Ontogeny of drug elimination by the human kidney

Chen, Nancy; Aleksa, Katarina; Woodland, Cindy; Rieder, Michael J.; Koren, Gideon

doi:10.1007/s00467-005-2105-4

Cited by 115 publications

(84 citation statements)

References 68 publications

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“…Since OC displays formation rate-limited kinetics due to the release rate of OC from hepatocytes (8, 9), CL m /F in adult subjects with normal renal function likely does not reflect the actual renal clearance of OC. The same should hold true for pediatric subjects given that GFR normalizes to adult values by the first year of age (24,25). However, in moderate and severe renal impairment, CL m /F likely reflects the renal clearance of OC, as this is now the rate-limiting step (8,20).…”

Section: Discussionmentioning

confidence: 96%

Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

Kamal

Wart

Rayner

et al. 2013

Antimicrob Agents Chemother

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fOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (␣ ‫؍‬ 0.01) and backward elimination (␣ ‫؍‬ 0.001). A two-compartment model with first-order absorption of oseltamivir and firstorder conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CL m /F) and central volume of distribution (Vc m /F). Creatinine clearance was a significant predictor of CL m /F, while Vc m /F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (C max ) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC 0 -24 ) was high (r 2 ‫؍‬ 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone. Oseltamivir is a potent antiviral medication that selectively inhibits influenza virus neuraminidase enzymes essential for efficient release of intact virions from an infected cell to allow further infection of cells in vivo. Oseltamivir has been shown to be safe and effective and is used worldwide for the treatment and prophylaxis of seasonal and pandemic influenza (1-6). Oseltamivir is orally administered as an inactive ethyl ester prodrug which undergoes rapid conversion by hepatic esterases into its active metabolite form, oseltamivir carboxylate (OC) (7, 8).The pharmacokinetic (PK) properties of both the prodrug and OC have been well studied (7). Approximately 80% of an oral dose of the prodrug is converted into OC by hepatic metabolism via carboxylesterase 1A1 (HCE1), with less than 5% of prodrug recovered unchanged in the urine. The rate-limiting step for the appearance of OC in plasma is the release of the formed OC metabolite from the hepatocyte (8, 9). Once in circulation, OC is predominately cleared by the kidney via glomerular filtration and renal secretion (8, 9). OC dist...

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Section: Discussionmentioning

confidence: 96%

Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

Kamal

Wart

Rayner

et al. 2013

Antimicrob Agents Chemother

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“…In children, certain differences in kidney function, e.g., the glomerular filtration of inulin (41) and the excretion of antibiotics (42), can clearly be attributed to kidney maturation on an anatomical level, e.g., length and number of nephrons. However, other differences, e.g., the increased clearance of digoxin in young children, cannot be explained solely by these anatomical changes (43)(44)(45). In such cases, transporters are likely to play a crucial role; however, the underlying molecular processes for differences in renal clearance are poorly understood in a developmental context.…”

Section: Wwwannualreviewsorg • Renal Drug Transporters 521mentioning

confidence: 99%

Renal Transporters in Drug Development

Morrissey

Stocker

Wittwer

et al. 2013

Annu. Rev. Pharmacol. Toxicol.

279

277

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The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.

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“…Digoxin is extensively secreted via P-gp within the tubular cell. Preschool children require three-fold higher doses of digoxin kg −1 body weight than adults, which may be linked to P-gp ontogeny [65].…”

Section: Eliminationmentioning

confidence: 99%

Paediatric pharmacokinetics: key considerations

Batchelor

Marriott

2015

Brit J Clinical Pharma

231

163

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A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.

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Ontogeny of drug elimination by the human kidney

Cited by 115 publications

References 68 publications

Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

Renal Transporters in Drug Development

Paediatric pharmacokinetics: key considerations

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