Background: Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods: Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library and ClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cutoff value, which we set as 800, 900, 1000, 1125, 1350, and 1500 μM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results: Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 μM × min, the mean AUC value of < 900 μM × min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 μM × min (RR = 0.370, 95% CI: 0.205-0.666) and < 1500 μM × min (RR = 0.409, 95% CI: 0182-0.920). Conclusions: In children, Bu mean AUC above the cutoff value of 900 μM × min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cutoff value of 1350 μM × min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

Purpose The aim of this study was to develop a novel busulfan dosing regimen, based on a population pharmacokinetic (PPK) model in Chinese children, and to achieve better area under the concentration-time curve (AUC) targeting. Patients and Methods We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulated patients, and has been verified on real patients. Limited sampling strategy (LSS) was established by Bayesian forecasting. Mean absolute prediction error (MAPE) and relative root mean Squared error (rRMSE) were calculated to evaluate predictive accuracy. Results A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, body surface area (BSA) and aspartate aminotransferase (AST) were found to be significant covariates of Bu clearance, and BSA had significant impact of the volume of distribution. Moreover, two equations were obtained for recommended dose regimens: dose (mg)=34.14×BSA (m 2 )+3.75 (for GSTA1 *A/*A ), Dose (mg)=30.99×BSA (m 2 )+3.21 (for GSTA1 *A/*B ). We also presented a piecewise dosage based on BSA categories for each GSTA1 mutation. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision (rRMSE=1.026%, MAPE=6.55%). Conclusion We recommend a GSTA1 -BSA and BSA-based dosing (Q6 h) based on a PPK model for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C 2h and C 4h ) provides convenience for therapeutic drug monitoring (TDM) in the future.

Information on the comparative efficacy is important for drug development as well as drug therapy. Up to now, the relative efficacy of approved biologics and many agents under investigation in ankylosing spondylitis (AS) are still unclear. The objective of this study was to quantify the relative efficacy and time course of various treatments measured by the Ankylosing Spondylitis Assessment Study group response criteria 20 scores (ASAS20), change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index (BASFI). There were 34 double‐blinded trials of 10 biologics and small molecules encompassing 5,339 patients with AS were included in this analysis. Three mathematical models with nonparametric placebo estimations were used to describe the longitudinal profile for the above three efficacy measures. The results detected significant differences among included treatments, and infliximab and golimumab were found to have the highest efficacy in given dosage regimens across all measures.

Background Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However,the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.049, 95% CI: 1.285-7.234). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min(RR=0.409, 95% CI: 0182-0.920). Conclusions In children, Bu the mean AUC of 900 µM × min should be considered the lowest threshold associated with its effective prevention of graft failure, while the mean AUC of >1350 µM × min is associated with increased VOD, particularly for the patients not undergoing VOD prophylaxis therapy.