Quantifying the effect of kidney disease on glomerular filtration rate (GFR) is important when describing variability in the clearance of drugs eliminated by the kidney. We developed a continuous model for renal function (RF) from prematurity to adulthood based on consistent models for fat-free mass (FFM), creatinine production rate (CPR), and GFR. A model for fractional FFM in premature neonates to adults was developed using pooled data from 4462 subjects and 2847 FFM observations. Girls were found to have an FFM higher than that predicted from adult women based on height, total body mass, and sex. Boys have an FFM lower than adult men until around the onset of puberty, when it approaches adult male values. Data from 108 subjects with measurements of GFR and serum creatinine (Scr) were used to construct a model for CPR, predicted using FFM, postmenstrual age, and sex. Individual CPR may then be used with individual Scr to predict the estimated GFR (eGFR; eGFR = CPR/Scr). A previously published model for human GFR based on 1153 GFR observations in 923 subjects without known kidney disease was updated using the model for fractional FFM to predict individual size and age-consistent values for the expected normal GFR (nGFR). Individual renal function was then calculated using RF = eGFR/nGFR.

Background: By analogy with hepatic clearance, glomerular filtration rate (GFR) provides an upper limit for the filtration component of renal clearance.
Aims: To describe how GFR and renal function (RF) provide a physiological basis to distinguish clearance constrained by GFR and a component, not associated with GFR, also linked to RF.
Methods: Methods for estimation of normal GFR (nGFR) RF have been described (1). A population pharmacokinetic analysis was used to quantitate components of plasma clearance as a function of RF (2).
Equation 1: CLGFRplasma=fu×nGFR×asymmetrical sigmoid function(RF)
Equation 2: CLNGFRplasma=POP_CLNGFR×RF
Results: Plasma GFR clearance was described by the unbound fraction (fu), nGFR and an asymmetrical sigmoid function of RF (Equation 1). Plasma non-GFR clearance based on a population estimate (POPCLNGFR) used a linear function of RF (Equation 2).
Conclusions: The unbound fraction in plasma is an important determinant of plasma clearance based on nGFR. The use of nGFR as the physiological determinant of filtration.

A single-center, prospective study in haemodialysis (HD) or haemodiafiltration (HDF) patients was used to describe amikacin pharmacokinetics. The theory describing dialyser blood clearance [1] was extended to HDF. Target exposures (area under the concentration time curve for 24 hours from the start of dialysis (AUC24h), peak (Cpeak) and trough concentrations (Ctrough), were used to evaluate alternative dosing designs. The current recommended dosing regimen (5 mg/kg 4 hours of dialysis) achieves neither the target AUC24h nor the target peak with either HD or HDF. For HD, increasing the dose to 17.5 mg/kg achieves AUC24h, Cpeak and Ctrough within the acceptable range. For HDF, 25 mg/kg achieves AUC24h and Ctrough but not Cpeak within the acceptable range, 30 mg/kg achieves Cpeak within the acceptable range but leads to higher Ctrough, which may be associated with toxicity [2]. The principles used to develop target exposure based dosing in patients on dialysis are not limited to amikacin but are generally applicable to other drugs. The consequences on dosing in HDF when compared with HD are better predicted by considering dialyser clearance rather than dialysis efficiency because of the additional effects of dialyser blood flow on elimination.

Colistin (administered as the inactive prodrug colistin methanesulphonate [CMS]) is often used to treat infections in critically-ill patients undergoing sustained low-efficiency dialysis (SLED).
We aimed to develop a population pharmacokinetic (popPK) model for colistin in patients undergoing SLED, and evaluate the probabilities of antibacterial benefit and colistin nephrotoxicity for different dosing regimens via simulations.
A prospective popPK study included 13 critically-ill patients treated with CMS and receiving SLED (6-8h) for renal support. The PK of formed colistin was studied on both a nonSLED and a SLED day. Colistin plasma concentrations were analysed using the popPK approach. Monte Carlo simulations (MCS) for dosing regimen evaluation were performed.
A linear one-compartment PK disposition model best described the data. The total body clearance of colistin (excluding SLED clearance) was 1.69L (21%) [population mean (between subject variability)] with 42% interoccasion variability. Colistin clearance during the SLED period was estimated to be 3.49L (42%). We evaluated the probability of target attainment defined as percentage of patients achieving relevant average colistin plasma concentration (Cavg) targets: >80% for Cavg ≥2 mg/L, >90% for Cavg ≥1.5 mg/L and <30% for Cavg ≥4 mg/L for the first 24h of therapy initiation on a SLED or nonSLED day as well as maintenance therapy.
Colistin clearance was substantially higher during SLED; therefore, SLED should be accounted for in CMS dosing regimens. This analysis provides comprehensive information regarding the achievement of clinically desirable average plasma colistin concentrations (including evaluation of loading doses) for two dosing regimens and six different SLED administration scenarios.

Key words:
Population pharmacokinetic modelling, colistin, sustained low-efficiency dialysis

Model-informed precision dosing (MIPD) has been a topic of growing interest in clinical pharmacology in recent years. However, there is still a significant challenge to make the MIPD results more readily accepted by physicians and to demonstrate its impact on clinical practice. During the upcoming presentation, Dr. Zhu will discuss his experience using MIPD to improve dosing for renally eliminated anti-infective drugs in pediatric patients. He will also share insights gained through years of collaboration with pediatricians and highlight the bridging role that clinical pharmacometricians play in implementing MIPD.