This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose, 51Cr-EDTA, mannitol or iohexol) from eight studies (n = 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg [95% confidence interval (CI) 117–125]. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1–50.5), with a Hill coefficient of 3.40 (95%CI 3.03–3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.

Human renal function maturation: a quantitative description using weight and postmenstrual age

A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models

Objectives: To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units.

Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution

Purpose: To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer. Methods: A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model. Results: A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t1/2) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P<0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance. Conclusion: This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.

Population pharmacokinetics of trastuzumab in patients With HER2+ metastatic breast cancer

Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m² would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.

https://espace.library.uq.edu.au/view/UQ:250569/UQ250569_OA.pdf

Vancomycin Dosing in Critically Ill Patients: Robust Methods for Improved Continuous-Infusion Regimens

The population pharmacokinetics of cyclosporine (CsA) in adult recipients of cardiac transplants were determined from sparse, retrospective drug monitoring data accumulated for at least 3 months after surgery. All were receiving oral CsA twice daily, and morning trough levels in whole- blood were measured by high-performance liquid chromatography. Additional data included height, weight, gender, age, ethnicity, hematocrit, total bilirubin, and concurrent drug use. Population modeling was performed using NONMEM on 36 randomly selected patients, assuming a one-compartment model with first-order absorption and elimination. Improved fits were obtained by incorporating the following expression in the model to adjust oral bioavailability as a function of postoperative day (POD): F = 0.2 + 10 x ABS (POD 7) / ([POD + 10] x 60). Interpatient variability (CV%) in clearance (CL) was 20.2%. There was a mean bias of 8.5% at the average CsA concentration of 250 ng/ml when the predictive performance was assessed statistically in a reserved subset of 33 patients who received cardiac transplants. For the entire population (n = 69 patients), the average CsA CL and terminal half- life (T(1/2)) were, respectively: CL (l/h) = 0.256 x weight (kg); T(1/2) = 11.0 hours, or CL (l/h) = 0.184 x weight (kg); T(1/2) = 14.7 hours, if there was concomitant diltiazem administration. These results compared favorably with those reported elsewhere for studies of postcardiac transplant kinetics using the traditional multiple blood sampling approach.

NONMEM Population Pharmacokinetic Modeling of Orally Administered Cyclosporine From Routine Drug Monitoring Data After Heart Transplantation

Carbamazepine (CBZ) clearance decreases from childhood to adulthood and the factors determining this change could include age, size, autoinduction, or maturational changes This study aims to describe the population pharmacokinetics of CBZ in children and young adults and test the hypothesis that CBZ clearance correlates with weight, surface area, and age CBZ therapeutic drug monitoring data (sparse data) were collected from child and adult epileptics, and rich data were obtained from a bioequivalence study of CBZ in young adults Population pharmacokinetic analysis was performed using NONMEM V Forward stepwise, multiple regression was performed on the covariates Bootstrap validation was performed A total of 946 observations from 91 subjects, ages 07–37 years, were collected and analyzed A one-compartment, first-order absorption and elimination model, with exponential interindividual error and additive residual error models was developed The population model was: Clearance (Lhr−1)=((224 · Surface area (m2))+(0047 · Dose (mg · kg−1)); Volume of distribution (L)=037 · weight (kg); Absorption rate constant=0013 (hr−1) CBZ clearance increased with surface area and dose

Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

Objective: To determine factors affecting the population pharmacokinetics of oral cyclosporin (CsA) in cardiac allograft recipients during the first 3 weeks after surgery. 
Methods: Data were obtained from routine trough monitoring and from two extra samples drawn during a dosing interval on a randomly selected day. Whole blood CsA concentrations were assayed using high-performance liquid chromatography (HPLC). Approximately equal numbers of patients were prescribed Sandimmun (SAN) or Neoral (NEO) CsA formulations. Parameter values of a one-compartment kinetic model with first-order absorption and elimination were sought together with the inter-patient and intra-patient variances using the NONMEM program. 
Results: Improved fits resulted from using the following expression in the model to adjust apparent bioavailability as a function of post-operative day (POD): f=0.2 + 10 × ABS (POD−5)/[(POD + 7) × 60]. The CsA clearance (CL/f ) was found to be influenced by current body weight (WT). There was an absorption lag time of about 35 min with SAN, but zero lag time with NEO. Oral bioavailability (f ) was increased by about 35% with concomitant diltiazem and about 18% with NEO. The CL/f was10% higher during the daytime than at night. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. 
Conclusions: Using a validated population modelling approach, it was found that a number of factors influence the pharmacokinetics of CsA during the early post-operative period in cardiac transplant patients. These influences affecting oral bioavailability and clearance may need to be taken into account for maintaining appropriate concentrations of CsA in the bloodstream.

J. Parke

Papers

A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models

NONMEM Population Pharmacokinetic Modeling of Orally Administered Cyclosporine From Routine Drug Monitoring Data After Heart Transplantation

Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

Factors affecting oral cyclosporin disposition after heart transplantation: bootstrap validation of a population pharmacokinetic model.

Population pharmacokinetic modeling of steady state carbamazepine clearance in children, adolescents, and adults (vol 28, pg 79, 2001)