Online Resource
Journal: Metabolomics
Prediction of Intravenous Busulfan Clearance by Endogenous Plasma Biomarkers Using Global Metabolomics
Supplemental Fig.1 Histograms of IV busulfan clearance in the entire study population. The left panel shows IV busulfan clearance by dosing weight(ml/min/kg) and the right panel shows IV busulfan clearanceby normal fat mass (ml/min/kg NFM). Dotted vertical lines are the95% confidence intervals
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Supplemental Fig. 2 Flowchart of data analysis and metabolite identification
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Supplemental Fig. 3 BCT evaluation assessing within-subject correlation of the abundance of the sevenpredictive ions. Each colored dot is one subject (n=39); r2correlation shown in the upper left corner for the seven predictive ions in the discovery dataset (i.e., citrateBCT with no HCT conditioning in metabolomics samples) and validation dataset (i.e., EDTA BCT with or without non-busulfan HCT conditioning in metabolomics samples)
Supplemental Fig. 4 BCTevaluationof the estimated IV busulfan clearance using the seven-ion predictive model. The middle solid line represents the line of unity and the outer dotted lines represent 80 and 125% of the predicted clearance in citrate BCT
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Supplemental Methods
As specified by the subject’s HCT treatment protocol, dose 1 of IV busulfanwas calculated based on body weight, administered as an IV infusion, and serial PK blood samples were collected. IV busulfan was given either four times daily (Q6h) or once daily (Q24h). In subjects receiving Q6h IV busulfan, PK samples were typically drawn at the end of the infusion (EOI), EOI+15 min, EOI+30 min, 3, 4, 5, and 6 h after the start of the two-hour infusion.(Laboratory 2013) In subjects receiving Q24h IV busulfan, PK samples were typically collected at the EOI, EOI+15 min, 4, 5, 6, and 8 h after the start of the three-hour infusion.(Laboratory 2013) The samples were analyzed using gas chromatography(GC)-mass spectrometry (MS) as previously described.(Slattery and Risler 1998; Yeh et al. 2012) The dynamic range of the assay was from 25 to 4500 ng/mL, and the inter-day coefficient of variation was < 8%.(Salinger et al. 2010)
To characterize IV busulfan pharmacokinetics over the entire age continuum, all clearance (CL,Q) and volume (V1,V2) parameters were scaled for body size and composition using allometric theory and predicted fat free mass (FFM).(Janmahasatian et al. 2005; Anderson and Holford 2008, 2009) The TBW-available cohort (n=133) was used to estimate the fraction of fat mass (Ffat) contributing normal fat mass (NFM) for IV busulfan. Ffat is a drug- and pharmacokinetic-parameter-specific quantity; the value of Ffat was estimated for each pharmacokinetic parameter.(Anderson and Holford 2009) Ffat parameters are based on total body weight (TBW).(Karlsson et al. 1998; Mould et al. 2002) FFM was predicted using Equation 1:
Equation 1
whereWHSmax is the maximum FFM for any given height (HT, m) and WHS50 is the TBW value when FFM is half of WHSmax. WHSmax is 42.92 kg/m2 and 37.99 kg/m2 and WHS50 is 30.93 kg/m2 and 35.98 kg/m2 for males and females, respectively.(Janmahasatian et al. 2005) The NFM was predicted using Equation 2:
Equation 2
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