Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations

Brittain, Scott; Wheless, James W.

doi:10.1016/j.yebeh.2015.08.029

Cited by 28 publications

(39 citation statements)

References 16 publications

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“…21,22 MR formulations appear to minimize effects of delayed doses, 21,22 although steady-state concentrations took longer to recover after missed MR doses compared to IR doses. Modeling studies of oxcarbazepine and LTG, however, predicted similar trough levels after missed or delayed IR or MR doses.…”

Section: Resultsmentioning

confidence: 96%

Assessing bioequivalence of generic modified-release antiepileptic drugs

et al. 2016

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Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence.

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Section: Resultsmentioning

confidence: 96%

Assessing bioequivalence of generic modified-release antiepileptic drugs

et al. 2016

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“…dosing, peak topiramate concentrations are higher and trough concentrations are at least 30% lower compared with b.i.d. administration . This pharmacokinetic profile may be less favorable for optimizing migraine treatment.…”

Section: Extended‐release Topiramatementioning

confidence: 99%

“…Nonadherence (delayed or missed dose) would have a much greater impact on the plasma concentration‐time profile when IR topiramate is dosed q.d. vs b.i.d . Once‐daily dosing with IR topiramate may improve adherence, but can lead to greater concentration fluctuations.…”

Section: Extended‐release Topiramatementioning

confidence: 99%

Topiramate in Migraine Prevention: A 2016 Perspective

Silberstein

2016

Headache

103

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Topiramate has activity at multiple molecular targets, which may account for why it is effective in migraine and most other, more specific, anticonvulsants are not. Based on randomized controlled trials, topiramate reduces migraine frequency and acute medication use, improves quality of life, and reduces disability in patients with episodic migraine and in those with chronic migraine with or without medication overuse headache. Its efficacy in chronic migraine is not improved by the addition of propranolol. Topiramate's ability to prevent progression from high-frequency episodic migraine to chronic migraine remains unclear. Consistent with clinicians' perceptions, migraineurs are more sensitive to topiramate-associated side effects than patients with epilepsy. Paresthesia is a common occurrence early in treatment but is rarely cause for terminating topiramate treatment. Cognitive problems occur much less frequently than paresthesia but are more troublesome in terms of treatment discontinuation. Cognitive complaints can often be managed by slowly increasing the topiramate dose in small increments to allow habituation. As with other carbonic anhydrase inhibitors, topiramate has metabolic effects that favor the development of metabolic acidosis and possibly renal stones. Because migraineurs have an increased risk of renal stones independent of topiramate exposure, clinicians should counsel all migraine patients to maintain hydration. Abrupt onset of blurring, other visual disturbances, and/or ocular pain following topiramate's initiation should be evaluated promptly since this may indicate rare but potentially sight-threatening idiosyncratic events. Postmarketing evidence has shown that first-trimester exposure to topiramate monotherapy is associated with increased occurrence of cleft lip with or without cleft palate (Pregnancy Category D). Even though topiramate's long half-life would seemingly support q.d. dosing, randomized controlled migraine trials used b.i.d. administration of immediate-release (IR) topiramate, which has more favorable plasma concentration-time profile (ie, lower peak concentrations and higher trough concentrations) than q.d. IR dosing. Given the sensitivity of migraineurs to topiramate-related adverse events, particularly cognitive effects, pharmacokinetic profiles should be considered when optimizing migraine outcomes. The extended-release (XR) formulations Qudexy XR (Upsher-Smith Laboratories) and Trokendi XR (Supernus Pharmaceuticals) were specifically designed to achieve the adherence benefits of q.d. dosing but with more favorable (ie, more constant) steady-state plasma concentrations over the 24-hour dosing interval vs IR topiramate b.i.d. Intriguing results from a study in healthy volunteers showed consistently less impairment in neuropsychometric tests of verbal fluency and mental processing speed with an XR topiramate formulation (Trokendi XR) vs IR topiramate b.i.d. These findings suggest a pharmacodynamic effect associated with significantly reducing plasma concentration fluctuatio...

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“…A computer simulation study using a population PK model for steady-state concentrations was used to compare strict dosing protocols with those that delayed TKR or TPM-IR doses by 4,8,12,16, and 24 hours. 19 For patients not receiving enzyme-inducing drugs, C min was 9% to 31% lower in patients receiving TPM-IR and 6% to 27% lower in patients receiving TKR after the delayed dose. Although the changes were greater in patients receiving drugs that induced TPM metabolism, the overall effects were comparable.…”

Section: Factors That Determine Adherencementioning

confidence: 87%

“…These data came from PWE undergoing formulation change studies. 18,19 A randomized, open-label, single-centered, multiple-dose study assessed 38 patients receiving TPM-IR 100 mg administered every 12 hours or QXR 200 mg once daily. Patients were assessed over two 14-day maintenance periods, a crossover period, and 12-day titration period.…”

Section: Pharmacology Pharmacokinetics and Dosingmentioning

confidence: 99%

Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

Wang

Wagner

Kaufman

et al. 2017

Clinical Medicine Insights: Therapeutics

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Topiramate (TPM) is effective for multiple seizure types and epilepsy syndromes in children and adults. Topiramate has adverse effects (including cognitive, depression, renal stones), but many of these are low incidence when started at a low dose and slowly titrated to 100 to 200 mg/day. Also, TPM has proven benefit for migraine, obesity, eating disorders, and alcohol use disorders, which can be comorbid in patients with epilepsy and may also be effective in subpopulations within specific psychiatric diagnoses. Recently approved extended-release formulations of TPM (Trokendi and Qudexy in the United States) have reliable data supporting their safety and efficacy for patients with epilepsy. They have potential for more rapid titration within 1 month to 200 mg/day and have better patient retention than TPM immediate-release, but there are no robust double-blind randomized controlled trials comparing the different formulations. We expect the once per day extendedrelease formulations to improve medication adherence compared with the twice per day formulations. This has significant potential to improve outcomes in epilepsy and the other TPM-responsive disorders.

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Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations

Cited by 28 publications

References 16 publications

Assessing bioequivalence of generic modified-release antiepileptic drugs

Assessing bioequivalence of generic modified-release antiepileptic drugs

Topiramate in Migraine Prevention: A 2016 Perspective

Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

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