Oseltamivir Pharmacokinetics and Clinical Experience in Neonates and Infants during an Outbreak of H1N1 Influenza A Virus Infection in a Neonatal Intensive Care Unit

Standing, Joseph F.; Nika, A.; Tsagris, V.; Kapetanakis, Ioannis; Maltezou, Helena C.; Kafetzis, Dimitris A.; Τσολιά, Μαρία

doi:10.1128/aac.00290-12

Cited by 26 publications

(22 citation statements)

References 32 publications

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“…Other recent studies also highlight the role of opportunistic methods to obtain PK data in infants. For example, opportunistic PK studies were promptly employed during an H1N1 outbreak and were instrumental for studying oseltamivir in term and preterm infants . Scavenged samples have also been used to characterize the PK of several antimicrobials in term and preterm infants, including piperacillin, metronidazole, and fluconazole .…”

Section: Clinical Trial Optimizationmentioning

confidence: 99%

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Balevic

Cohen‐Wolkowiez

2018

The Journal of Clinical Pharma

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Almost half of recent pediatric trials failed to achieve labeling indications, due in large part to inadequate study design. Therefore, innovative study methods are crucial to optimize trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic (PK) data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and non-invasive matrices, and micro-volume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically-based models that individualize pediatric dosing recommendations and support drug approval. Lastly, given the low prevalence of many pediatric diseases, collecting de-identified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.

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Section: Clinical Trial Optimizationmentioning

confidence: 99%

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Balevic

Cohen‐Wolkowiez

2018

The Journal of Clinical Pharma

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“…Metronidazole and hydroxymetronidazole were simultaneously fitted using the well‐stirred liver model, using a similar model to previous study on oseltamivir carboxylate formation from oseltamivir . A common absorption rate constant and fixed hepatic plasma flow were used to allow for both first‐pass and hydroxymetronidazole formation from circulating drug to be identified.…”

Section: Methodsmentioning

confidence: 99%

Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

Standing

Ongas

Ogwang

et al. 2018

Clin Pharma and Therapeutics

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Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.

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“…Two recent publications reported oseltamivir PK in term and preterm infants using an opportunistic design in the context of nosocomial exposure to influenza A (H1N1) (45, 46). Oseltamivir was administered for treatment or prophylaxis, and a protocol was rapidly implemented for the collection of PK samples in the context of standard-of-care therapy.…”

Section: Opportunistic Pk Studiesmentioning

confidence: 99%

“…Population PK analysis suggested that premature infants required half the dose needed to treat older children because of underdeveloped renal function and hepatic metabolizing enzymes (45). Another PK model for oseltamivir was developed using four samples per infant (46). These data confirmed the results from the original population PK model for preterm infants ≤ 37 weeks postmenstrual age (PMA) but found that a lower dose than originally recommended in the previous trial was adequate for infants > 37 weeks PMA (46).…”

Section: Opportunistic Pk Studiesmentioning

confidence: 99%

“…Another PK model for oseltamivir was developed using four samples per infant (46). These data confirmed the results from the original population PK model for preterm infants ≤ 37 weeks postmenstrual age (PMA) but found that a lower dose than originally recommended in the previous trial was adequate for infants > 37 weeks PMA (46). …”

Section: Opportunistic Pk Studiesmentioning

confidence: 99%

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Pharmacokinetic Studies in Infants Using Minimal-Risk Study Designs

Autmizguine¹,

Benjamin²,

Smith³

et al. 2014

CCP

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Infants are therapeutic orphans. Many drugs used in infants are used “off-label”, increasing the risk of drug toxicity and suboptimal efficacy in this vulnerable population. This knowledge gap in clinical pharmacology is partly attributed to challenges associated with conducting clinical trials in infants. Consequently, there is a need for novel and efficient study designs more suited to this population. Available literature describing the use of minimal-risk approaches to characterize the pharmacokinetics (PK) of drugs in infants was critically reviewed. Population PK approach with sparse sampling was found to be well established. Other, more recent alternatives, like dried blood spots sampling, opportunistic design, and the use of non-blood matrices are promising strategies with an increasing number of applications in infants. Physiologically based pharmacokinetic modeling provides valuable insight in drug disposition but still needs more prospective validation. Increasing experience with these methods provides understanding of their strengths and limitations and will help improve the design of future PK studies in infants.

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Oseltamivir Pharmacokinetics and Clinical Experience in Neonates and Infants during an Outbreak of H1N1 Influenza A Virus Infection in a Neonatal Intensive Care Unit

Cited by 26 publications

References 32 publications

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

Pharmacokinetic Studies in Infants Using Minimal-Risk Study Designs

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