Dataset Information

Pediatric Safety of Polysorbates in Drug Formulations.

ABSTRACT: Polysorbates 20 and 80 are the most frequently used excipients in biotherapeutics, the safety data for which have been well documented in adults. The polysorbate content in therapeutic formulations that are administered to children, however, has been less clearly regulated or defined with regard to safety. In pediatric patients, excessive amounts of polysorbate in biotherapeutics have been linked to hypersensitivity and other toxicity-related effects. To determine safe levels of polysorbates for young patients, we have developed the progressive pediatric safety factor (PPSF), an age- and weight-based tool that estimates the amount of parenterally administered polysorbates 20 and 80 in formulations that will avoid excipient-related adverse events. Compared with existing modalities for calculating maximum acceptable doses of excipients for initial clinical trials in pediatrics, the PPSF is far more conservative, thus constituting an added margin of safety for excipient exposure in the most sensitive subpopulations-i.e., neonates and infants. Further, the PPSF may be applied to any relevant excipient, aiding pharmaceutical developers and regulatory authorities in conservatively estimating the safety assessment of a biotherapeutic's formulation, based on excipient levels.

SUBMITTER: Kriegel C

PROVIDER: S-EPMC7022221 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pediatric Safety of Polysorbates in Drug Formulations.

Kriegel Christina C Festag Matthias M Kishore Ravuri S K RSK Roethlisberger Dieter D Schmitt Georg G

Children (Basel, Switzerland) 20191220 1

Polysorbates 20 and 80 are the most frequently used excipients in biotherapeutics, the safety data for which have been well documented in adults. The polysorbate content in therapeutic formulations that are administered to children, however, has been less clearly regulated or defined with regard to safety. In pediatric patients, excessive amounts of polysorbate in biotherapeutics have been linked to hypersensitivity and other toxicity-related effects. To determine safe levels of polysorbates for ...[more]

PMID: 31877624

Similar Datasets

Project description:BackgroundDrug safety in children is a major concern; however, there is still a lack of methods for quantitatively measuring, let alone to improving, drug safety in children under different clinical conditions. To assess pediatric drug safety under different clinical conditions, a computational method based on Electronic Medical Record (EMR) datasets was proposed.MethodsIn this study, a computational method was designed to extract the significant drug-diagnosis associations (based on a Bonferroni-adjusted hypergeometric P-value <?0.05) among drug and diagnosis co-occurrence in EMR datasets. This allows for differences between pediatric and adult drug use to be compared based on different EMR datasets. The drug-diagnosis associations were further used to generate drug clusters under specific clinical conditions using unsupervised clustering. A 5-layer quantitative pediatric drug safety level was proposed based on the drug safety statement of the pediatric labeling of each drug. Therefore, the drug safety levels under different pediatric clinical conditions were calculated. Two EMR datasets from a 1900-bed children's hospital and a 2000-bed general hospital were used to test this method.ResultsThe comparison between the children's hospital and the general hospital showed unique features of pediatric drug use and identified the drug treatment gap between children and adults. In total, 591 drugs were used in the children's hospital; 18 drug clusters that were associated with certain clinical conditions were generated based on our method; and the quantitative drug safety levels of each drug cluster (under different clinical conditions) were calculated, analyzed, and visualized.ConclusionWith this method, quantitative drug safety levels under certain clinical conditions in pediatric patients can be evaluated and compared. If there are longitudinal data, improvements can also be measured. This method has the potential to be used in many population-level, health data-based drug safety studies.

Project description:Lipid nanoparticles (LNPs) have been recognized as efficient vehicles to transport a large variety of therapeutics. Currently in the spotlight as important constituents of the COVID-19 mRNA vaccines, LNPs play a significant role in protecting and transporting mRNA to cells. As one of their key constituents, polyethylene glycol (PEG)-lipid conjugates are important in defining LNP physicochemical characteristics and biological activity. PEGylation has proven particularly efficient in conferring longer systemic circulation of LNPs, thus greatly improving their pharmacokinetics and efficiency. Along with revealing the benefits of PEG conjugates, studies have revealed unexpected immune reactions against PEGylated nanocarriers such as accelerated blood clearance (ABC), involving the production of anti-PEG antibodies at initial injection, which initiates accelerated blood clearance upon subsequent injections, as well as a hypersensitivity reaction referred to as complement activation-related pseudoallergy (CARPA). Further, data have been accumulated indicating consistent yet sometimes controversial correlations between various structural parameters of the PEG-lipids, the properties of the PEGylated LNPs, and the magnitude of the observed adverse effects. Detailed knowledge and comprehension of such correlations are of foremost importance in the efforts to diminish and eliminate the undesirable immune reactions and improve the safety and efficiency of the PEGylated medicines. Here, we present an overview based on analysis of data from the CAS Content Collection regarding the PEGylated LNP immunogenicity and overall safety concerns. A comprehensive summary has been compiled outlining how various structural parameters of the PEG-lipids affect the immune responses and activities of the LNPs, with regards to their efficiency in drug delivery. This Review is thus intended to serve as a helpful resource in understanding the current knowledge in the field, in an effort to further solve the remaining challenges and to achieve full potential.

Project description:BackgroundSkeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration.MethodsRelevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase.ResultsTizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel.ConclusionTizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

Dataset Information

Pediatric Safety of Polysorbates in Drug Formulations.

Publications

Pediatric Safety of Polysorbates in Drug Formulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets