Sequential Exposure of Bortezomib and Vorinostat Is Synergistic in Multiple Myeloma Cells

Sequential Exposure of Bortezomib and Vorinostat is Synergistic in Multiple Myeloma Cells

Charvi Nanavati and Donald E. Mager

Supplemental Information

Charvi Nanavati

Department of Pharmaceutical Sciences, University at Buffalo

State University of New York

433 Kapoor Hall

Buffalo, New York 14260, USA

Corresponding Author: Donald E. Mager

Department of Pharmaceutical Sciences, University at Buffalo

State University of New York

431 Kapoor Hall

Buffalo, New York 14260, USA

e-mail:

Tel: (716) 645-2903

Fax: (716) 829-6569

Supplemental Figure S1 Pharmacokinetic Model Fittings for (A)0.25 mg/kg Bortezomib IV Bolus and (B)10 mg/kg IV Bolus Vorinostat in BALB/c Mice. Symbols represent data digitized from original publications [1,2] and lines represent model fits

Supplemental Figure S2 Goodness of fit Plots (observed vs. predicted) for combination regimens (A) Bortezomib pre-incubation for 6 hours followed by vorinostat for 18 hours and their simultaneous combination for 24 hours (B) Bortezomib pre-incubation for 24 hours followed by vorinostat for 24 hours and their simultaneous combination for 48 hours and (C) Vorinostat pre-incubation for 24 hours followed by bortezomib for 24 hours and their simultaneous combination for 48 hours. Blue symbols represent simultaneous data and red symbols represent sequential data

Supplemental Table S1 Pharmacokinetic Parameter Estimates for (A) 0.25 mg/kg IV Bolus Bortezomib and (B) 10mg/kg IV Bolus Vorinostat in BALB/c Mice

Parameter / Definition / Estimate / CV %
CL (mL/hr) / Clearance from the central compartment / 19.0 / 10.8
CLD (mL/hr) / Distribution Clearance / 550 / 0.55
V1 (mL) / Volume of the central Compartment / 150 / 0.15
V2 (mL) / Volume of the peripheral compartment / 2470 / 2.47
Parameter / Definition / Estimate / CV %
kel (hr-1) / First-order eliminate rate constant from central compartment / 6.56 / 0.913
k12 (hr-1)* / Inter-compartmental distribution rate constant / 0.551 / 11.3
V1 (mL/kg) / Volume of the central Compartment / 2015 / 0.822

* Inter-compartmental distribution rate constant from central to peripheral compartment and from peripheral to central compartment were estimated as same parameters because of parsimonious data

References

1. Yeo P, Xin L, Goh E, New LS, Zeng P, Wu X, Venkatesh P, Kantharaj E (2007) Development and validation of high-performance liquid chromatography-tandem mass spectrometry assay for 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide, a novel HDAC inhibitor, in mouse plasma for pharmacokinetic studies. Biomed Chromatogr 21 (2):184-189. doi:10.1002/bmc.734

2. Zhang L, Mager DE (2015) Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice. J Pharmacokinet Pharmacodyn 42 (5):541-552. doi:10.1007/s10928-015-9445-x