Population analysis of the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812) in treating experimental influenza A and B virus in healthy volunteers

Iyer, Ganesh; Liao, Sam; Massarella, Joseph

doi:10.1208/ps040422

Cited by 17 publications

(8 citation statements)

References 10 publications

(6 reference statements)

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“…Results from both observed and pharmacokinetic-pharmacodynamic models in healthy volunteers inoculated with influenza A or B and treated with peramivir showed that patients with greater drug exposure had a greater decline in viral titers compared with those given placebo. 8 However, the optimal pharmacokinetic parameters for peramivir efficacy in humans have not been defined. 2…”

Section: Discussionmentioning

confidence: 99%

Peramivir Pharmacokinetics in Two Critically Ill Adults with 2009 H1N1 Influenza A Concurrently Receiving Continuous Renal Replacement Therapy

Bazan¹,

Bauer²,

Hollister³

et al. 2010

Pharmacotherapy

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The first patient had a slower peramivir plasma clearance compared with the second patient, but both patients had higher peramivir clearances as calculated from AUC(0-24) than those predicted by CRRT. Thus, the dosage of intravenous peramivir was appropriate in these patients. Additional pharmacokinetic data are needed to confirm these results and help guide dosing in patients receiving various forms of CRRT.

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Section: Discussionmentioning

confidence: 99%

Peramivir Pharmacokinetics in Two Critically Ill Adults with 2009 H1N1 Influenza A Concurrently Receiving Continuous Renal Replacement Therapy

Bazan¹,

Bauer²,

Hollister³

et al. 2010

Pharmacotherapy

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“…Tissue distribution of oral and IV peramivir has not been reported. A population analysis of the pharmacokinetics of oral peramivir in treating experimental influenza A and B virus in healthy volunteers resulted in a 2‐compartmental model with first‐order absorption and elimination and volume of distribution of the central compartment (V C /F) and volume of distribution of the peripheral compartment (V P /F) of 860 and 4500 L, respectively . Weight was found to be the only significant covariate for estimated CL/F and V C /F.…”

Section: Peramivirmentioning

confidence: 99%

“…Weight was found to be the only significant covariate for estimated CL/F and V C /F. The pharmacokinetic properties were not influenced by viral type (A or B) . A population pharmacodynamic analysis showed a relationship between reduction in viral titers and increase in drug exposure …”

Section: Peramivirmentioning

confidence: 99%

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Pharmacokinetic Properties ofAnti‐Influenza Neuraminidase Inhibitors

Chairat

Tärning

White

et al. 2013

The Journal of Clinical Pharma

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Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(1/2) β) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(1/2) β of approximately 3.0 hours). Peramivir is slowly eliminated (t(1/2) β of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation.

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“…(4B) and (4D)) [34]. BCX-1812 showed good oral bioavailability and efficacy in animal models of influenza virus infection, as well as in early clinical studies in experimentally infected subjects [36,37].…”

Section: Bcx-1812 (Rwj-270201; Peramivir)mentioning

confidence: 99%

Optimization of Small Molecule Drugs Binding to Highly Polar Target Sites: Lessons from the Discovery and Development of Neuraminidase Inhibitors

Klumpp

Graves²

2006

CTMC

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Binding affinity optimization of small molecules interacting with polar binding sites on target proteins is a formidable, but not uncommon challenge in drug discovery. The challenge relates to the difficulty of integrating favourable and unfavourable polar, non-polar and conformation contributions into overall favourable binding energies. This review describes the surprising breakthrough findings leading to the development of Tamiflu, a clinically efficacious orally bioavailable drug targeting the active site of influenza neuraminidase (NA). The NA active site is highly polar and formed mostly by arginine, aspartate and glutamate residues. This active site structure evolved for efficient interaction with charged sialic acid moieties on glycoproteins and stabilization of an oxocarbonium ion in the transition state of the neuraminidase reaction. The initial strategy of optimizing polar interactions in transition state analogs led to NA inhibitors (NAIs) with sub-nanomolar binding affinities, but such compounds were highly polar and lacked oral bioavailability. The realization of the possibility to achieve high affinity binding in a highly polar active site through optimization of non-polar and van-der-Waals interactions initially appeared counterintuitive and required a few serendipitous findings, but was key to reduce the polarity of drug candidates, avoid large desolvation penalties and achieve oral bioavailability.

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Population analysis of the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812) in treating experimental influenza A and B virus in healthy volunteers

Cited by 17 publications

References 10 publications

Peramivir Pharmacokinetics in Two Critically Ill Adults with 2009 H1N1 Influenza A Concurrently Receiving Continuous Renal Replacement Therapy

Peramivir Pharmacokinetics in Two Critically Ill Adults with 2009 H1N1 Influenza A Concurrently Receiving Continuous Renal Replacement Therapy

Pharmacokinetic Properties ofAnti‐Influenza Neuraminidase Inhibitors

Optimization of Small Molecule Drugs Binding to Highly Polar Target Sites: Lessons from the Discovery and Development of Neuraminidase Inhibitors

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