Pediatric Population Pharmacokinetic Model Research Articles

Population Pharmacokinetic Modeling of Abacavir/Dolutegravir/Lamivudine to Support a Fixed-Dose Combination in Children with HIV-1.

Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥ 6kg. This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using dispersible tablet (DT) and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study. IMPAACT 2019 was a Phase I/II study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC in children with HIV-1. Intensive and sparse PK samples were collected over 48weeks. Existing drug-specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 drug concentration data without re-estimation (external validation) of PopPK parameters. Drug exposures were then simulated across World Health Organization weight bands for children weighing ≥ 6 to < 40kg for each drug and compared with pre-defined exposure target ranges. Goodness-of-fit and visual predictive check plots demonstrated that the previously developed pediatric PopPK models sufficiently described and predicted the data. Thus, new PopPK models describing the IMPAACT 2019 data were unnecessary. Across weight bands, the predicted geometric mean (GM) for ABC AUC0-24 ranged from 14.89 to 18.50μg*h/ml, DTG C24 ranged from 0.74 to 0.95μg/ml, and 3TC AUC0-24 ranged from 10.50 to 13.20μg*h/ml. These exposures were well within the pre-defined target ranges set for each drug. This model-based approach leveraged existing pediatric data and models to confirm dosing of ABC/DTG/3TC FDC formulations in children with HIV-1. This analysis supports ABC/DTG/3TC FDC dosing in children weighing ≥ 6kg.

Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients.

Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients. Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.

Population Pharmacokinetic Modeling for Ceftazidime-Avibactam Renal Dose Adjustments in Pediatric Patients 3 months and Older.

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination developed to treat serious Gram-negative bacterial infections; approved indications include complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired pneumonia including ventilator-associated pneumonia in patients ≥ 3 months old. Because of the predominantly renal clearance of ceftazidime and avibactam, dose adjustments (reductions) are required for patients with estimated creatinine clearance (CrCL) ≤ 50 mL/min. We describe the application of combined adult and pediatric population pharmacokinetic models in developing ceftazidime-avibactam dose recommendations for pediatric patients ≥ 2 to < 18 years old with body surface area-normalized CrCL ≤ 50 mL/min/1.73 m2 , including moderate, severe, or very severe renal impairment, or end-stage renal disease requiring hemodialysis, and for patients ≥ 3 months to < 2 years old with mild, moderate, or severe renal impairment. Models included allometric scaling for all subjects and simulations (1,000 subjects per age group, renal function group, and indication) were performed nonparametrically using post hoc random effects. Doses were selected based on simulated pediatric patients achieving steady-state exposures similar to adults and high probability of target attainment (using a simultaneous joint target for both ceftazidime and avibactam). Because there were few children with renal impairment in the ceftazidime-avibactam clinical trials, selected pediatric doses were guided by extrapolation and matching of adult exposures associated with efficacy and within established safety margins. The recommended doses for pediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m2 use equivalent adjustments in dose quantity and/or administration interval (vs. the corresponding age group with normal renal function) as those for adults.

Bridging Fixed Dose to Body Weight-based Regimen of Adalimumab in Paediatric Ulcerative Colitis Using a Pharmacometric Modelling Approach: Case Study with the Phase 3 ENVISION I Trial.

The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in paediatric patients with moderate to severe ulcerative colitis. The protocol-specified high-dose adalimumab regimen was numerically more efficacious than the standard-dose regimen. The objective of this work was to bridge a fixed-dosing regimen to the protocol-specified high-induction/high-maintenance, body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modelling and simulation approach. A stepwise strategy was implemented, including developing an adalimumab paediatric population pharmacokinetic model; using this model to determine a fixed-dosing regimen in paediatric ulcerative colitis patients which achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in paediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I. Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression [p <0.01]. Simulated efficacy suggested that the fixed-dosing regimen performs similarly to the more efficacious dosing regimen used in ENVISION I, by providing comparable clinical remission per Partial Mayo Score response rates over time. No relationship between adalimumab exposure and adverse events was identified. The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of the fixed-dosing regimen in the paediatric ulcerative colitis population.

Avelumab Dose Selection for Clinical Studies in Pediatric Patients with Solid Tumors.

Background and ObjectiveA phase I/II trial evaluated the safety, antitumor activity, and pharmacokinetics of avelumab (anti-PD-L1 antibody) in pediatric patients with refractory/relapsed solid tumors (NCT03451825). This study aimed to inform avelumab dose selection in pediatric populations using population pharmacokinetic modeling and simulations.MethodsPatients aged < 18 years with refractory/relapsed solid tumors enrolled in phase I received avelumab 10 or 20 mg/kg intravenously every 2 weeks. A pediatric population pharmacokinetic model was developed via the frequentist prior approach.ResultsPharmacokinetic parameters from 21 patients who received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15) were analyzed. Patients had a wide range of weights and ages (medians, 37.3 kg and 12 years). Exposures with 10-mg/kg dosing were lower vs adult dosing, particularly in patients weighing < 40 kg, whereas 20-mg/kg dosing achieved or exceeded adult exposures, irrespective of body weight. A two-compartment linear model with time-varying clearance using body weight as a covariate, with the frequentist prior approach, best described pediatric data. In this model, optimal overlap in exposure with adult data was achieved with 800 mg every 2 weeks for patients aged ≥ 12 years and weighing ≥ 40 kg, and 15 mg/kg every 2 weeks for patients aged < 12 years or weighing < 40 kg.ConclusionsBased on exposure matching, the recommended doses for further avelumab studies, including combination studies, are 15 mg/kg every 2 weeks for pediatric patients aged < 12 years or weighing < 40 kg and the adult flat dose of 800 mg every 2 weeks for pediatric patients aged ≥ 12 years and weighing ≥ 40 kg.Clinical Trial RegistrationClinicalTrials.gov NCT03451825.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01111-8.

Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial

Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax. This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC[0-∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496. Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC(0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) μg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) μg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) μg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) μg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study. For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting. GlaxoSmithKline and Medicines for Malaria Venture. For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Model-based approach to sampling optimization in studies of antibacterial drugs for infants and young children.

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Dosing Recommendations for Lamotrigine in Children: Evaluation Based on Previous and New Population Pharmacokinetic Models.

Lamotrigine is a broad-spectrum antiepileptic drug with high interindividual variability in serum concentrations in children. The aims of this study were to evaluate the predictive performance of pediatric population pharmacokinetic (PPK) models published on lamotrigine, to build a new model with our monitoring data and to evaluate the current recommended doses. A validation cohort included patients treated with lamotrigine who had a serum level assayed during therapeutic drug monitoring (TDM). PPK models published in the literature were first applied to the validation cohort. We assessed their predictive performance using mean prediction errors, root mean squared errors, and visual predictive checks. A new model was then built using the data. Dose simulations were performed to evaluate the doses recommended. We included 270 lamotrigine concentrations ranging from 0.5 to 17.9mg/L from 175 patients. The median (range) age and weight were 11.8 years (0.8-18 years) and 32.7kg (8-110kg). We tested 6 PPK models; most had acceptable bias and precision but underestimated the variability of the cohort. We built a 1-compartment model with first-order absorption and elimination, allometric scaling, and effects of inhibitor and inducer comedications. In our cohort, 22.6% of trough concentrations were below 2.5mg/L. In conclusion, we proposed a PPK model that can be used for TDM of lamotrigine in children. In our population, a high percentage of children had low trough concentrations of lamotrigine. As the intervals of recommended doses are large, we suggest aiming at the higher range of doses to reach the target concentration.

Population Pharmacokinetics of Metoclopramide in Infants, Children, and Adolescents.

Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. Opportunistic pharmacokinetic data were collected from pediatric patients receiving enteral or parenteral metoclopramide per standard of care and these data were simultaneously fitted using NONMEM. Allometric scaling with body weight was included a priori in the model. Using the final model, the steady‐state maximum concentrations (Css,max) and the area under the metoclopramide plasma concentration‐time curve at steady state from 0 to 6 hours (AUCss,0–6h) were simulated following 0.1 or 0.15 mg/kg orally every 6 hours in virtual patients, and compared with previously reported ranges associated with toxicity or the efficacy for gastroesophageal reflux in infants. A two‐compartment model with first‐order absorption best characterized 87 concentration measurements from 50 patients (median [range] postnatal age of 8.89 years [0.01–19.13]). There were 20 infants (≤ 2 years), 9 children (2 years to age ≤ 12 years), and 21 adolescents (> 12 years). Body weight was the only covariate included in the final model. For > 75% of virtual patients, simulated Css,max and AUCss,0–6h estimates were within the range associated with efficacy for gastroesophageal reflux in infants; however, slightly lower exposures were predicted in virtual patients < 2 years. Our study suggests that a metoclopramide enteral dose of 0.1 mg/kg every 6 hours, which was previously recommended for pediatric patients, results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux.

Population Pharmacokinetics of Adjunctive Lacosamide in Pediatric Patients With Epilepsy.

A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose.

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models.

Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6mg/L and a root mean squared error of 25.1mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50mg/L. Simulations suggested increasing doses, especially for children ≤40kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

Modeling and simulation for the evaluation of dose adaptation rules of intravenous lacosamide in children

A combined adult and pediatric population pharmacokinetic model including covariate effects was developed; simulations were subsequently performed to guide intravenous pediatric dosing adaptations. Two pharmacokinetic trials with sparse blood sampling were conducted in children with epilepsy and two trials in healthy adults with serial blood sampling. Lacosamide plasma concentration–time data were available from 43 healthy adults (18–45 years of age; body weight 50–101 kg; n = 1735 concentration vs time records), and from 79 children with epilepsy (6 months–17 years of age; body weight 6–76 kg; n = 402 concentration vs time records), with 14, 22, 25 and 18 participants in age groups <2 years, 2 to <6 years, 6 to <12 years and 12 to <18 years, respectively. A two-compartment population pharmacokinetic model was developed using nonlinear mixed effects modeling. Plasma clearance was scaled using a fixed allometric exponent on body weight, while central volume of distribution used a freely estimated allometric exponent. The model-based pharmacokinetic predictions suggested that there is no need to adapt the recommendations regarding intravenous infusion durations in children compared with adults.

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures

Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4–17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2–18 years of age treated with ESL 5–30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters. Model evaluation performed using a simulation-based visual predictive check and a non-parametric bootstrap procedure indicated no substantial bias in the overall model and in the accuracy of estimates. The model estimated that concomitant use of carbamazepine or phenobarbital-like AEDs with ESL would decrease the exposure of eslicarbazepine, and that concomitant use of levetiracetam with ESL would increase the exposure of eslicarbazepine, although the small effect of levetiracetam may not represent a true difference. Model-based simulations were subsequently performed to apply target exposure matching of selected ESL doses for pediatric subjects (aged 4–17 years) to attain eslicarbazepine exposures associated with effective and well-tolerated ESL doses in adults. Overall, model-based exposure matching allowed for extrapolation of efficacy to support pediatric dose selection as part of the submission to obtain FDA approval for ESL (adjunctive therapy and monotherapy) in subjects aged 4–17 years, without requiring an additional clinical study.

Abstract P-215: PIPERACILLIN PHARMACOKINETICS AND DOSING REGIMEN OPTIMIZATION IN CRITICALLY ILL CHILDREN WITH NORMAL AND AUGMENTED RENAL CLEARANCE

Aims & Objectives: Our objectives were to build a pediatric population pharmacokinetic model for Piperacillin, in order to optimize individual dosing regimen. Methods All children admitted in pediatric intensive care unit and receiving intermittent Piperacillin infusions were included. Piperacillin was quantified by high performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed effect modelling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimen, in order to maintain plasma concentration above the minimum inhibitory concentration (16 mg.L-1 for Pseudomonas aeruginosa) throughout the dosing interval (100% fT>MIC). Results We included 50 children with a median (range) post natal age of 27.2 (1.1–222.9) months, median (range) body weight of 11.9 (2.7–50) kg, median (range) PELOD-2 score of 4 (0–16) and median (range) estimated creatinine clearance of 142 (29–675) mL.min-1.m-2. A one compartment model with first-order elimination adequately described the data. Median (range) values for clearance and volume of distribution were respectively 3 (0.71–10) L.h-1 and 3.8 (0.72–25.8) L. Body weight (allometric relationship), estimated creatinine clearance and PELOD-2 severity score were the covariates explaining the estimated between subject variability. To reach the target and according to the simulated dosing regimens, children with acute kidney injury should receive intermittent infusion every 6 hours, administered on 30 minutes. Those with augmented renal clearance should receive a continuous infusion. Conclusions To reach the target, standard intermittent Piperacillin dosing regimen in critically ill children is not appropriate. In addition to body weight, dosing regimens should take into account the creatinine clearance. Continuous infusion is adequate for children with augmented renal clearance.

Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children.

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods. We applied our model by performing dosing simulations targeting plasma concentrations previously associated with analgesia (>100ng/mL) and anesthesia awakening (750ng/mL). A total of 113 children (50 intramuscular and 63 intravenous ketamine) with a median age of 3.3years (range 0.02 to 17.6years), and median weight of 14kg (2.4 to 176.1) contributed 275 plasma samples (149 after intramuscular, 126 after intravenous ketamine). A 2-compartment model with first-order absorption following intramuscular administration and first-order elimination described the data best. Allometrically scaled weight was included in the base model for central and peripheral volume of distribution (exponent 1) and for clearance and intercompartmental clearance (exponent 0.75). Model-estimated bioavailability of intramuscular ketamine was 41%. Dosing simulations suggest that doses of 2mg/kg intravenously and 8mg/kg or 6mg/kg intramuscularly, depending on age, provide adequate sedation (plasma ketamine concentrations>750ng/mL) for procedures lasting up to 20minutes.

Pediatric Development of Bosentan Facilitated by Modeling and Simulation.

Bosentan is approved for use in adult patients with pulmonary arterial hypertension. The primary aim of the pharmacokinetic modeling was the provision of a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range. A physiologically based pharmacokinetic model was developed for the pediatric population; starting from an adult model, the effects of body weight, age, and maturation of relevant metabolizing enzymes were incorporated to extrapolate the pharmacokinetics to children. A pediatric population pharmacokinetic model was developed to identify relevant covariates. Based on model predictions, a dose of 0.5mg/kg led to an exposure distinguishable from a dose of 2mg/kg, and an additional blood sampling time point at 2 h (the predicted time of maximum concentration) allowed more precise estimation of bosentan exposure in children. The lower exposure observed in children compared with adults could be explained by maturation-related changes in clearance. Clinical data confirmed the model predictions. Maturational changes in drug clearance and developmental changes in body weight were identified as key elements of bosentan pharmacokinetics in pediatric patients. Estimating bosentan exposure using physiologically based and population pharmacokinetic modeling and simulation supported dose selection in pediatric patients. Model-based exposure estimates helped in reducing the number of the youngest pediatric patients to be studied. Pharmacokinetic models can provide a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range.

Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury

Milrinone is an inotropic agent with vasodilating properties used in the treatment of ventricular dysfunction. Milrinone is predominantly eliminated by the kidneys and accumulates in the setting of acute kidney injury (AKI). The purpose of this study was to evaluate milrinone pharmacokinetics in children with AKI with or without continuous renal replacement therapy (CRRT). Retrospective collection of milrinone therapeutic drug monitoring data in patients with AKI, including those requiring CRRT, through chart review from January 2008 to March 2014. Pharmacokinetic (PK) data were analyzed by Bayesian estimation using a pediatric population PK model (MW/Pharm). Clearance estimates were allometrically scaled to body weight. Data on 11 patients were available for analysis. Three patients required CRRT. Milrinone concentrations during continuous infusion varied 30-fold and ranged from 44 to 1343 ng/mL. Of the 33 samples obtained in 11 patients, 24 were outside the target range (72.7%), with 16 (48.5%) above and 8 (24.2%) below. Patients with AKI had significantly lower milrinone clearance (4.72 ± 2.26 L/h per 70 kg) compared with published data in patients without AKI. There was large between-patient variability in milrinone clearance (range: 2.91-13.6 L/h per 70 kg). Clearance in patients on CRRT ranged from 2.8 to 7.19 L/h per 70 kg. A significant correlation between milrinone clearance and estimated creatinine clearance was observed (r = 0.70, P = 0.0097). Allometrically scaled milrinone clearance was lower in the youngest patients (younger than 2 years), suggestive of ongoing renal maturation and existing AKI. Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in this population of critically ill patients. Evaluation of PK model-based milrinone dose optimization and the use of biomarkers as predictors of changes in clearance warrant further study.

Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children.

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Validation of a pediatric population pharmacokinetic model for vancomycin.

Vancomycin is often required to treat serious infections in children, including methicillin-resistant Staphylococcus aureus infections. The pharmacodynamic index that best predicts efficacy with vancomycin use for methicillin-resistant S. aureus infection in adults is the 24-hour area under the curve (AUC) over the minimum inhibitory concentration. Although multiple pediatric population pharmacokinetic (PK) vancomycin models have been published, few use Bayesian optimization. The current standard of care remains measuring vancomycin serum trough concentrations as a surrogate marker of AUC. A prospective validation of a pediatric population PK model of vancomycin was performed. Hospitalized children younger than 18 years receiving vancomycin at Cincinnati Children's Hospital Medical Center were invited to participate. Peak, trough, and random vancomycin serum concentrations were used for Bayesian estimation of individual PK parameters. Model covariates included age, weight, and serum creatinine. To evaluate the predictive performance of the model, precision and bias were measured and compared using the 95% confidence interval. Fifteen subjects were enrolled; 13 subjects had vancomycin serum concentrations drawn per protocol. Of those 13 subjects, the median age was 6 years and 54% were male. Significant medical conditions included cancer (54%), lung disease (23%), neurologic disorders (23%), and prior transplantation (15%). The initial serum creatinine was normal (median, 0.33; interquartile range, 0.23-0.4 mg/dL), and none had underlying renal dysfunction. Equivalence of bias and precision between the original model validation and the Cincinnati Children's Hospital Medical Center validation were found. Pediatric population PK models for vancomycin with Bayesian estimation can be used to reliably predict vancomycin exposure in children. Using AUC instead of trough serum concentrations alone can provide an opportunity to maximally optimize vancomycin administration in children.

Development of a paediatric population pharmacokinetic model for valacyclovir from literature non-compartmental values originating from sparse studies and Bayesian priors: a simulation study.

A preliminary population pharmacokinetic (PopPK) model of valacyclovir in children was developed from non-compartmental analysis (NCA) parameter values from literature, including several age groups, combined with Bayesian priors from a PopPK model of acyclovir, the active metabolite of valacyclovir, from literature too. Also a simulation study was carried out to evaluate the performance of various modelling choices related to the estimation of model parameters from NCA parameters originating from sparse PK studies. Assuming a one-compartment model with first order absorption, a mixed effects, meta-analysis approach was utilized which allows accounting the random intergroup variability, the detection of covariates and the application of informative Bayesian priors on the parameters. The conclusions from the simulation study calculating bias and precision for various cases, were that a model which takes explicitly into account the sampling schedule, performs better than a model using the theoretical expressions of calculating the NCA parameters. Also by using the geometric rather than the arithmetic means of NCA parameters, less biased results are obtained. These findings guided the choices for the valacyclovir model, for which informative priors from a PopPK model of acyclovir were applied for some of the parameters, in order to include a richer covariate model for clearance, not supported by the NCA dataset and a value for bioavailability. This preliminary valacyclovir model can be used in simulations to provide dosage recommendations for children of various ages and to help design more efficiently prospective clinical trials.