-130.53%), and 1.17 (90% CI, 103.95%-133.66%), respectively, when the contents were sprinkled, with 90% CIs laying outside the 0.80 to 1.25 ratio established by regulatory authorities for bioequivalence. A total of 31 adverse events were reported by 17 of the 28 subjects (61%), including 15 subjects (54%) with the intact capsule reporting 18 events and 11 subjects (39%) with the sprinkled contents reporting 13 events. No serious adverse events or deaths were reported, and no subjects were discontinued due to adverse events. CONCLUSIONS The contents of the tizanidine capsule sprinkled in applesauce were not bioequivalent to the intact 6-mg capsule in these fasted healthy volunteers. Therefore, if switching from the intact capsule to the capsule contents mixed in applesauce, monitoring for adverse events is recommended; in this situation, dose adjustment could be necessary.

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.

Abstract 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.

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

Abstract 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.