A population pharmacokinetic model of gentamicin in paediatric oncology patients to facilitate improved therapeutic drug monitoring

To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, -3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model

Life course socioeconomic position and body composition in adulthood: a systematic review and narrative synthesis

INTRODUCTION: Multiple systematic reviews have investigated the relation between socioeconomic position (SEP) and body mass index (BMI) throughout the life course. However, BMI does not capture quantity and distribution of fat and muscle, which are better indicators of obesity than BMI, and have been independently linked to adverse health outcomes. Less is known about the relation between SEP and body composition, and the literature has not been reviewed. We therefore systematically reviewed the literature on the association between life course SEP and body composition in adulthood. METHODS: A protocol was registered on PROSPERO (CRD42019119937), and the review followed PRISMA guidelines. An electronic search of three databases (MEDLINE, Embase Classic + Embase and SPORTDiscus) was conducted. Original studies in the English language were included that examine the association between any recognised measure of SEP at any age and body composition (fat mass, fat-free mass, ratio and distribution) in adulthood, measured using a direct technique, i.e., not an anthropometric measure. A narrative synthesis was conducted. RESULTS: A total of 47 papers were included in the final review, none were from low-income countries (LICs). Greater advantage in childhood and adulthood was associated with lower fat levels in high-income countries (HICs). Associations in the opposite direction were found exclusively in middle-income countries (MICs). No studies in MICs reported associations for childhood SEP. For measures of lean mass, the majority of papers reported no association, or greater advantage in adulthood associated with higher lean mass, with little variation between HICs and MICs. Associations in HICs are more often observed in women than men. CONCLUSION: The results indicate that fat measures follow similar patterns to those seen for BMI, and that women in HICs are more likely to experience inequalities in both fat and lean measures. Further research in LICs and MICs is needed

Socioeconomic position and body composition in childhood in high- and middle-income countries: a systematic review and narrative synthesis

BACKGROUND: The relation between socioeconomic position (SEP) and obesity measured by body mass index (BMI), a measure of weight for height, has been extensively reviewed in children, showing consistent associations between disadvantaged SEP and higher BMI in high-income countries (HICs) and lower BMI in middle-income countries (MICs). Fat mass (FM), a more accurate measure of adiposity, and fat-free mass (FFM) are not captured by BMI, but have been shown to track from childhood to adulthood, and be important for cardiovascular health and functional outcomes in later life. It is not clear whether body composition is associated with SEP. We systematically reviewed the association between SEP and body composition in childhood. METHODS: A systematic review was carried out following PRISMA guidelines. The protocol was pre-registered with PROSPERO (CRD42019119937). Original studies in the English language, which examined the association between SEP and body composition in childhood, were included. An electronic search of three databases was conducted. Two independent reviewers carried out screening, data extraction and quality assessment. Due to heterogeneity in results, a narrative synthesis was conducted. Heterogeneity in findings according to SEP, sex, body composition measure and country income level was investigated. RESULTS: 50 papers were included, the majority from HICs. No papers were from low-income countries. Disadvantage in childhood was associated with greater FM and lower FFM in HICs, but with lower FM and lower FFM in MICs. When measures of FFM indexed to height were used there was no evidence of associations with SEP. In HICs, more studies reported associations between disadvantaged SEP and higher FM among girls comparative to boys. CONCLUSIONS: Inequalities in FM are evident in HICs and, in the opposite direction, in MICs and follow similar trends to inequalities for BMI. Inequalities in height are likely important in understanding inequalities in FFM

Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis

This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis. This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation. A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms. In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT

Population pharmacokinetics of doripenem in critically ill patients with sepsis in a Malaysian intensive care unit

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CLCR), such that a 30-ml/min increase in the estimated CLCR would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every8hasa4-hinfusion is optimal for patients with a CLCR of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CLCR of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involve

Comparison of the influence of cyclosporine and tacrolimus on the pharmacokinetics of prednisolone in adult male kidney transplant recipients

Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus