Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1–18 Years

Vancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received \u3e1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function

Dose–Exposure–Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR:An Analysis from FIDELIO-DKD

Background and Objective: Finerenone reduces the risk of kidney failure in patients with chronic kidney disease and type 2 diabetes. Changes in the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are surrogates for kidney failure. We performed dose–exposure–response analyses to determine the effects of finerenone on these surrogates in the presence and absence of sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from the FIDELIO-DKD study. Methods: Non-linear mixed-effects population pharmacokinetic/pharmacodynamic models were used to quantify disease progression in terms of UACR and eGFR during standard of care and pharmacodynamic effects of finerenone in the presence and absence of SGLT2i use. Results: The population pharmacokinetic/pharmacodynamic models adequately described effects of finerenone exposure in reducing UACR and slowing eGFR decline over time. The reduction in UACR achieved with finerenone during the first year predicted its subsequent effect in slowing progressive eGFR decline. SGLT2i use did not modify the effects of finerenone. The population pharmacokinetic/pharmacodynamic model demonstrated with 97.5% confidence that finerenone was at least 94.1% as efficacious in reducing UACR in patients using an SGLT2i compared with patients not using an SGLT2i based on the 95% confidence interval of the SGLT2i-finerenone interaction from 94.1 to 122%. The 95% confidence interval of the SGLT2i-finerenone interaction for the UACR-mediated effect on chronic eGFR decline was 9.5–144%. Conclusions: We developed a model that accurately describes the finerenone dose–exposure–response relationship for UACR and eGFR. The model demonstrated that the early UACR effect of finerenone predicted its long-term effect on eGFR decline. These effects were independent of concomitant SGLT2i use

The effect of food and formulation on the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy male volunteers

We aimed to characterise the population pharmacokinetics of cholesteryl ester transferase protein inhibitor DRL-17822 in healthy males and explore the effect of food and formulation on the oral absorption of DRL-17822 in 4 phase I studies. DRL-17822 was dosed orally (2-1000 mg) in 2 different drug formulations (nanocrystal formulation and amorphous solid dispersion formulation) after either an overnight fast, or a low-fat, continental or high-fat breakfast. A 2-compartment model with 6 transit absorption compartments best characterised the data. Additionally, a strong interaction of food and formulation on bioavailability was observed and parsimoniously characterised in the model by binning combinations of food state and formulation with similar bio-availabilities. The final model adequately characterised the pharmacokinetic data of DRL-17822 in healthy males including the complex interaction of food and drug formulation. The amorphous solid dispersion formulation has a lower food effect on bioavailability compared with the nanocrystal formulation.Pharmacolog

Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration‐effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT‐Behavior (COMFORT‐B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up‐titration). In responders to morphine up‐titration, the COMFORT‐B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT‐B score is expected. In general, lower baseline COMFORT‐B scores (2.1 points on average) in younger children (postnatal age 10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Aims: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400–700 mg h L−1). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. Methods: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0–234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg−1, maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11–13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60–230 kg) were performed using NONMEM. Results: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p  90% target attainment (area under the curve > 400 mg h L−1) in individuals up to 200 kg, with corresponding trough concentrations of 5.7–14.6 mg L−1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for s

Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after c

Towards personalized treatment of pain using a quantitative systems pharmacology approach

Pain is a complex biopsychosocial phenomenon of which the intensity, location and duration depends on various underlying components. Treatment of pain is associated with considerable inter-individual variability, and as such, requires a personalized approach. However, a priori prediction of optimal analgesic treatment for individual patients is still challenging. Another challenge is the assessment and treatment of pain in patients unable to self-report pain. In this mini-review, we first provide a brief overview of the various components underlying pain, and their associated biomarkers. These include clinical, psychosocial, neurophysiological, and biochemical components. We then discuss the use of empirical and mechanism-based pharmacokinetic-pharmacodynamic modelling to support personalized treatment of pain. Finally, we propose how these concepts can be extended to a quantitative systems pharmacology (QSP) approach that integrates the components of clinical pain and treatment response. This integrative approach can support predictions of optimal pharmacotherapy of pain, compared with approaches that focus on single components of pain. Moreover, combination of QSP modelling with state-of-the-art metabolomics approaches may offer unique possibilities to identify novel pain biomarkers. Such biomarkers could support both the personalized treatment of pain and translational drug development of novel analgesic agents. In conclusion, a QSP approach will likely improve our ability to predict pain and treatment response, paving the way for personalized treatment of pain

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

Aims: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. Methods: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFR birth (GFR at birth), and an Emax model dependent on PNA (with GFR max, PNA 50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. Result: In the GFR model, GFR birth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA 50, and current weight for GFR max. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. Conclusions: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.</p

Lomitapide

Pharmacolog

Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Therapeutic drug monitoring (TDM) is being considered as a tool to individualise sunitinib treatment of gastrointestinal stromal tumours (GIST). Here, we used computer simulations to assess the expected impact of sunitinib TDM on the clinical outcome of patients with GIST.Monte Carlo simulations were performed in R, based on previously published pharmacokinetic-pharmacodynamic models. Clinical trials with dose-limiting toxicity and patient dropout were simulated to establish the study size required to obtain sufficient statistical power for comparison of TDM-guided and fixed dosing.The simulations revealed that TDM might increase time to tumour progression by about 1-2 months (15-31 %) in eligible patients. However, the number of subjects required for a sufficient statistical power to quantify clinical benefit of TDM guided is likely to be prohibitively high (> 1000).Although data from randomised clinical trials on the clinical impact of sunitinib TDM are lacking, our findings support implementation of sunitinib TDM in clinical practice. For rare cancers with well-defined exposure-response relationships, modelling and simulation might allow the optimisation of dosing strategies when clinical trials cannot be performed due to low number of patients