Body Size Descriptors Research Articles

Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors

PurposeNLG207 (formerly CRLX101) is a nanoparticle–drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model.MethodsFrom 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling.ResultsThe PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%).ConclusionThe popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.

Independent and Combined Effects of Weight Status and Maturation on Aerobic Fitness in Adolescent School-Aged Males.

Batista, MB, Valente-dos-Santos, J, Duarte, JP, Sousa-e-Silva, P, Coelho-e-Silva, MJ, Werneck, AO, Ohara, D, Cyrino, ES, and Ronque, ERV. Independent and combined effects of weight status and maturation on aerobic fitness in adolescent school-aged males. J Strength Cond Res 34(9): 2663-2671, 2020-This study aimed to examine the independent and combined effects of pubertal and weight status on concurrent measurements of peak oxygen (V[Combining Dot Above]O2peak) in school-aged adolescent males. The final sample included 49 boys (12.3 ± 0.8 years). V[Combining Dot Above]O2peak was derived from an incremental progressive maximal protocol using a motorized treadmill. In addition, maximal oxygen uptake was estimated from a 20-m shuttle run test. Static allometric models were obtained as an alternative to performance output per unit of size descriptors. Weight status had a significant effect on V[Combining Dot Above]O2peak using simple ratio standards per unit of body mass (BM) with adolescents classified as overweight and obese (OWOB) attaining lower values of V[Combining Dot Above]O2peak. A similar trend was noted for the allometric models adopting body mass (ml·kgBM·min), stature (L·m·min), and fat-free mass (FFM; ml·kgFFM·min). Findings also suggest the influence and interaction of pubertal and weight status on absolute values of V[Combining Dot Above]O2peak. Considering the data obtained, linear equations to estimate V[Combining Dot Above]O2peak from the 20-m shuttle run test should not be applied to boys who are OWOB because it will produce inaccurate assessments of cardiorespiratory fitness and penalize those who are heavier. Equations for V[Combining Dot Above]O2peak prediction need to be specific for pubertal status and preferably consider FFM as a body size descriptor.

Clofazimine pharmacokinetics in patients with TB: dosing implications.

BackgroundClofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.ObjectivesTo determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.Patients and methodsClinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.ResultsWe analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.ConclusionsClofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

Scaling left ventricular mass in adolescent female soccer players

BackgroundThe aim of the study was to examine the contribution of chronological age (CA), skeletal maturation, training experience and concurrent body size descriptors, to inter-individual variance in left ventricular mass (LVM) among female adolescent soccer players.MethodsThe sample included 228 female soccer players 11.8–17.1 years. Training experience defined as years of participation in competitive soccer (range 2–9 years), was obtained by interview. Stature, body mass and skinfolds (triceps, medial calf) were measured. Fat mass was estimated; Fat-free mass was derived. LVM was assessed by echocardiography. Skeletal maturity status was as the difference of skeletal age (SA, Fels method) minus CA.ResultsFat-free mass was the most prominent single predictor of LVM (R2 = 36.6%). It was associated with an allometric coefficient close to linearity (k = 0.924, 95%CI: 0.737 to 1.112). A significant multiplicative allometric model including body mass, fat-free mass, CA, training experience and skeletal maturity status was also obtained (R = 0.684; R2 = 46.2%).ConclusionStature has limitations as a valid size descriptor of LVM. Body mass, fat-free mass, training experience, CA, body mass and skeletal maturity status were relevant factors contributing to inter-individual variability in LVM.

Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients.

Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (Cmax) of ≥25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC24) of ≥70 mg · h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a Cmax target of >25 mg/liter than an AUC24 target of ≥70 mg · h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required.

P072 Evaluation of dosing strategies of anti-TNFα monoclonal antibodies using pharmacokinetic modelling and simulation

Abstract Background Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). References

Propofol Sedation for Intragastric Balloon Removal: Looking for the Optimal Body Weight Descriptor.

Sedation is considered as a prerequisite for the safe and effective conclusion of Bioenterics Intragastric Balloon (BIB) removal (our aim was to ascertain the most appropriate body size scalars for propofol dosing and assess the efficacy and safety of a sedative approach involving the infusion of propofol for BIB removal. Retrospective analysis of prospectively collected data of 414 adults scheduled to undergo BIB removal. Our primary end-point was to delineate the relationship between propofol dosing and body size descriptors namely body mass index, total body weight, ideal body weight, lean body weight (LBW) and normalized LBW. Sedative efficacy of this practice, anesthesia or procedural-related adverse events and patients' satisfaction level served as secondary outcome parameters. Propofol dose (mg/kg/min) was positively related to all body weight descriptors in an important manner (p < 0.001). Among them, LBW was singled out as the body size descriptor to best capture the appropriate needs of propofol (R2= 0.432; p= 0.000). Hypoxemia, hemodynamic compromise, gastroesophageal reflux or moderate movement occurred rarely; all of them were readily reversed. The majority of participants had no recollection of the noxious phase of the procedure or declared at least adequately satisfied from the experience (84% and 95%, respectively). LBW could serve as relatively more accurate dosing scalar compared to actual or ideal body weight descriptors, in obese individuals undergoing BIB removal under propofol sedation. The conscious/deep sedation based on propofol infusion emerges as a feasible and efficacious sedative approach for this procedure.

Allometric scaling of aerobic fitness outputs in school-aged pubertal girls

BackgroundThis study aimed to determine the allometric exponents for concurrent size descriptors (stature, body mass and fat-free mass) and also to examine the contribution of chronological age and pubertal status combined with above mentioned size descriptors to explain inter-individual variability in the peak of oxygen uptake (VO2peak) among girls during circumpubertal years.MethodsThe final sample included 51 girls (10.7–13.5 years). VO2peak was derived from an incremental progressive maximal protocol using a motorized treadmill. Anthropometry included body mass, stature and skinfolds. Measurements were performed by a single trained observer. Sexual maturation was assessed as self-reported stage of pubic hair (PH) development. Static allometric models were explored as an alternative to physiological output per unit of size descriptors. Allometry also considered chronological age and sexual maturation as dummy variable (PH2 vs. PH3 and PH3 vs. PH4).ResultsScaling coefficients for stature, body mass and fat-free mass were 1.463 (95%CI: 0.476 to 2.449), 0.516 (95%CI: 0.367 to 0.666) and 0.723 (95%CI: 0.494 to 0.951), respectively. The inclusion of sexual maturation increased explained variance for VO2peak (55% for PH2 vs. PH3 and 47% for PH3 vs. PH4). Body mass was identified as the most prominent body size descriptor in the PH2 vs. PH3 while fat-free mass was the most relevant predictor combined with PH3 vs. PH4.ConclusionsBody mass and fat-free mass seemed to establish a non-linear relationship with VO2peak. Across puberty, inter-individual variability in VO2peak is explained by sexual maturation combined with whole body during early puberty and by sexual maturation and fat-free mass during late puberty. Additional studies need to confirm ontogenetic allometric models during years of maximal growth.

Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

BackgroundFludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used.ObjectiveWe sought to describe the population PK of fludarabine in HCT recipients of all ages.MethodsFrom 258 HCT recipients aged 0.3–74 years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling.ResultsVariability was extensive where area under the curve ranged from 10 to 66 mg h/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.24 ± 20% L/h/70 kg) and renal (eGFR × 0.782 ± 11% L/h/70 kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 ± 8%, 20 ± 11%, and 50 ± 9% L/70 kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 ± 8% and 3.8 ± 13% L/h/70 kg, respectively.ConclusionBW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome.

Accuracy and reproducibility of simplified QSPECT dosimetry for personalized 177Lu-octreotate PRRT

BackgroundRoutine dosimetry is essential for personalized 177Lu-octreotate peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs), but practical and robust dosimetry methods are needed for wide clinical adoption. The aim of this study was to assess the accuracy and inter-observer reproducibility of simplified dosimetry protocols based on quantitative single-photon emission computed tomography (QSPECT) with a limited number of scanning time points. We also updated our personalized injected activity (IA) prescription scheme.MethodsSeventy-nine NET patients receiving 177Lu-octreotate therapy (with a total of 279 therapy cycles) were included in our study. Three-time-point (3TP; days 0, 1, and 3) QSPECT scanning was performed following each therapy administration. Dosimetry was obtained using small volumes of interest activity concentration sampling for the kidney, the bone marrow and the tumor having the most intense uptake. Accuracy of the simplified dosimetry based on two-time-point (2TP; days 1 and 3, monoexponential fit) or a single-time-point (1TPD3; day 3) scanning was assessed, as well as that of hybrid methods based on 2TP for the first cycle and 1TP (day 1 or 3; 2TP/1TPD1 and 2TP/1TPD3, respectively) or no imaging at all (based on IA only; 2TP/no imaging (NI)) for the subsequent induction cycles. The inter-observer agreement was evaluated for the 3TP, 2TP, and hybrid 2TP/1TPD3 methods using a subset of 60 induction cycles (15 patients). The estimated glomerular filtration rate (eGFR), body size descriptors (weight, body surface area (BSA), lean body weight (LBW)), and products of both were assessed for their ability to predict IA per renal absorbed dose at the first cycle.ResultsThe 2TP dosimetry estimates correlated highly with those from the 3TP data for all tissues (Spearman r > 0.99, P < 0.0001) with small relative errors between the methods, particularly for the kidney and the tumor, with median relative errors not exceeding 2% and interdecile ranges spanning over less than 6% and 4%, respectively, for the per-cycle and cumulative estimates. For the bone marrow, the errors were slightly greater (median errors < 6%, interdecile ranges < 14%). Overall, the strength of correlations of the absorbed dose estimates from the simplified methods with those from the 3TP scans tended to progressively decrease, and the relative errors to increase, in the following order: 2TP, 2TP/1TPD3, 1TPD3, 2TP/1TPD1, and 2TP/NI. For the tumor, the 2TP/NI scenario was highly inaccurate due to the interference of the therapeutic response. There was an excellent inter-observer agreement between the three observers, in particular for the renal absorbed dose estimated using the 3TP and 2TP methods, with mean errors lesser than 1% and standard deviations of 5% or lower. The eGFR · LBW and eGFR · BSA products best predicted the ratio of IA to the renal dose (GBq/Gy) for the first cycle (Spearman r = 0.41 and 0.39, respectively; P < 0.001). For the first cycle, the personalized IA proportional to eGFR · LBW or eGFR · BSA decreased the range of delivered renal absorbed dose between patients as compared with the fixed IA. For the subsequent cycles, the optimal personalized IA could be determined based on the prior cycle renal GBq/Gy with an error of less than 21% in 90% of patients.ConclusionsA simplified dosimetry protocol based on two-time-point QSPECT scanning on days 1 and 3 post-PRRT provides reproducible and more accurate dose estimates than the techniques relying on a single time point for non-initial or all cycles and results in limited patient inconvenience as compared to protocols involving scanning at later time points. Renal absorbed dose over the 4-cycle induction PRRT course can be standardized by personalizing IA based on the product of eGFR with LBW or BSA for the first cycle and on prior renal dosimetry for the subsequent cycles.

The Glomerular Filtration Rate and Proteinuria in Obese Children

Background: Obesity increases the risk of many pathologies, including cardiovascular and renal diseases. This study aimed to determine the association between obesity and proteinuria as well as glomerular hemodynamic changes (an early marker of kidney damage) in obese children and its relationship with metabolic syndrome. Methods: This case-control study included 112 overweight and obese male and female patients aged 7 - 16 years, and 35 age- and gender-matched healthy controls. The obese patients were divided into 4 subgroups according to BMI:normal weight (control group), overweight, obese, morbidly obese. The glomerular filtration rate was estimated using classical and adjusted formulas based on the various body size descriptors of Leger, Schwartz, Filler, and Zappitelli, and chronic kidney disease formulas in all patients and controls. Creatinine, cystatin C, 24-hour urine protein, and the estimated glomerular filtration were compared between groups. Results: Blood pressure, creatinine, and 24-hour urine protein values were significantly higher in the overweight and obese patient subgroups (P < 0.05). The estimated glomerular filtration rate, which was calculated using creatinine or cystatin C, was higher in the obese patients and subgroups than in the control group (P < 0.05). In contrast, the estimated glomerular filtration rate measured using both classical and adjusted formulas was significantly lower in the obese patients than in the controls (P < 0.05). Conclusions: Early indicators of renal damage are elevated urine protein and renal function test results compatible with impaired renal function. As such, obese pediatric patients should be routinely monitored for blood pressure, renal function, and proteinuria.

Appropriate drug dosages in obese patients

Drug dosage recommendations in obese patients are largely lacking, as data on dosages are generally derived from clinical studies conducted in healthy subjects of average body weight. As morbid obesity (i.e. body mass index ≥ 40 kg/m2) is associated with comorbidities affecting drug pharmacokinetics, relatively few obese subjects are included in clinical studies. To insure optimal drug dosages in obese patients, efficacy and safety trials should provide subgroup analysis of data in patients with varying degrees of obesity. The body-size descriptor used to determine the optimal drug dosage in obese patients should be based on the pharmacological properties of the drug, the clinical context and other factors, and should be clearly specified (including the method of conversion from total body weight to the appropriate body-size descriptor).

Lean body weight is the best scale for venous thromboprophylaxis algorithm in severely obese patients undergoing bariatric surgery

Severely obese patients undergoing bariatric surgery (BS) are at increased risk for venous thromboembolism (VTE). How standard low molecular weight heparin (LMWH) regimen should be adapted to provide both sufficient efficacy and safety in this setting is unclear. We aimed to compare the influence of four body size descriptors (BSD) on peak anti-Xa levels in BS obese patients receiving LMWH fixed doses to identify which one had the greatest impact. One hundred and thirteen BS obese patients [median body mass index (BMI), 43.3 kg/m2 (IQR, 40.6–48.7 kg/m2)] receiving subcutaneous dalteparin 5000 IU twice daily were included in this prospective monocenter study. Peak steady-state anti-Xa levels were measured peri-operatively following thromboprophylaxis initiation. Only 48% of patients achieved target anti-Xa levels (0.2–0.5 IU/ml). In univariate analysis, age, gender, total body-weight (TBW), lean body-weight (LBW), ideal body-weight (IBW), BMI and estimated glomerural filtration rate (eGFR) were associated with anti-Xa levels. The strongest negative association was observed with LBW (r = −0.56, p < .0001). Receiver operating characteristic curves indicated that among BSD, LBW (cut-off >55.8 kg) had the highest sensitivity (73%) and specificity (69%) to predict sub-prophylactic anti-Xa levels. In multivariate analysis, LBW and eGFR remained associated with anti-Xa levels (β = −0.47 ± 0.08, p < .0001 and β = −0.19 ± 0.08; p = .02, respectively). In BS morbidly obese patients receiving LMWH for thromboprophylaxis after BS, LBW and eGFR are the main determinants of anti-Xa level, and could be proposed in LMWH-based thromboprophylaxis dosing algorithms. The efficacy of a LBW-scale based dosing algorithm for optimal VTE prevention deserves further prospective randomized trials.

Population Pharmacokinetics and Dosing Considerations for the Use of Linezolid in Overweight and Obese Adult Patients.

Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600mg every 12h. The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24h (AUC24)/minimum inhibitory concentration (MIC) ratio>100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤25% of probability of a linezolid trough of >8.06mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450mg every 12h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI <130mL/min/1.73m2. Dose escalation to 450mg every 8h may be optimal for patients with a CrCLCKD-EPI ≥60mL/min/1.73m2. Escalation to 600mg every 8h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥130mL/min/1.73m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors.

Estimation of once-daily amikacin dose in critically ill adults

This study aimed at investigating variables affecting amikacin pharmacokinetics in order to propose optimal initial dosing in critically ill adult patients treated with once-daily amikacin regimen. Amikacin pharmacokinetics was calculated based on plasma concentrations using one compartmental analysis. Relationships between pharmacokinetic parameters and demographic/clinical data were explored in linear regression models. Simulated dose and dosing intervals were derived from body size descriptors and estimated creatinine clearances for each patient. Amikacin volume of distribution best correlated with body surface area, while amikacin clearance was best predicted by CKD-EPI creatinine clearance. Our study suggests that dose of 517 mg per m2 of body surface area leads to amikacin levels most approaching target peak concentration. Dosing interval calculated as 228.7 × e−3.08 × CKD-EPI creatinine clearance (mL s−1) + 15.84 most closely approximated optimal dosing intervals based on individual pharmacokinetics. The dosing nomogram based on CKD-EPI creatinine clearance was designed.

Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism.

A simple approach is proposed to predict drug clearance in children when no paediatric data are available for drugs metabolised by cytochromes. The maturation functions of cytochrome activity and binding proteins in plasma were combined with several measures of body size to describe drug clearance increase with age. The complete model and different reduced models were evaluated on a large panel of drug clearance data in children. The parameters of the models were estimated by nonlinear regression. Bias and precision of predictions were determined. Two hundred and ten clearance ratios were available for the analysis, corresponding to 53 drugs mainly eliminated by cytochrome metabolism. The age range was 1.5day to 16years and there were 30 values for children aged less than 2years. Fat-free mass at power 0.75 yielded better results than the other body size descriptor tested. The model with the best fit was based on the fat-free mass ratio, the unbound fraction ratio, maturation functions for cytochromes and no maturation function for clearance by other routes. In children aged less than 2years, the predictive performances were much better with the final model than with the model based on body surface area. The final model was almost unbiased. This model allows the calculation of the maintenance dose of drugs eliminated mainly by cytochromes. After external validation, it could be used in children aged less than 2years. In older children, the model reduces to a simple approach based on body surface area or preferably on fat-free mass at power 0.75. The model is not suitable for preterm neonates.

Comparison of Appropriate Piperacillin/Tazobactam Doses in Korean Obese Patients with Cancer Based on Different Body Size Descriptor Equations in a Tertiary Care Hospital

Comparison of Appropriate Piperacillin/Tazobactam Doses in Korean Obese Patients with Cancer Based on Different Body Size Descriptor Equations in a Tertiary Care Hospital

Comparison of appropriate piperacillin/tazobactam doses in Korean obese patients with cancer based on different body size descriptor equations in a tertiary care hospital

Comparison of appropriate piperacillin/tazobactam doses in Korean obese patients with cancer based on different body size descriptor equations in a tertiary care hospital

Normalization of glomerular filtration rate in obese children.

Glomerular filtration rate (GFR) is conventionally indexed to body surface area (BSA), but this may lead to biased results when applied to subjects of abnormal body size. The aim of our study was to examine the impact of normalization to the BSA and alternative body size descriptors on measured and estimated GFR in overweight and obese children. This was a cross-sectional study of 313 children aged 8-9years old. GFR was measured by 24-h creatinine clearance (CrCl) and additionally estimated from serum creatinine and cystatin C (CysC) using the combined Zappitelli formula, both as absolute values and adjusted to various body size descriptors. The results were compared between 163 normal-weight, 89 overweight and 61 obese children. Compared to the normal-weight children, mean absolute GFR (both measured and estimated) was higher in the overweight and obese children, whereas BSA-adjusted GFR was lower. Linear regression models fitted in normal-weight children revealed equally close associations between absolute GFR and squared height, ideal body weight (IBW) and BSA derived from IBW. Normalization of GFR to the IBW-derived BSA completely eliminated the discrepancy between absolute and BSA-indexed GFR in overweight and obese children. Indexing of GFR to BSA calculated from the ideal-rather than actual-body weight is a promising approach to avoid overcorrection when studying obese children. Further studies should assess the accuracy of this approach across the full range of age and BMI distribution.

Is Dose Adjustment Based on Several Factors of Body Size Descriptors Effective for Prevention of Thrombocytopenia by Linezolid Therapy in Hemodialysis Patients?

Previous study suggested that low body weight was one of the risk factors of thrombocytopenia induced by linezolid in non-hemodialysis patients. However, there have been little investigations for the linezolid-induced thrombocytopenia in hemodialysis patients. This study was to evaluate the association between several factors of body size descriptors and thrombocytopenia in hemodialysis-patients. No factor of body size descriptors showed significant correlation with linezolid-induced thrombocytopenia (patients with thrombocytopenia vs patients without thrombocytopenia: body weight; 60.0 kg vs 55.3 kg, p = 0.82: body mass indices; 21.1 kg/m2 vs 21.2 mg/m2, p = 0.44: ideal body weight; 61.2 kg vs 59.5 kg, p = 0.21: lean body weight; 50.1 kg vs 45.7 kg, p = 0.64: dosage amount; 20.0 mg/kg vs 21.7 mg/kg, p = 0.74: body surface area; 1.65 m2 vs 1.54 m2, p = 0.43). There were not significant differences in the body size descriptors between linezolid therapy for more than 14 days and for less than 13 days (more than 14 days vs less than 13 days: body weight; 53.5 kg vs 56.8 kg, p = 0.75: body mass indices; 20.9 kg/m2 vs 21.1 mg/m2, p = 0.47: ideal body weight; 60.3 kg vs 59.9 kg, p = 0.17: lean body weight; 44.3 kg vs 47.7 kg, p = 0.56: dosage amount; 22.4 mg/kg vs 21.1 mg/kg, p = 0.67: body surface area; 1.51 m2 vs 1.59 m2, p = 0.37). Our data suggested that dosage adjustment of linezolid based on body weight was not recommended in hemodialysis-patients.