Effect of Kidney Function on Drug Kinetics and Dosing in Neonates, Infants, and Children

Rodieux, Frédérique; Wilbaux, Mélanie; Anker, Johannes N. van den; Pfister, Marc

doi:10.1007/s40262-015-0298-7

Cited by 117 publications

(118 citation statements)

References 318 publications

(235 reference statements)

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“…Little pharmacokinetic information is available for children younger than 5 years of age. Because renal function reaches the adult level by 2 years of age [51], lenalidomide clearance in children ≥2 years of age is not anticipated to be highly different from that in adults.…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration–time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3–4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug–drug interactions.

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Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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“…It is well known that the neonatal kidney function is impaired compared with adults due to immature glomerular filtration and tubular function and reduced kidney perfusion pressure [16]. Moreover, mitochondrial diseases are associated with renal functional impairment, despite normal serum creatinine levels [17].…”

Section: Discussionmentioning

confidence: 99%

Maternal Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes Syndrome and Neonatal Magnesium Toxicity: A Case Report

Tinier¹,

Lorenzini²,

Joal³

et al. 2017

Gynecol Obstet

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Introduction: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a progressive disorder associated with neurologic, cardiac, neuromuscular, hepatic, metabolic and gastrointestinal dysfunction, including potential anesthetic and obstetrical complications. Increased susceptibility to drugs in patient with MELAS syndrome can be due to drug-induced mitochondrial toxicity and/or decreased elimination. We present here a case of severe neonatal magnesium sulfate toxicity in the context of MELAS syndrome.

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“…Studies reported to-date using PBPK models have mostly been limited to investigating impact of changes in GFR and plasma protein binding in renally impaired patients on the CL R (39,40,62). However, CL R may reduce linearly with GFR for many drugs, even when secretion or reabsorption contributes, in accordance with the intact nephron hypothesis (63,64).…”

Section: Assessing Dosage Adjustment In Chronic Kidney Diseasementioning

confidence: 99%

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

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Effect of Kidney Function on Drug Kinetics and Dosing in Neonates, Infants, and Children

Cited by 117 publications

References 318 publications

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Maternal Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes Syndrome and Neonatal Magnesium Toxicity: A Case Report

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

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