Dataset Information

The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study.

ABSTRACT: Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CL_R for drugs with different properties in children. A physiology-based model for CL_R in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hypothetical drugs with a range of drug-specific properties, including transporter-mediated intrinsic clearance (CL_int,T) values, that are substrates for renal secretion transporters with different ontogeny patterns. To assess the impact of transporter ontogeny on ATS and total CL_R, a percentage prediction difference (%PD) was calculated between the predicted CL_R in the presence and absence of transporter ontogeny. The contribution of ATS to CL_R ranges between 41 and 90% in children depending on fraction unbound and CL_int,T values. If ontogeny of renal transporters is R predictions are unacceptable (%PD?>?50%) for the majority of drugs regardless of the pediatric age. Ignoring ontogeny patterns of secretion transporters increasing with age in children younger than 2 years results in CL_R predictions that are not systematically acceptable for all hypothetical drugs (%PD?>?50% for some drugs). This analysis identified for what drug-specific properties and at what ages the contribution of ATS on total pediatric CL_R cannot be ignored. Drugs with these properties may be sensitive in vivo probes to investigate transporter ontogeny.

SUBMITTER: Cristea S

PROVIDER: S-EPMC7306484 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study.

Cristea Sînziana S Krekels Elke Henriëtte Josephina EHJ Rostami-Hodjegan Amin A Allegaert Karel K Knibbe Catherijne Annette Jantine CAJ

The AAPS journal 20200621 4

Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CL<sub>R</sub> for drugs with different properties in children. A physiology-based model for CL<sub>R</sub> in adults was extrapolated to the pediatric population by including maturation func ...[more]

PMID: 32566984

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Project description:OBJECTIVES:To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN:Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS:A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute. MEASUREMENTS AND MAIN RESULTS:Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION:The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.

Dataset Information

The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study.

Publications

The Influence of Drug Properties and Ontogeny of Transporters on Pediatric Renal Clearance through Glomerular Filtration and Active Secretion: a Simulation-Based Study.

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