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To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the  in vivo  functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CL R ) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL R   post-hoc  values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CL R  was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CL int,OAT1,3,invivo ) and its ontogeny. CL int,OAT1,3,invivo  ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CL R  predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months–15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an  in vivo  functional ontogeny profile for CL int,OAT1,3,invivo  that yields accurate CL R  predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.   Supplementary Information  The online version contains supplementary material available at 10.1208/s12248-021-00595-9.

the aaps journal

Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3