The propylene glycol research project to illustrate the feasibility and difficulties to study toxicokinetics in neonates

Kulo, Aida; Hoon, Jan N. de; Allegaert, Karel

doi:10.1016/j.ijpharm.2012.05.014

Cited by 22 publications

(25 citation statements)

References 13 publications

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“…The excretion of excipients, which are coadministered with drugs, is often not considered. Excipients have been associated with adverse effects and large amounts can be administered to hospitalized neonates [68][69][70] and are difficult to study [71]. The neonatal administration of propylene glycol [72] and benzyl alcohol [31] in injectable drug formulations has been associated with serious adverse effects, including death.…”

Section: Excretionmentioning

confidence: 99%

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

O’Hara

Wright

Schneider

et al. 2015

Brit J Clinical Pharma

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Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

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Section: Excretionmentioning

confidence: 99%

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

O’Hara

Wright

Schneider

et al. 2015

Brit J Clinical Pharma

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“…Critically ill neonates receiving medications by continuous infusions are at higher risk of being exposed to PG. However, a median PG exposure of 34 mg/kg per 24 h seems to be well tolerated [53][54][55]. Treatment of toxicity includes termination of any PG-containing medication and initiation of hemodialysis in severe cases to effectively remove PG [49].…”

Section: Pathophysiologymentioning

confidence: 99%

Drug-induced acid-base disorders

et al. 2014

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The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal antiinflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g

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“…For neonates and very young children, it is always a good idea to use the least amount and number of excipients. 72 …”

Section: Pediatric Biopharmaceutics Classification Systemmentioning

confidence: 99%

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

Abdel‐Rahman

Amidon

Kaul

et al. 2012

Clinical Therapeutics

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The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community as an enabling guide for the rational selection of compounds, formulation for clinical advancement and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) working group was convened to consider the possibility of developing an analogous pediatric based classification system. Since there are distinct developmental differences that can alter intestinal contents, volumes, permeability and potentially biorelevant solubilities at the different ages, the PBCS working group focused on identifying age specific issues that would need to be considered in establishing a flexible, yet rigorous PBCS. Objective To summarize the findings of the PBCS working group and provide insights into considerations required for the development of a pediatric based biopharmaceutics classification system. Methods Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development (NICHD)-US Pediatric Formulation Initiative (PFI) workshop (November 2011) and via teleconferences, the PBCS working group considered several high level questions that were raised to frame the classification system. In addition, the PBCS working group identified a number of knowledge gaps that would need to be addressed in order to develop a rigorous PBCS. Results It was determined that for a PBCS to be truly meaningful, it would need to be broken down into several different age groups that would account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal transit. Several critical knowledge gaps where identified including: 1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the gastrointestinal (GI) tract, in the liver and in the kidney; 2) an incomplete understanding of age-based changes in the GI, liver and kidney physiology; 3) a clear need to better understand age-based intestinal permeability and fraction absorbed required to develop the PBCS; 4) a clear need for the development and organization of pediatric tissue biobanks to serve as a source for ontogenic research; and 5) a lack of literature published in age-based pediatric pharmacokinetics in order to build Physiologically- and Population-Based Pharmacokinetic (PBPK) databases. Conclusions To begin the process of establishing a PBPK model, ten pediatric therapeutic agents were selected (based on their adult BCS classifications). Those agents should be targeted for additional research in the future. The PBCS working group also identified several areas where a greater emphasis on research is needed to enable the development of a PBCS.

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The propylene glycol research project to illustrate the feasibility and difficulties to study toxicokinetics in neonates

Cited by 22 publications

References 13 publications

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

Drug-induced acid-base disorders

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

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