Body Weight-based Dosing Research Articles

Optimization of injection dose in 18F-FDG PET/CT based on the 2020 national diagnostic reference levels for nuclear medicine in Japan

ObjectiveRecently, the national diagnostic reference levels (DRLs) in Japan were revised as the DRLs 2020, wherein the body weight-based injection dose optimization in positron emission tomography/computed tomography using 18F-fluoro-2-deoxy-D-glucose (18F-FDG PET/CT) was first proposed. We retrospectively investigated the usefulness of this optimization method in improving image quality and reducing radiation dose.MethodsA total of 1,231 patients were enrolled in this study. A fixed injection dose of 240 MBq was administered to 624 patients, and a dose adjusted to 3.7 MBq/kg body weight was given to 607 patients. The patients with body weight-based injection doses were further divided according to body weight: group 1 (≤ 49 kg), group 2 (50–59 kg), group 3 (60–69 kg), and group 4 (≥ 70 kg). The effective radiation dose of FDG PET was calculated using the conversion factor of 0.019 mSv/MBq, per the International Commission on Radiological Protection publication 106. Image quality was assessed using noise equivalent count density (NECdensity), which was calculated by excluding the counts of the brain and bladder. The usefulness of the injection dose optimization in terms of radiation dose and image quality was analyzed.ResultsThe body weight-based injection dose optimization significantly decreased the effective dose by 11%, from 4.54 ± 0.1 mSv to 4.05 ± 0.8 mSv (p < 0.001). Image quality evaluated by NECdensity was also significantly improved by 10%, from 0.39 ± 0.1 to 0.43 ± 0.2 (p < 0.001). In no case did NECdensity deteriorate when the effective dose was decreased. In group 1, the dose decreased by 32%, while there was no significant deterioration in NECdensity (p = 0.054). In group 2, the dose decreased by 17%, and the NECdensity increased significantly (p < 0.01). In group 3, the dose decreased by 3%, and the NECdensity increased significantly (p < 0.01). In group 4, the dose increased by 14%, but there was no significant change in the NECdensity (p = 0.766).ConclusionBody weight-based FDG injection dose optimization contributed to not only the reduction of effective dose but also the improvement of image quality in patients weighing between 50 and 69 kg.

Panitumumab: A Review of Clinical Pharmacokinetic and Pharmacology Properties After Over a Decade of Experience in Patients with Solid Tumors.

Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen. In this review, we summarize the key clinical pharmacokinetic and pharmacology data for panitumumab, and considerations for its use in special populations. Panitumumab has a nonlinear pharmacokinetic profile and its approved dosing regimen (6mg/kg every 2weeks) is based on body weight; dose adjustments are not needed based on sex, age, or renal or hepatic impairment. Drug interactions do not occur when panitumumab is combined with chemotherapy drugs including irinotecan, paclitaxel, and carboplatin. The level of tumor EGFR expression was found to have no effect on panitumumab pharmacokinetics or efficacy. The incidence of anti-panitumumab antibodies is low; when anti-panitumumab antibodies are produced, they do not affect the efficacy, safety, or pharmacokinetics of panitumumab. In summary, the pharmacokinetic and pharmacodynamic profile of panitumumab is well suited for standard dosing, and the approved body weight-based dosing regimen maintains efficacy and safety in the treatment of wild-type RAS metastatic colorectal cancer across a broad range of patients.

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT

BackgroundREFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group.MethodsThe study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed.ResultsSurvival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5–15.7] compared to 13.7 months (95% CI 12.0–15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4–9.2; ≥ 60 kg group: 95% CI 6.9–9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group.ConclusionsThis exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups.Clinincal trialTrial registration ID: ClinicalTrials.gov # NCT01761266

Ideal Body Weight-Based Dosing of Rabbit Antithymocyte Globulin for Cost Minimization in Kidney Transplantation.

Contemporary dosing strategies for rabbit anti-thymocyte globulin (rATG) in kidney transplantation aim to reduce cumulative exposure, minimizing long-term adverse events. The use of ideal body weight-based dosing has been trialed, however concern for increased rejection post-transplant exists due to lower doses of rATG. Research Questions: The primary aim of this study was to compare rejection rates between rATG dosing protocols using actual body weight and ideal body weight and secondarily to evaluate cost savings following protocol implementation. This was a retrospective study surrounding implementation of an ideal body weight-based dosing protocol for rATG. We compared 75 kidney transplant recipients in whom rATG was dosed based on actual body weight (pre-protocol group) to 64 in whom dosing was based on ideal body weight (post-protocol group), following a nine-month washout. The mean cumulative rATG dose in the pre-protocol group was 6.3 mg/kg of actual body weight. When ideal body weight was used in the post-protocol group, the mean dose was 4.5 mg/kg of actual body weight. The rejection rate was 18.7% pre-protocol and 23.4% postprotocol, which did not represent a statistically significant difference (p = 0.491). The actual annual cost savings after protocol implementation exceeded $162,000, approximately $2,500 per patient. Results suggest ideal body weight-based dosing of rATG may reduce exposure and cost, without significantly impacting the risk of rejection in kidney transplant recipients. More studies are needed to confirm these findings.

Avoiding Tacrolimus Underexposure and Overexposure with a Dosing Algorithm for Renal Transplant Recipients: A Single Arm Prospective Intervention Trial.

Bodyweight‐based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on target at first steady‐state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug‐related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post‐transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single‐arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight‐based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post‐transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic (< 5.0 ng/mL) and supratherapeutic (> 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy‐proven acute rejection occurred in three patients (5%). In conclusion, algorithm‐based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.

Unfractionated heparin using actual body weight without dose capping in obese pediatric patients—Subgroup analysis from an observational cohort study

To evaluate the correlation between an uncapped, actual body weight-based unfractionated heparin dosing strategy, we performed a body mass index-based subanalysis of a previously reported pediatric cohort. Nearly half (45%) of obese patients were supra-therapeutic on initial anti-FXa assessment. Obese patients achieved therapeutic anti-FXa significantly faster than nonobese patients (median 4 vs 12hours, P=.0192) and were more likely to have any supra-therapeutic anti-FXa levels (77% vs 35%; P=.0021). There was no statistically significant difference in major or clinically relevant nonmajor bleeding rates between weight categories (P=.69). Prospective pediatric studies are warranted to confirm our findings.

Application of a Two-Analyte Integrated Population Pharmacokinetic Model to Evaluate the Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Polatuzumab Vedotin in Patients with Non-Hodgkin Lymphoma

PurposeThe established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing.MethodsModel simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance.ResultsNo clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100–146 kg versus 38–<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK.ConclusionsIn patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100–146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.

Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by pathologic immune activation and hyperinflammation. It typically manifests during infancy and is invariably fatal if untreated. Interferon gamma (IFNy) is considered a key contributor to the hyperinflammation of HLH. Thus, neutralization of IFNy could help control the disease until haematopoietic stem cell transplantation, the only curative treatment. Emapalumab, a fully human, anti-IFNy monoclonal antibody, binds to and neutralizes IFNy. Emapalumab is the first and only approved (FDA) treatment for primary HLH. It is indicated for the treatment of adult and pediatric patients with HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy. Objective: To develop a population pharmacokinetic (PK) model to describe the PK profile of emapalumab. Methods: PK data were obtained from patients with primary HLH administered emapalumab intravenously during an open-label, single-group, phase 2/3 clinical trial (NCT01818492) and as part of a compassionate use program. A population PK analysis was performed using nonlinear mixed effects modeling (NONMEM® version 7.3.0). Predictive performance of the model was assessed using a visual predictive check. Results: The PK of emapalumab was adequately described by a two-compartment model. All model parameters were estimated with good precision. Central and peripheral volumes of distribution were 0.059 and 0.079 L/kg, respectively. Exploratory graphical analysis showed that (i) IFNy production varied significantly between and within patients as a function of time; (ii) the higher the IFNy production, the faster the elimination of emapalumab due to target-mediated drug disposition; and (iii) the higher the IFNy production, the higher the dose of emapalumab required to reach the neutralizing concentration of IFNy (evidenced by a higher target-mediated clearance of emapalumab). Of the parameters examined, only body weight and total IFNy (free and bound) levels were found to significantly influence the PK of emapalumab. The allometric exponents of body weight for the volume of distribution and clearance were 1 (fixed) and 0.886 (95% confidence interval 0.68, 1.09), respectively. These values support the bodyweight-based dosing of emapalumab (i.e. mg/kg). At values of total IFNy from 103 to 106 pg/mL, the total clearance (linear + target mediated) of emapalumab ranged from 0.0012 to 0.0140 L/h for a bodyweight of 5 kg, with corresponding terminal half-lives from 17.5 to 2.3 days. This wide variance in clearances and half-lives partly explains the emapalumab dose adaptations that are required for treating primary HLH patients. Conclusion: The population PK model reliably predicted serum concentrations of emapalumab in patients with primary HLH. The central and peripheral volumes of distribution were low, clearance was slow, and the terminal half-life long. The expected dynamic of the biology of IFNy was confirmed and included in the population PK model. Simulations using this model supported the proposed dosing scheme of emapalumab in patients with primary HLH. Disclosures Laveille: Sobi: Consultancy. Jacqmin:Sobi: Consultancy. de Min:Sobi: Consultancy.

Abstract 3027: Application of machine learning and grid search approaches to minimize lucitanib pharmacokinetic variability following different dosing regimens

Abstract Background: Lucitanib is a potent tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors 1, 2, and 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDGFRα/β), and fibroblast growth factor receptors types 1, 2, and 3 (FGFR1-3). Lucitanib is being evaluated in patients with solid tumors in combination with other anticancer agents. The pharmacokinetics (PK) of lucitanib were described by a 2-compartment population PK model with first-order absorption and elimination. Body weight was a covariate on clearance and volume of distribution. Objective: We sought to compare the variability of lucitanib PK between body weight-based and fixed-dose regimens to inform dosing regimen selection. Methods: Lucitanib PK were simulated for 5000 virtual patients with a uniform distribution of body weight (40-120 kg). Patients either received a fixed dose (10 mg once daily) or a body weight-based dose. Genetic and grid search algorithms were used to identify the body weight-based dosing regimens that resulted in the smallest fraction of outliers, defined as subjects outside of the 5th and 95th prediction interval of the area under the curve during the dosing interval (tau) at steady state (AUCtau,ss) for 70-kg patients receiving the fixed dose. The genetic algorithm used a continuous body weight and dose search space, whereas the grid search algorithm limited the search space to discrete values of body weight and dose (ie, 5 kg increments for body weight and 0.25 mg increments for dose). The penalty function in both algorithms was the fraction of outliers. The optimized body weight-based regimens were compared to the fixed-dose regimen to evaluate lucitanib PK variability. Results: The genetic and grid search algorithms identified similar and reasonable dosing regimens. Two or 3 body weight-based dosing regimens decreased the fraction of outliers by 1%-4% in the overall population (40-120 kg) versus the fixed dose. However, within the low body weight group (40-50 kg), body weight-based dosing regimens substantially decreased the fraction of outliers, with exposure greater than the 95th percentile reduced by 10%-15% compared with the fixed dose. On the other hand, the fixed-dose regimen predicted fewer outliers with exposure below the 5th percentile versus the body weight-based dosing regimens. Conclusions: The genetic algorithm provided similar results to the more computationally demanding method of grid searching. Compared with a fixed-dose regimen, body weight-based regimens showed a small reduction in PK variability for lucitanib in the overall population, suggesting that there is limited benefit with body weight-based dosing. Dose optimization will be further evaluated with a growing understanding of the target therapeutic range and exposure-response relationships. Citation Format: Michelle Liao, Jessie Zhou, Mark Sale, Jim J. Xiao. Application of machine learning and grid search approaches to minimize lucitanib pharmacokinetic variability following different dosing regimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3027.

Dose Regimen Rationale for Panitumumab in Cancer Patients: To Be Based on Body Weight or Not.

IntroductionBody weight can affect exposure, safety and efficacy of antibody-based therapies; sometimes these effects may not be clinically relevant. Panitumumab is approved for wild-type RAS metastatic colorectal cancer, using a body weight–based dosing regimen. Recently, a report cited fixed-dose usage of panitumumab, rather than approved body weight–based dosing. The current work evaluates optimal dosing regimen scientifically based on clinical data, modeling and simulation. Herein, we assessed the effect of fixed and body weight–based dosing on panitumumab pharmacokinetics to determine which approach resulted in the least interpatient pharmacokinetic variability.Patients and MethodsFrom the Vectibix program, 352 patients enrolled in three studies were evaluated; they had received panitumumab (body weight–based dose: 6 mg/kg every 2 weeks) and had pharmacokinetic (maximum serum [Cmax] and trough [Cmin] concentrations) and body weight data available. Additionally, concentration-time profiles at fixed (480 mg) and body weight–based doses (6 mg/kg) were simulated using a population pharmacokinetics model developed from 1200 patients.ResultsAfter administration of panitumumab 6 mg/kg, Cmax and Cmin increased with increasing body weight; the mean Cmax and Cmin for patients weighing <65 kg (lower quartile) were 23% and 30% lower, respectively, than for those weighing >88 kg (upper quartile). The simulated area under the concentration–time curve (AUC) data also indicated that overall panitumumab exposure increased with increasing body weight for the body weight–based regimen. When AUC was simulated for a fixed dose (480 mg), the opposite effect was observed. Over the range of body weights, interpatient variability in simulated AUC was lower for the weight-based dose (29%) than for the fixed dose (34%).ConclusionResults demonstrate that the weight-based dose (6 mg/kg) reduced variability in panitumumab exposure across the range of body weights compared with the fixed-dose approach, indicating that a body weight–based approach is the recommended patient dosing strategy.

Calculatin the Effective Intravenous Heparin Dose: Comparison between Lean and Actual Body Weight-Based Dosing in Obese Patients

Abstract Background: Despite the availability of newer anticoag-ulants, unfractionated heparin remains a mainstay anticoagulant for atrial fibrillation, acute coronary syndrome with or without percutaneous intervention, treatment and prevention of deep vein thrombosis (DVT), pulmonary embolism (PE), and other thromboembolic disorders. Aim of Study: The aim of this study is to investigate if intravenous heparin dosing based on lean body weight (LBW) of obese patients would be safe and effective in achieving activated partial thromboplastin time (APTT) within 24 hours compared to the usual practice. Patients and Methods: This is a case-control study con-ducted in Cardiology Department Sammanaud General Hos-pital from May 2017 to May 2018 to investigate if intravenous heparin dosing based on LBW of obese patients would be safe and effective in achieving target APTT within 24 hours compared to the usual practice. The study included 50 obese patients with a diagnosis of atrial fibrillation, suspected or confirmed deep venous thrombosis or pulmonary embolism, unstable angina or Non ST elelvation myocardial infarction with hemodynamic stability, or peripheral vascular disease. Patients aged >18 years randomized into two groups (1) and (2). Results: Studies found that unfractionated heparin dosage adjustments based on the patient's LBW provided therapeutic anticoagulation more rapidly and safely, but protocols based on total body weight increase the risk of a supra-therapeutic PTT. Conclusion: Unfractionated heparin remains a mainstay anticoagulant for atrial fibrillation, acute coronary syndrome with or without percutaneous intervention, treatment and prevention of deep vein thrombosis (DVT), pulmonary embo-lism (PE), and other thromboembolic disorders. As lean body weight contributes to approximately 99% of a drug's clearance, it is useful for guiding dosing in obesity. These findings may enhance the utility of LBW as body descriptor instead of TBW in calculating the effective doses of UFH in treatment of thromboembolic disorders.

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus.

AimsRacemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight‐based dosing guidelines are based on total ibuprofen, while only the S‐enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer‐specific population pharmacokinetic model.MethodsWe prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S‐ and R‐ibuprofen.ResultsWe found that S‐ibuprofen clearance (CLS, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11‐fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R‐ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R‐ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S‐ibuprofen and R‐ibuprofen.ConclusionS‐ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3‐fold increase in CLS during a 3‐day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.

Unfractionated heparin dosing in obese patients

Background The effect of obesity on the pharmacokinetics and pharmacodynamics of unfractionated heparin is not clearly understood, therefore to reduce the risk of bleeding, maximal dose (capped) nomograms are often used. This can lead to inadequate anticoagulation and increased mortality and morbidity. In Queensland, Australia, statewide nomograms recommend total-body-weight-based dosing, with capped initial bolus and maintenance doses. Objective To determine if current practices for unfractionated heparin dosing leads to inadequate anticoagulation in obese patients. Setting Princess Alexandra Hospital, Queensland, Australia. Method A retrospective audit of unfractionated heparin dosing in 200 patients divided into cohorts of; < 100kg (defined as non-obese), 100-124.9kg, 125-150kg and > 150kg, Main outcomes measured Mean maintenance doses in U/h and U/kg/h required to achieve two consecutive therapeutic activated partial thromboplastin times' and the corresponding time to achieve this endpoint. Results The mean ± standard deviation maintenance doses required to achieve two consecutive therapeutic activated partial thromboplastin times' in U/h were 1229 ± 316, 1673 ± 523, 2031 ± 596 and 2146 ± 846, and in U/kg/h were 16 ± 4.1, 15.1 ± 4.8, 14.9 ± 4.2 and 11.6 ± 4.2 for the weight cohorts respectively. The median time (inter-quartile range) to therapeutic activated partial thromboplastin times' for obese patients was 39 (21.5-56) h. Conclusions Our results suggest inadequate dosing in obese patients. We recommend the use of larger absolute doses (U/h) of nfractionated heparin but reduced uncapped total body weight-based doses-(U/kg/h) as patient weight increases.

1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications

BackgroundBaloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients.MethodsThe population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients.ResultsA 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately.ConclusionThe results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil. Disclosures All authors: No reported disclosures.

Drug Dose Selection in Pediatric Obesity: Available Information for the Most Commonly Prescribed Drugs to Children.

Obesity rates continue to rise in children, and little guidance exists regarding the need for adjustment away from total body weight-based doses for those prescribing drugs to this population of children. A majority of drugs prescribed to children with obesity result in either sub-therapeutic or supra-therapeutic concentrations, placing these children at risk for treatment failure and drug toxicities. In this review, we highlight available obesity-specific pharmacokinetic and dosing information for the most frequently prescribed drugs to children in the inpatient and outpatient clinical settings. We also comment on available dosing recommendations for drugs prescribed to treat common pediatric obesity-related comorbidities. This review highlights that there is no safe or proven 'rule of thumb,' for dosing drugs for children with obesity, and a striking lack of pharmacokinetic data to support the creation of dosing guidelines for children with obesity for the most commonly prescribed drugs. It is important that those prescribing for children with obesity are aware of these gaps in knowledge and of potential drug treatment failure or adverse events related to drug toxicity as a result of these knowledge gaps. Until more data are available, we recommend close monitoring of drug response and adverse events in children with obesity receiving commonly prescribed drugs.

Actual body weight-based vancomycin dosing in neonates

This study aimed to explore vancomycin pharmacokinetics and its covariates in critically ill neonates and to propose an easy applicable dosing nomogram for initial treatment. Individual vancomycin pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a one-compartmental model. A linear regression model was used for examination of covariates. The mean (SD) volume of distribution (Vd) and clearance (CL) for vancomycin were 0.73 (0.31) L/kg and 0.052 (0.020) L/h/kg, respectively. Vd was related to actual body weight (ABW), gestational and postmenstrual age. CL was also associated with ABW, gestational, postmenstrual age and also creatinine clearance. ABW was the strongest predictor for vancomycin pharmacokinetics and consequently dosing. Loading dose (mg) of 11.81 × ABW (kg) + 7.86 and maintenance dose (mg/day) of 40.92 × ABW (kg) −22.18 most closely approximated pharmacokinetic target. Vancomycin pharmacokinetics was mainly influenced by ABW in neonates and a practical ABW-based dosing algorithm was developed.

Relationship between the muscle relaxation effect and body muscle mass measured using bioelectrical impedance analysis: A nonrandomized controlled trial.

ObjectiveThe dose of neuromuscular blocking drugs is commonly based on body weight, but using muscle mass might be more effective. This study investigated the relationship between the effect of neuromuscular blocking drugs and muscle mass measured using bioelectrical impedance analysis.MethodsPatients who were scheduled for elective surgery using a muscle relaxant were screened for inclusion in this study. Under intravenous anaesthesia, 12 mg or 9 mg of rocuronium was administered to males and females, respectively; and the maximal relaxation effect of T1 was measured using a TOF-Watch-SX® acceleromyograph.ResultsThis study enrolled 40 patients; 20 males and 20 females. For both sexes, the maximal relaxation effect of T1 did not correlate with the body weight-based dose of neuromuscular blocking drugs (males, r2 = 0.12; females, r2 = 0.26). Instead, it correlated with the dose based on bioelectrical impedance analysis-measured muscle mass when injected with the same dose of rocuronium (males, r2 = 0.78, female, r2 = 0.82).ConclusionsThis study showed that the muscle relaxation effect of rocuronium was correlated with muscle mass and did not correlate with body weight when using the same dose. Therefore, a muscle mass-based dose of neuromuscular blocking drugs is recommended.

Changes in the Treatment Strategies for Helicobacter pylori Infection in Children and Adolescents in Korea.

The policies developed for the treatment of Helicobacter pylori infection in adults may not be the most suitable ones to treat children and adolescents. Methods used to treat children and adolescents in Europe and North America may not be appropriate for treating children and adolescents in Korea due to differences in epidemiological characteristics of H. pylori between regions. Moreover, the agreed standard guidelines for the treatment of H. pylori infection in children and adolescents in Korea have not been established yet. In this study, the optimal treatment strategy for H. pylori infection control in children and adolescents in Korea is discussed based on these guidelines, and recent progress on the use and misuse of antimicrobial agents is elaborated. Non-invasive as well as invasive diagnostic test and treatment strategy for H. pylori infection are not recommendable in children aged less than ten years or children with body weight under 35 kg, except in cases of clinically suspected or endoscopically identified peptic ulcers. The uncertainty, whether enough antimicrobial concentrations to eradicate H. pylori can be maintained when administered according to body weight-based dosing, and the costs and adverse effects outweighing the anticipated benefits of treatment make it difficult to decide to eradicate H. pylori in a positive non-invasive diagnostic test in this age group. However, adolescents over ten years of age or with a bodyweight of more than 35 kg can be managed aggressively as adults, because they can tolerate the adult doses of anti-H. pylori therapy. In adolescents, the prevention of future peptic ulcers and gastric cancers is expected after the eradication of H. pylori. Bismuth-based quadruple therapy (bismuth-proton pump inhibitor-amoxicillin/tetracycline-metronidazole) with maximal tolerable doses and optimal dose intervals of 14 days is recommended, because in Korea, the antibiotic susceptibility test for H. pylori is not performed at the initial diagnostic evaluation. If the first-line treatment fails, concomitant therapy plus bismuth can be attempted for 14 days as an empirical rescue therapy. Finally, the salvage therapy, if needed, must be administered after the H. pylori antibiotic susceptibility test.

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.

Converting immunosuppression from an oral suspension to a granule formulation of tacrolimus in pediatric renal transplant recipients.

OS of tacrolimus prepared from tacrolimus powder is not licensed for children. A licensed GF for OS allows flexibility for body weight-based dose adjustments. This study aimed at exploring the efficacy of conversion from OS to the GF of tacrolimus in stable pediatric renal transplant recipients. Records of 25 pediatric renal transplant recipients aged under 18years who were switched from an unlicensed tacrolimus OS to GF were reviewed. At day 0, 1week, and 4-8weeks post-conversion, there were no differences regarding daily tacrolimus dose (3.4±3 vs 3.5±2.9 vs 3.5±2.9mg/day), trough tacrolimus levels (4.5±2.7 vs 4.2±2.7 vs 4.4±3.1ng/mL), dose-normalized trough tacrolimus levels (1.7±1.1 vs 1.5±1.0 vs 1.7±1.3ng/mL/mg), PCr (65.6±29.4 vs 67.9±30.4 vs 69.8±27.9μmol/L), and eGFR (73±24.9 vs 68.7±20.2 vs 65.5±18.2mL/min/1.73m2 ) (P>.05). GF dose adjustment was required in 52% of participants. Eighty-eight percent of patients had to return for repeat tacrolimus levels following dose modifications, generating 33 extra visits (≥2 extra visits for 1/3 of subjects). No rejection episodes occurred in the year after conversion. In conclusion, conversion from tacrolimus OS to GF in stable pediatric renal transplant recipients is safe and efficacious. However, close therapeutic drug monitoring in the immediate post-conversion period is necessary.