Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam

Petrushevska, Marija; Berglez, Sandra; Krisch, Igor; Legen, Igor; Megušar, Klara; Peternel, Luka; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D.W.; Kopp, Sabine; Langguth, Peter; Mehta, Mehul; Polli, James E.; Shah, Vinod P.; Dressman, Jennifer B.

doi:10.1002/jps.24350

Cited by 26 publications

(13 citation statements)

References 37 publications

(119 reference statements)

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“…Although these processes have their challenges such as excipient selection and process repeatability. Furthermore, these powder bed-based techniques are useful in making porous structures and hence only found applicability for processing drugs such as levetiracetam [29] and acetaminophen [15], until we demonstrated the applicability of laser sintering 3D printing in the manufacturing of amorphous solid dispersion dosage forms for improved solubility of poorly soluble and thermolabile drugs such as ritonavir [11]. In our previous study, we encountered multiple printing-related issues leading to print failures which were mostly because of the powder bulk properties, which eventually led to weight variability and content uniformity issues in some of the formulations.…”

Section: Discussionmentioning

confidence: 99%

Synergistic application of continuous granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties

Thakkar

Zhang

et al. 2021

Preprint

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This study demonstrated the first case of combining novel continuous granulation with powder-based pharmaceutical 3-dimensional (3D) printing processes to enhance the dissolution rate and physical properties of a poorly water-soluble drug. Powder bed fusion (PBF) and binder jetting 3D printing processes have gained much attention in pharmaceutical dosage form manufacturing in recent times. Although powder bed-based 3D printing platforms have been known to face printing and uniformity problems due to the inherent poor flow properties of the pharmaceutical physical mixtures (feedstock). Moreover, techniques such as binder jetting currently do not provide any solubility benefits to active pharmaceutical ingredients (APIs) with poor aqueous solubility (>40% of marketed drugs). For this study, a hot-melt extrusion-based versatile granulation process equipped with UV-Vis process analytical technology (PAT) tools for the in-line monitoring of critical quality attributes (i.e. solid-state) of indomethacin was developed. The collected granules with enhanced flow properties were mixed with vinylpyrrolidone-vinyl acetate copolymer and a conductive excipient for efficient sintering. These mixtures were further characterized for their bulk properties observing an excellent flow and later subjected to a PBF-3D printing process. The physical mixtures, processed granules, and printed tablets were characterized using conventional as well as advanced solid-state characterization. These characterizations revealed the amorphous nature of the drug in the processed granules and printed tablets. Further, the in vitro release testing of the tablets with produced granules as a reference standard depicted a notable solubility advantage (100% drug released in 5 minutes at >pH 6.8) over the pure drug and the physical mixture. Our developed system known as DosePlus combines innovative continuous granulation and PBF-3D printing process which can potentially improve the physical properties of the bulk drug and formulations in comparison to when used in isolation. This process can further find application in continuous manufacturing of granules and additive manufacturing of pharmaceuticals to produce dosage forms with excellent uniformity and solubility advantage.

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Section: Discussionmentioning

confidence: 99%

Synergistic application of continuous granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties

Thakkar

Zhang

et al. 2021

Preprint

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“…Levetiracetam's half-life and apparent clearances are dose independent. It is considered that CMJ Cumhuriyet Medical Journal levetiracetam has low affinity for plasma protein binding as the volume distribution is close to the volume of total body water 12 . In our case, despite the use of high doses of levetiracetam, serum level was within normal limits.…”

Section: Discussionmentioning

confidence: 99%

Is high dose levetiracetam safe in the management of neonatal convulsion?

et al. 2015

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SUMMARYLevetiracetam is a novel anticonvulsant drug that was approved by the FDA in adult and pediatric convulsions. There is not sufficient information regarding the use of newborn such as the appropriate dose and interval, its safety, efficacy and adverse effects. We present a case of a 10 day-old male, who was accidentally administered 75 mg/kg/d levetiracetam for 3 days by his mother at home. The patient was discharged 4 days after admission to hospital without any signs and symptoms. The case demonstrated that high dose levetiracetam might be safe in newborn convulsions. Keywords: Levetiracetam, newborn, convulsion, dose, safe ÖZET Levatirasetam erişkin ve pediatrik konvülziyonlarda FDA tarafından onaylanan yeni birantikonvülziyon ilaçtır. Yenidoğan kullanımı ile ilgili doz ve aralığı, güvenliği, etkinliği ve yan etkileri konusunda yeterli bilgi bulunmamaktadır. Annesi tarafından evde 3 gün boyunca kaza ile 75 mg/kg/gün levatirasetam verilen 10 günlük bir erkek bebek olguyu sunuyoruz. Hasta, hastaneye başvurduktan 4 gün sonra hiçbir bulgu ve semptom olmadan taburcu edildi. Bu olgu yüksek doz levatirasetam yenidoğan konvülziyonlarında kullanılabileceğini gösterdi.

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“…We were unable to identify instances of BCS‐based biowaivers for gabapentin and lamotrigine products. Three generic products (each involving four strengths) approved with a BCS‐based biowaiver were identified for levetiracetam, 36–38 a drug that has been deemed especially suitable to meet BCS‐based biowaiver criteria 39 . It should be noted that BCS‐based criteria cannot be applied to narrow‐therapeutic index (NTI) drugs, which are discussed in the section below.…”

Section: The Distinction Between Bioequivalence and Statistical Testimentioning

confidence: 99%

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re‐appraisal based on analysis of generic ASM products approved in Europe

et al. 2021

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The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra‐subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow‐therapeutic‐index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second‐generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%–111%) applied to NTI drugs. Intra‐subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra‐subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non‐bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

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Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam

Cited by 26 publications

References 37 publications

Synergistic application of continuous granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties

Synergistic application of continuous granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties

Is high dose levetiracetam safe in the management of neonatal convulsion?

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re‐appraisal based on analysis of generic ASM products approved in Europe

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