Pharmacokinetics-pharmacodynamics analysis of spiroindolone analogs and KAE609 in. a murine malaria model
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1 Pharmacokinetics-pharmacodynamics analysis of spiroindolone analogs and KAE609 in a murine malaria model Suresh B. Lakshminarayana 1#, Céline reymond 2,3, Christoph ischli 2,3, Jing Yu 4, Sebastian Weber 5, Anne Goh 1, Bryan K. S. Yeung 1, Paul C. o 6, Véronique Dartois 1,a, Thierry T. Diagana 1, Matthias Rottmann 2,3 and rancesca Blasco 1# 6 7 (1) ovartis Institute for Tropical Diseases, Singapore 8 (2) Swiss Tropical and Public ealth Institute, Basel, Switzerland 9 (3) University of Basel, Switzerland 10 (4) ovartis Institutes for Biomedical Research, Cambridge, MA, USA 11 (5) ovartis Pharma, Basel, Switzerland 12 (6) Department of Pharmacy, ational University of Singapore, Singapore # Corresponding Authors SBL & B Suresh B. Lakshminarayana ovartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore, suresh.b_lakshminarayana@novartis.com; Phone: rancesca Blasco ovartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos 22 Singapore,
2 23 Phone: Present address: (a) Public ealth Research Institute Center, ew Jersey, USA
3 43 Supplementary material Table S1. In vitro PK properties of spiroindolone analogs igure S1: Structure of spiroindolone analogs igure S2. Goodness-of-fit plots for dose response relationship 49 igure S3. Goodness-of-fit plots for pharmacokinetic modeling of KAE igure S4. Dose proportionality for KAE609 in CD-1 mouse
4 67 Table S1: In vitro PK properties of spiroindolone analogs 68 Caco-2 (c) epatic CL int Compound Solubility (p 6.8, µm) (a) PAMPA (b) %A P app (A-B) 10-6 cm/sec in mouse liver microsomes (d) (µl/min/mg) Mouse PPB (e) (%) RBC to Plasma Ratio (f) (+) (+) n.t (+) (+) (+) (+) (+)-7 (KAE609) (-) (-) In vitro PK parameters like solubility, PAMPA, Caco-2 permeability, hepatic clearance, mouse plasma protein binding and RBC to plasma partitioning were determined in a medium 4
5 to high through put format using in-house standard assay protocols that are described in the literature. (a) T-Equilibrium solubility at p 6.8 (1); (b) Parallel Artificial Membrane Permeability Assay expressed in % fraction absorbed (A) (2, 3); (c) Apparent permeability from apical to basolateral in Caco-2 cells expressed as P app (A-B) 10-6 cm/sec (4, 5), n.t, not tested; (d) intrinsic clearance in mouse liver microsomes expressed as µl/min/mg protein, in the presence of liver enzymes (6); (e) Mouse plasma protein binding using rapid equilibrium dialysis method (7, 8), (f) RBC to plasma ratio, mean from 1 µm & 10 µm (9)
6 99 igure S1. Structure of spiroindolone analogs. Active spiroindolones O O ( + ) -1 ( + ) -2 O O O ( + ) -3 (+ ) -4 (+ ) -5 O O ( + ) -6 (+ ) -7 (ITD609) Inactive spiroindolones O O ( - ) -6 ( - ) Active spiroindolones have the 1R, 3S configuration while inactive spiroindolones have the 1S, 3R configuration (10)
7 111 igure S2. Goodness-of-fit plots for dose response relationship Goodness-of-fit plots for a representative compound [(+)-6] (A) observed data (DV) vs populations predictions (PRED) (B) weighted residuals (WRES) vs PRED (C) WRES vs Dose
8 128 igure S3. Goodness-of-fit plots for pharmacokinetic modeling of KAE Goodness-of-fit plots for KAE609 pharmacokinetic modeling (A) observed data (DV) vs populations predictions (PRED) (B) weighted residuals (WRES) vs PRED (C) WRES vs Time
9 145 igure S4. Dose proportionality for KAE609 in CD-1 mouse 100 A 1000 B C max (µg/ml) AUC (µg*h/ml) Dose (mg/kg) Dose (mg/kg) Dose linearity tests on C max and AUC 0-24 were carried out by the regression of logtransformed data (power regression model) (11, 12). Doses ( mg/kg) and PK parameters (C max and AUC 0-24 ) were log-transformed, and correlation coefficient (R 2 ), slope, and 95 % confidence intervals of slope were calculated using the GraphPad Prism version 5.02 for windows (GraphPad software, San Diego, California USA). The system was considered to be linear when R 2 ~ 1, Slope 95 % CI lower > 0.8, and CI upper < 1.25 (11, 12). (A) Dose vs C max (R 2 = 0.97, Slope = 1.18, 95 % CI lower = 0.52 and CI upper = 1.83); (B) Dose vs AUC 0-24 (R 2 = 0.97, Slope = 1.30, 95 % CI lower = 0.65 and CI upper = 1.96). Based on the above observations, KAE609 shows nonlinear behavior in CD-1 mouse between the doses studied
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