Target Area Under The Concentration-time Curve Research Articles

Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application

IntroductionVancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). MethodsIn this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. ResultsThe modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. ConclusionsThis study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.

A simulation study on model-informed precision dosing of amikacin for achieving target area under the concentration-time curve.

Amikacin requires therapeutic drug monitoring for optimum efficacy; however, the optimal model-informed precision dosing strategy for the area under the concentration-time curve (AUC) of amikacin is uncertain. This simulation study aimed to determine the efficient blood sampling points using the Bayesian forecasting approach for early achievement of the target AUC range for amikacin in critically ill patients. We generated a virtual population of 3000 individuals using 2 validated population pharmacokinetic models identified using a systematic literature search. AUC for each blood sampling point was evaluated using the probability of achieving a ratio of estimated/reference AUC at steady state in the 0.8-1.2 range. On day 1, the 1-point samplings for population pharmacokinetic models showed a priori probabilities of 26.3 and 45.6%, which increased to 47.3 and 94.4% at 23 and 15 h, respectively. Using 2-point sampling at the peak (3 and 4h) and trough (24 h) on day 1, these probabilities further increased to 72.3 and 99.5%, respectively. These probabilities were comparable on days 2 and 3, regardless of 3 and 6 sampling points or estimated glomerular filtration rate. These results indicated the higher predictive accuracy of 2-point sampling than 1-point sampling on day 1 for amikacin AUC estimation. Moreover, 2-point sampling was a more reasonable approach than rich sampling. This study contributes to the development of an efficient model-informed precision dosing strategy for early targeting of amikacin AUC in critically ill patients.

A cohort study of the risk factors and the target AUC to avoid vancomycin-associated acute kidney injury in pediatric patients

ObjectivesIn recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI. MethodsPediatric patients aged 1–15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters. ResultsThe ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 μg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUCSS. Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H2-receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 μg・h/mL (odds ratio 20.14, 95% CI 3.52–115.22, p < 0.001) and H2-receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38–54.87, p = 0.02) were independent factors for AKI incidence. ConclusionsWe showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H2-receptor blockers may increase the risk of AKI.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study

IntroductionIn therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. MethodsThis multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400–600 μg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). ResultsAmong 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400–600 μg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). ConclusionWe successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Model-Informed Precision Dosing of Vancomycin in Adult Patients Undergoing Hemodialysis.

Model-informed precision dosing (MIPD) maximizes the probability of successful dosing in patients undergoing hemodialysis. In these patients, area under the concentration-time curve (AUC)-guided dosing is recommended for vancomycin. However, this model is yet to be developed. The purpose of this study was to address this issue. The overall mass transfer-area coefficient (KoA) was used for the estimation of vancomycin hemodialysis clearance. A population pharmacokinetic (popPK) model was developed, resulting in a fixed-effect parameter for nonhemodialysis clearance of 0.316 liters/h. This popPK model was externally evaluated, with a resulting mean absolute error of 13.4% and mean prediction error of -0.17%. KoA-predicted hemodialysis clearance was prospectively evaluated for vancomycin (n = 10) and meropenem (n = 10), with a correlation equation being obtained (slope of 1.099, intercept of 1.642; r = 0.927, P < 0.001). An experimental evaluation using an in vitro hemodialysis circuit validated the developed model of KoA-predicted hemodialysis clearance using vancomycin, meropenem, vitamin B6, and inulin in 12 hemodialysis settings. This popPK model indicated a maximum a priori dosing for vancomycin-a loading dose of 30 mg/kg, which achieves the target AUC for 24 h after first dose with a probability of 93.0%, ensured by a predialysis concentration of >15 μg/mL. Maintenance doses of 12 mg/kg after every hemodialysis session could achieve the required exposure, with a probability of 80.6%. In conclusion, this study demonstrated that KoA-predicted hemodialysis clearance may lead to an upgrade from conventional dosing to MIPD for vancomycin in patients undergoing hemodialysis.

Model-informed precision dosing of teicoplanin for the rapid achievement of the target area under the concentration-time curve: A simulation study.

Teicoplanin, a glycopeptide antimicrobial, is recommended for therapeutic drug monitoring, but it remains unclear how to target the area under the concentration-time curve (AUC). This simulation study purposed to demonstrate the potential of the Bayesian forecasting approach for the rapid achievement of the target AUC for teicoplanin. We generated concordant and discordant virtual populations against a Japanese population pharmacokinetic model. The predictive performance of the Bayesian posterior AUC in limited sampling on the first day against the reference AUC was evaluated as an acceptable target AUC ratio within the range of 0.8-1.2. In the concordant population, the probability for the maximum a priori or Bayesian posterior AUC on the first day (AUC0-24 ) was 61.3% or more than 77.0%, respectively. The Bayesian posterior AUC on the second day (AUC24-48 ) was more than 75.1%. In the discordant population, the probability for the maximum a priori or Bayesian posterior AUC0-24 was 15.5% or 11.7-80.7%, respectively. The probability for the maximum a priori or Bayesian posterior AUC24-48 was 23.4%, 30.2-82.1%. The AUC at steady-state (AUCSS ) was correlated with trough concentration at steady-state, with a coefficient of determination of 0.930; the coefficients on days 7 and 4 were 0.442 and 0.125, respectively. In conclusion, this study demonstrated that early sampling could improve the probability of AUC0-24 and AUC24-48 but did not adequately predict AUCSS . Further studies are necessary to apply early sampling-based model-informed precision dosing in the clinical settings.

Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial.

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164mg×h/L ± 25%) was calculated. A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155mg × h/L vs 160mg × h/L (p = 0.436). We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. Clinicaltrials.gov identifier: NCT03655821.

Busulfan Pharmacogenetics and Drug Exposure in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Busulfan, a bifunctional alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HSCT), is metabolized via glutathione-S-transferases (GSTs) and cytochrome P450 (CYP) enzymes. Busulfan demonstrates wide interpatient variability in pharmacokinetics (PK); high drug exposure is associated with increased risk of toxicities (e.g. veno-occlusive disease) and low drug exposure is associated with increased risk of relapse and graft failure. Drug exposure within a narrow therapeutic range yields optimal results. PK-guided dosing is used in many patients to achieve optimal drug exposure; however, better methods to select the initial dose would improve consistency of busulfan exposure and the likelihood of achieving the target area under the concentration-time curve (AUC). Previous pharmacogenomic (PGx) studies have identified GST polymorphisms as predictors of drug exposure, however, these were primarily performed in pediatric populations and/or Asians. We performed a PGx study in adult HSCT patients to identify polymorphisms in candidate genes associated with busulfan AUC and clearance.Methods: Buccal swabs were collected from HSCT patients scheduled to receive busulfan as part of their conditioning regimen on the day of admission (one day prior to initiating busulfan) between 04/28/14 and 06/06/2017. DNA was extracted using the GenElute™ Mammalian Genomic DNA Kit. A custom Ion AmpliSeq™ PGx Panel and various orthogonal methods were used to genotype the samples for polymorphisms in GSTA1 (135T>C), GSTM1 (null/present), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), and MTHFR (A1298C, C677T). Phenotypes were inferred according to established guidelines or literature. IV busulfan was administered once daily over 3 hours at 2.8 mg/kg (for autos) or 3.2 mg/kg (for allos) for a total of 4 doses. PK samples were obtained at 15 mins, 1 hr, 2 hrs, 3 hrs, and 5 hrs after the end of the first infusion. Non-compartmental analysis was performed to estimate PK parameters and doses 3 and 4 were adjusted to target an AUC of either 4500 or 5000 uM*min/L, depending on transplant type and conditioning regimen. The primary objective was to investigate the impact of polymorphisms on busulfan AUC, which was measured using univariate linear regression analysis adjusting for dose. Secondary objectives included a comparison of mean AUCs between phenotypes, which was measured using ANOVA, and to determine the association between SNPs and busulfan clearance using univariate linear regression adjusting for dose.Results: A total of 36 patients were evaluable for the primary endpoint. The median age was 47 (22-73) years, 56% were male, 75% received busulfan/cyclophosphamide/etoposide, 22% received busulfan/cyclophosphamide with post-transplant cyclophosphamide, and 3% received thiotepa/busulfan/cyclophosphamide. The genotype and inferred phenotype frequencies are summarized in Table 1. The mean AUC across all patients was 4255 µM*min/L (range 2834-5989). Results from the univariate linear regression analysis identified that CYP2B6 polymorphisms were significantly associated with busulfan AUC (intermediate [IM] vs. poor metabolizer [PM], p = 0.05; normal/rapid metabolizer [NM/RM] vs. PM, p = 0.02) (Table 2). The mean AUC in CYP2B6 PMs, IMs, NM/RMs was 5242, 4277, and 4134 µM*min/L, respectively (p = 0.03 by ANOVA test). There was no association of polymorphisms in GSTA1, GSTM1, GSTP1, CYP2C8, CYP2C9, CYP2C19 and MTHFR with AUC. CYP2B6 polymorphisms were also associated with busulfan clearance (IM vs. PM, p = 0.07; NM/RM vs. PM, p = 0.03).Conclusion: CYP2B6 polymorphisms were significantly associated with busulfan AUC and clearance; these appear to be an important determinant of drug exposure, however, GST polymorphisms did not replicate as significant, possibly due to differences in patient populations. PGx testing for CYP2B6 may provide an important tool to individualize up front dosing and improve the likelihood of achieving the target AUC earlier or to achieve target AUC in a higher proportion of the many patients who do not receive PK-guided dosing; however, our findings require further validation in larger cohorts of patients. We plan to enroll more patients and assess the relationship between PK, PGx and clinical outcomes, including toxicity and response. [Display omitted] DisclosuresTrivedi:Pharmacyclics: Consultancy, Honoraria. Grunwald:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; ARIAD: Consultancy; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Janssen: Research Funding. Ghosh:AbbVie: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding.

Test-dose pharmacokinetics guided melphalan dose adjustment in reduced intensity conditioning allogeneic transplant for non-malignant disorders.

We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m2 or 4.7mg/kg in patients <10kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot. Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5mg*h/L (range, 3.0-9.5mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio. Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.

Therapeutic drug monitoring of intravenous busulfan in Thai children undergoing hematopoietic stem cell transplantation: A pilot study

Busulfan (Bu) is commonly used in myeloablative conditioning regimens for children undergoing hematopoietic stem cell transplantation. The standard target area under the concentration-time curve (AUC) of Bu is approximately 900–1500 µM min. In previous studies using five fixed doses (0.8–1.2 mg/kg) for Bu without dose adjustment, 75% patients achieved the target AUC. The aim of this pilot study was to determine the percentage of target AUC for intravenous (IV) Bu in Thai children. IV Bu was administered every 6 h over 16 doses. Blood samples were collected for pharmacokinetic (PK) analysis after the first, ninth, and thirteenth doses of Bu. Seven patients (2–14 years; median 6 years) were diagnosed with thalassemia (n = 4), acute myeloid leukemia (n = 2), and pure red cell aplasia. Three, two, and two patients received Bu at 1.1, 1.2, and 0.8 mg/kg, respectively. The AUC of Bu varied from 292–1714 µM min (median = 804). Nine (42.86%), eleven (52.38%), and one (4.76%) AUC values were within, below, and above the target, respectively. The median (range) Bu clearance was 5.93 (1.91–14.65) mL/min/kg. In this study, 42.86% AUC value achieved the target, which was lower than that in previous studies. Therapeutic drug monitoring (TDM) of Bu should be considered in Thai children receiving five fixed doses of IV Bu, and dose adjustment should be performed as necessary. Further PK studies for Bu with a larger sample size are warranted for confirming the necessity of TDM in every step dose of Bu. (Trial registration numbers; TCTR20190528003)

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce. Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6months after kidney biopsy and MMF initiation. Treatment response at 6months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5g/day or 50mg/mmol, and no hematuria. A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44mgh/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60mgh/L. At 6months, 14/25 patients were defined as responders (56%, median MPA-AUC 49mgh/L (40-59)) and 11/25 as non-responders (44%, 29mgh/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30mgh/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45mgh/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p= 0.03). Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45mgh/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.

Busulfan Pharmacokinetics in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Gene Therapy.

The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.

Prospective evaluation of a developed S-1 dosage formula based on renal function.

86 Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP, inhibitor of dihydoropyrimidine dehydrogenase) and potassium oxonate. Because CDHP is excreted in urine, renal dysfunction increases incidence of severe adverse drug reactions due to higher exposure of 5-FU. As approved dose of S-1 is determined by body surface area (BSA) for patients with normal renal function, dose of S-1 is practically reduced according to renal function of creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation. In a previous pharmacokinetic study (n = 16), we had developed an S-1 dosage formula based on renal function achieving the target area under the concentration-time curve (AUC) of 5-FU: Dose = target AUC x (21.9 + 0.375 x CLcr) x BSA. We conducted a prospective study to evaluate and refine this formula if necessary. Methods: Thirty patients with various renal function received S-1 at dose determined by our developed formula. A series of blood samples were obtained at predefined times after the first dose to calculate the AUC of 5-FU. Predictability of the formula was evaluated by comparison between the observed and the target AUCs. Results: The observed daily AUC was ranged from 712.6 to 2868.7 ng‧h/mL in 30 patients with BSA in the range of 1.14-1.84 m2 and CLcr in the range of 23.8-96.4 mL/min. Eighteen patients of them achieved the target AUC (1447.8 ± 545.4 ng‧h/mL). Since population pharmacokinetic analysis using combined pharmacokinetic data of 30 patients in this study and 16 patients in the previous study demonstrated that clearance of 5-FU is significantly lower in female than in male, the S-1 dosage formula was refined including gender as an additional factor: Dose = target AUC × (14.5 + 8.23 x GENDER [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms showing recommended daily dose of S-1 were proposed for males and females taking into account tablet strengths. Conclusions: The refined formula for determining S-1 dosage on the basis of renal function, BSA and gender can be applied to clinical practice to ensure efficacy and safety for cancer patients treated with S-1. Clinical trial information: UMIN 000023880.

Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once-daily intravenous busulfan dosing nomogram.

Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once-daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6-22.2 years), who received IV busulfan once-daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once-daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration-time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once-daily regimen without therapeutic drug monitoring (TDM). A one-compartment open linear PK model incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration-time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. A novel once-daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.

Pharmacometabolomics for Predicting Variable Busulfan Exposure in Pediatric HSCT Patients

Optimal dosing for busulfan is important for minimization of systemic toxicity from overexposure and graft failure or relapse from underexposure. Herein, we investigated potential markers for predicting individual variation in the pharmacokinetics of busulfan, and suggested possible mechanism for inter-individual variability by using pharmacometabolomics.Fifty-nine pediatric patients undergoing busulfan-based conditioning chemotherapy for hematopoietic stem cell transplantation were divided into three groups according to the area under the concentration-time curve (AUC) of busulfan; low-, medium-, and high-AUC group. Nontargeted metabolic profiling of baseline urine samples showed that deferoxamine metabolites were abundant, while 2 acylcarnitines and phenylacetylglutamine were significantly lower in high-AUC group, compared with low-AUC group. Higher level of deferoxamine, an iron-chelating agent for the patients with a high serum ferritin level during the conditioning chemotherapy, suggested pharmacokinetic interaction between serum ferritin level and busulfan exposure. Retrospective analysis of the correlation between serum ferritin level and busulfan AUC showed positive correlation in 130 pediatric patients. The optimal busulfan dose to meet the target AUC of 18,750 μg*h/L/day was calculated to be 119.7 ± 30.1 mg/m2 in patients with ferritin < 1,000 ng/mL and 106.1 ± 29.3 mg/m2in patients with ferritin ≥ 1,000 ng/mL (P=0.021).Mechanismly, previous studies have indicated that ferritin, acylcarnitine and phenylacetylglutamine are closely associated with liver function. Increased serum ferritin is thought to be responsible for an increased production of oxygen free radicals and activation of GSH turnover, which means reduction of GSH levels in both plasma and erythrocytes and this depletion seems to be related to the decrease of busulfan metabolism. Down regulation of acylcarnitines is associated with deregulation of mitochondrial fatty acid β-oxidation by hepatic injury. PAGN, a marker of waste nitrogen scavenger, was down-regulated which indicates ammonia-related metabolism could also be involved in busulfan exposure. Hyperammonemia, a clinical condition of elevated ammonia levels, is mainly lead by liver cell damage.Taken together, our findings demonstrate that elevated serum ferritin levels are a potential biomarker correlated with busulfan exposure and provide some evidence that busulfan metabolism seems to decrease in the patients with reduced liver function. DisclosuresNo relevant conflicts of interest to declare.

A Nonparametric Method to Optimize Initial Drug Dosing and Attainment of a Target Exposure Interval: Concepts and Application to Busulfan in Pediatrics.

The traditional approach for model-based initial dosing is based on the use of a single vector of typical population parameters for targeting a specific exposure. This approach is theoretically ill-suited for targeting a range of exposure. The objective of this work was to develop a general approach for optimal (OPT) targeting of a drug exposure interval. After methodological purposes, we applied our method to the busulfan case. We used a nonparametric population pharmacokinetic model of intravenous busulfan to estimate the individual pharmacokinetic parameters of 163 bone marrow-transplanted children. Then, an array of 151 doses of busulfan ranging from 0.5 to 2mg/kg was simulated a priori in each patient. For each dose, 29 possible busulfan plasma concentration profiles, corresponding to the nonparametric prior, each associated with a probability, were obtained. The multiple-model-based, OPT dose was identified as the dose maximizing the a priori probability of achieving the busulfan target area under the concentration-time curve (AUC). Two AUC targets were considered: 900-1500 (conventional) or <1500µMmin-1. Finally, the OPT dose was individually simulated in each patient. We compared the ability of this method to achieve the target exposure interval with that of three other traditional model-based methods and one based on the non-parametric approach. When targeting the busulfan conventional AUC range, the OPT dose provided better attainment than the best of the three other methods after one dose (82.2 vs. 41.7%, p<0.005), two doses (79.1 vs. 65.0%, p<0.005), and at the end of therapy (80.4 vs. 76.7%, p<0.42). The approach provided a balanced distribution between under- (10.4%) and overexposure (9.2%), while other approaches showed higher rates of underexposure (≥19%). When targeting an AUC <1500µMmin, the OPT dose was successful in minimizing overexposure as 0% of children showed simulated AUC >1500µMmin-1. Our approach has been designed to optimize the targeting of an exposure interval. When applied to busulfan in children, it outperformed the traditional model-based dosing approach, with earlier and better achievement of busulfan target AUC. The approach can be applied for OPT dosing of many drugs, when the target objective is an interval.

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20min, 50-60min and 3h after an initial 20mgkg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115mgl(-1) h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly.

Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation.

The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW0.5 mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUCPRED). The accuracy and precision of the AUCPRED values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and −2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT.

カルボプラチン投与量算出におけるCalvert式利用に関する実態調査

The renal clearance of carboplatin, which is a second-generation platinum compound, is correlated with the glomerular filtration rate (GFR). As the area under the concentration-time curve (AUC) of free carboplatin is related with efficacy and toxicity following carboplatin administration, carboplatin dosing is defined as a target AUC and generally calculated by the Calvert formula according to the patient's GFR. We conducted a survey on the usage of the Calvert formula to clarify the current situation in Japan. As a result, the value of creatinine clearance (CLcr), which is higher than GFR due to the tubular secretion of creatinine, has been used as a substitute for GFR for the Calvert formula without appropriate correction in 71 of 109 institutions, where CLcr estimated by a Cockcroft-Gault equation and/or obtained by 24-h urinary collection are used. On the other hand, body surface area-indexed values of renal function have been directly used without conversion to individual values in 42 of 71 institutions, where GFR estimated by a Japanese equation and/or CLcr estimated by a Jelliffe equation are used. It was found that the desired dosing of carboplatin has not been administered to patients in a number of institutions. Back to the original concept of the Calvert formula, it is reasonable to use a GFR estimated by the Japanese equation and converted to an individual value. In addition, we need to assess tolerability following carboplatin administration and discuss the appropriateness of the starting dose for each patient without being overly reliant on the dose obtained by the Calvert formula.

A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy.

Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting. Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities. At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%). PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.