Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment

Kamal, Mohamed; Brennan, Barbara J.; Subramoney, Vishak; Lien, Yi Ting Kayla; Morcos, Peter N.; Frey, Nicolas; Rayner, Craig R.

doi:10.1002/cpdd.203

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…Different PopPK models have been developed previously . The same structural model as applied to adult patients with and without renal impairment was used, as it accounts for physiological aspects of the PK of oseltamivir.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants

Gibiansky¹,

Ravva

Parrott

et al. 2020

Clin Pharma and Therapeutics

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A mechanistic population‐pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (≥ 38 weeks postmenstrual age (PMA), ≥ 13 days old) and 119 adult subjects < 40 years). Concentration–time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four‐compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6–49.6) with a Hill coefficient of 2.35 (95% CI 1.67–3.04). The model supports the European Union/United States‐approved 3 mg/kg twice‐daily oseltamivir dose for infants < 1 year (PMA ≥ 38 weeks) and allows prediction of exposures in preterm neonates.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants

Gibiansky¹,

Ravva

Parrott

et al. 2020

Clin Pharma and Therapeutics

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“…Numerous oseltamivir population PK models have been developed to evaluate PK for specific purposes including impact of obesity, pregnancy, end‐stage renal dysfunction, ontogeny in infants younger than 1 year and the impact of probenecid to incite a drug–drug interaction . Whilst fit for their specific purpose, such models were too narrow for application in this program.…”

Section: Discussionmentioning

confidence: 99%

Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics

Kamal

Smith

Chaiyakunapruk

et al. 2017

Brit J Clinical Pharma

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A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. METHODSThe pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R 0 ), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R 0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. British Journal of Clinical Pharmacology RESULTSOseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. CONCLUSIONThis methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• To date, modelling of influenza has been conducted in discrete discipline areas.• The discrete pharmacology, epidemiology and health economic models are not linked and make assumptions about the adjacent disciplines that are inappropriate.• There are no epidemiological or health economic models which have taken into account between subject variability in the pharmacology of influenza treatments. WHAT THIS STUDY ADDS• This study provides the first integrated interdisciplinary framework to understand the cost-utility of antiviral therapy under various influenza pandemic scenarios linking drug pharmacokinetics/pharmacodynamics, epidemiological and health economics endpoints. • This quantitative framework was able to show that oseltamivir reduced the median number of infected individuals, increased quality-adjusted life years by deaths averted, and was cost-saving under most pandemic scenarios.• Given the growing need to justify pricing of medicines to society and payer, the methodology of interdisciplinary pharmacometrics can be applied across all disease areas where the pharmacokinetics/pharmacodynamics, clinical or epidemi...

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“…Patients received 75 mg OP orally as a single dose 48 h before the start of their next HD session, 30 min after a standard meal. Serial blood samples for pharmacokinetic analysis were taken immediately before dosing and 0.5, 1, 1.5, 2, 3, 4, 5,6,8,10,12,15,24,36, and 48 h postdose. During HD (at 48.5, 49, 49.5, 50, 51, and 52 h postdose), additional blood samples were drawn from the dialyzer inflow and outflow.…”

Section: Methodsmentioning

confidence: 99%

“…Simulations were also compared with historical data for patients with normal renal function treated with oseltamivir at the highest dosage accepted as well tolerated (450 mg twice daily). The respective reference limits were as follows: median C min of 168 ng/ml (95% CI, 56.1 to 315 ng/ml) after 75 mg twice daily, median C min of 40 ng/ml (90% CI, 14 to 75 ng/ml) after 75 mg once daily, and median C max of 2,390 ng/ml (95% CI, 1,470 to 3,930 ng/ml) after 450 mg twice daily (2,5,17). material).…”

Section: Methodsmentioning

confidence: 99%

“…HD significantly alters the pharmacokinetic profile of drugs which are cleared renally, making it harder to predict a suitable dosing regimen. A recent population analysis of oseltamivir pharmacokinetics in patients with various degrees of renal impairment showed that those with creatinine clearance (CL CR ) rates of Ͼ60 ml/min do not require any dosage adjustments (5). In adult patients with severe renal impairment (CL CR of 10 to 30 ml/min), recommended oseltamivir doses are 30 mg once daily for treatment and 30 mg every other day for prophylaxis, but the ideal treatment and prophylaxis dosages for patients with ESRD are less clear.…”

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confidence: 99%

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Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach

Kamal

Lien

Robson

et al. 2015

Antimicrob Agents Chemother

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f End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.

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Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment

Cited by 5 publications

References 15 publications

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants

Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics

Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach

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