Topiramate Is Absorbed Rapidly Biology Essay

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Topamax topiramate is an anti-epileptic drugs AEDs approved by the FDA to treat seizures in adults and children with epilepsy.1,2 Additionally, topiramate is indicated for the prevention of migraine headaches. 1,2 It is considered a broad spectrum AED because it works to prevent both partial onset and generalized seizures. 1,2 The exact mechanism of action of topiramate is not known. 1 There are several potential mechanisms: the blocking of voltage-sensitive sodium channels; enhancement of GABA-A receptors; inhibitory effect of glutamate receptors; weak carbonic anhydrase inhibitor (isozymes II and IV). 1,2 Data from clinical trials for epilepsy has associated the drug with weight loss.3

After oral administration, topiramate is absorbed rapidly with peak plasma concentrations occurring about 2 hours after a 400 mg dose. 1,2 Bioavailability is 80% orally versus solution and is not affected by food. 1,2 Oral sprinkle capsules are bioequivalent to the tablets. 1,2 The protein binding of topiramate ranges from 15%-41% to human plasma proteins over the concentration range of 0.5-250 mcg/ml. 1,2 It is not extensively metabolizes. 1,2 There are six metabolites that have been identified which are formed via hydroxylation, hydrolysis, and glucuronidation. 1,2 These metabolites constitute less than 5% of an administered dose. 1,2 Topiramate is 70% eliminated as unchanged drug in the urine. 1,2 Animal studies suggests that topiramate may undergo renal tubular reabsorption. 1,2 The mean plasma elimination half-life is 21 hours following single or multiple doses. 1,2 Steady-state concentrations are reached in 4-8 days in adult patients with normal renal function. 1,2 In hepatically impaired patients, topiramate clearance may be decreased. 1,2 The clearance of topiramate is reduced by roughly 42% in moderate renal impairment; steady-state may be increased to 10-15 days. 1,2 The weight-adjusted clearance of topiramate is roughly 50% higher in children versus adults. 1,2 With the same mg/kg dose, plasma concentrations in children may be lower than in adults. 1,2 Absorption and clearance of topiramate is not affected in elderly patients. 1,2

Topiramate carries an increased risk of suicidal ideation and behavior.3 An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%).3 Depression was also an adverse effect reported during clinical trials and accounted for 2.6% of patients who discontinued. 3 The most commonly reported adverse reactions were drowsiness, dizziness, ataxia, aphasia, psychomotor impairment, nystagmus, and paresthesias. 3 A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate who do not have a history of such conditions. 3 Symptoms and signs include acute onset of visual impairment and/or ocular pain, diplopia, myopia, blurred vision, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure.1,2 Topiramate has weak carbonic anhydrase inhibitor activity and some adult patients report nephrolithiasis. 1,2 Oligohidrosis and hyperthermia have occurred primarily in children who were exposed to elevated environmental temperatures or were performing vigorous activity. 1,2

Literature search:

Literature search was conducted using EMBASE Drugs and Pharmacology (1980 to 4th Quarter 2003(, and MEDLINE databases (1966 to November week 1 2003). Key words included topiramate, weight, weight loss, and the search was limited to humans, English language, and clinical trials. The number of articles found was 80 and 3 articles were chosen for further evaluation.

DATA:

Bray G, et al5 study results: the objective was to evaluate the efficacy and safety of topiramate for weight loss in healthy obese subjects. 5 It was a six-month, placebo-controlled, dose-ranging study with 385 obese patients randomized to placebo or topiramate. 5 385 subjects (18 and 75 years of age) were randomized to receive either placebo or topiramate at 64-, 96-, 192-, or 384- mg daily. 5 Dosing began at 16 mg once daily. 5 In week 2, the dose was increased to 16 mg twice daily. 5 Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. 5 Twenty-four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. 5 All participants received the same lifestyle program. 5 Mean percent weight loss from baseline to week 24 was 2.6% in placebo-treated patients vs. 5.0%, 4.8%, 6.3%, and 6.3% in the 64 mg/d, 96 mg/d, 192 mg/d, and 384 mg/d topiramate groups, respectively. 5 Greater percentages of topiramate-treated patients lost at least 5% or 10% of body weight compared with placebo. 5 The most frequent adverse events were related to the central or peripheral nervous system: paresthesia, somnolence, and difficulty with memory, concentration, and attention. 5 Most events were dose-related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving topiramate withdrew due to adverse events compared with 11% on placebo. 5 TPM produced significantly greater weight loss than placebo at all doses. 5

Wilding J, et al6 study results: The objective of this randomized, double-blind, placebo-controlled study was to investigate the long-term efficacy and safety of topiramate in obese subjects. 6 1289 obese subjects (18-75 y with a body mass index >/=30 kg/m(2) and <50 kg/m(2) in the absence of comorbidities, or >/=27 kg/m(2) and <50 kg/m(2) in the presence of controlled hypertension and/or dyslipidemia) randomized to placebo or topiramate doses 96-, 192-, or 256- mg/day. 6 All subjects also participated in a nonpharmacological weight-loss program. 6 This trial was terminated early due to the sponsor's desire to pursue a time-release formulation. 6 The 854 subjects completed one year of the trial before it was terminated. 6 These patients lost 1.7%, 7%, 9.1%, and 9.7% of their initial body weight in the placebo, 89-, 192-, and 256-mg groups, respectively (P<0.001). 6 Participants in the topiramate groups also had significant improvement in blood pressure and glucose tolerance. 6 Topiramate treatment of obese subjects over the course of 1 year resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.6

Astrup A, et al7 study results: The objective of this study was to examine the safety and efficacy of topiramate (TPM) for maintaining weight following a low-calorie diet. 7 701 obese subjects enrolled (30 < or = BMI < 50 kg/m(2)), 18 to 75 years old, and received a low-calorie diet for 8 weeks. 7 Those who lost > or =8% of their initial weight received TPM (96 or 192 mg/d) or placebo; all were on a lifestyle modification plan. 7 Efficacy was analyzed in subjects who completed 44 weeks of treatment before study termination. 7 Subjects were treated with a very low-calorie diet to induce an 8% loss of initial body weight. 7 560 subjects achieved an 8% weight loss and were randomized topiramate 96- or 192- mg/day, or placebo. 7 This study was terminated early as well. 7 At the time of termination, 293 subjects had completed 44 weeks of the trial. 7 Participants in the topiramate groups lost 15.4% and 16.5% of their baseline weight and the placebo group lost 8.9% (p < 0.001). 7 During a treatment period of 44 weeks, TPM was generally well tolerated; subjects initially maintained weight loss. 7

Summary:

Although topiramate has been shown to cause weight loss in clinical trials, the development program to obtain an FDA indication for obesity treatment has been terminated because of associated adverse events8; therefore, it is not advisable to recommend topiramate as a weight loss agent. Topimarate is available as an antiepileptic drug.

Topiramate is not indicated for weight loss and has not been shown to be both safe and efficacious when treating overweight individuals.

Criteria for its use includes: monotherapy or adjunctive therapy for partial onset seizures and primary generalized tonic-clonic seizures; adjunctive treatment of seizures associated with Lennox-Gastaut syndrome; prophylaxis of migraine headache

Dosing recommendations are not available for the use of topiramate as a weight loss agent.

General monitoring parameters of topiramate include serum bicarbonate (baseline and periodically during treatment) and serum creatinine. Ammonia level in patients with unexplained lethargy, vomiting, or mental status changes. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression.

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