Sensitivity Analysis of Unperturbed Tumor Growth.

<p>Simulated model profiles of varying values of A) Tumor cell lifespan (<i>T</i>), B) Initial division efficiency (<i>p₀</i>), C) Tumor size threshold (<i>w_th</i>) for decrease in division efficiency, and D) Past tumor growth rate (<i>k_in0</i>). Simulation were carried with parameters values of <i>T</i> = 1 day, <i>p₀</i> = 2, <i>k_in0</i> = 0.05 g/day and <i>w_th</i> = 10 g, unless otherwise specified for each figure. Dashed lines in panels A–C indicate the <i>w_th</i> value.</p

Tumor Growth Inhibition by AZD1208.

<p>A) Pharmacokinetic profile of AZD1208 was described using a 1 compartment model with equal values for absorption and elimination rate constants. PK data (symbols) were collected following a single oral administration of AZD1208 at 3, 10 and 30 mg/kg (model prediction in lines). B) Observed (symbol) and lifespan model predicted (lines) tumor growth and inhibition by AZD1208 at 0.3, 1, 3, 10 and 30 mg/kg given orally. Initial tumor volume was fixed to 170 mm³, which is the value of the first tumor size measurement.</p

Modeling Tumor Growth Inhibition by Paclitaxel.

<p>A) Observed (black squares) and model fitted (black line) tumor weight during untreated tumor growth. Data was digitized from (Simeoni et al, 2004). Initial tumor volume was fixed at 0.033 g as estimated from original publication. B) Simultaneous fitting of unperturbed tumor growth data (black square) with model preduction (black line) and tumor growth inhibition data (grey triangle) and model prediction using the cycle-specific drug effect model (grey line) by 30 mg/kg of paclitaxel administered every 4 days for 3 rounds starting from day 8.</p

Simulated Effect of Division Efficiency on Tumor Growth.

<p>A) Semi-log plot of tumor growth with constant division efficiency of <i>p₀</i> = 2. Upper and lower dashed lines indicate upper and lower bound described by eq. 12. B) Simulation of cell division efficiency function, <i>p(w)</i>, vs tumor weight, <i>w</i>, for different values of <i>ψ</i>. The threshold, <i>w_th</i>, was set to 10 g, and initial efficiency, <i>p₀</i> is set to 2.</p

Sensitivity Analysis of Cycle-Specific Drug Effect Model.

<p>Simulated model profiles with changes in: A) Apoptosis duration, <i>T_A</i>, B) Maximum drug efficacy, <i>E_max</i>, and C) Drug potency, <i>EC₅₀</i>. D) Signature profile of cycle-specific drug mechanism model with dose escalation. Simulation were carried with parameters values of <i>T</i> = 1 day, <i>T_A</i> = 4 days, <i>p₀</i> = 2, <i>k_in0</i> = 0.05 g/day, <i>w_th</i> = 10 g, <i>E_max</i> = 1 and <i>EC₅₀</i> = 0.01 concentration, unless otherwise indicated. Arrows indicate dose administration at days 10, 20 and 30.</p

Parameter Estimates for Simultaneous Fitting of Unperturbed and Paclitaxel Inhibited Tumor Growth with Cycle-Specific Drug Effect.

<p>Parameter Estimates for Simultaneous Fitting of Unperturbed and Paclitaxel Inhibited Tumor Growth with Cycle-Specific Drug Effect.</p

Model Schematics.

<p>A) Unperturbed tumor growth, B) Non-cycle-specific perturbed tumor growth, and C) Cycle-specific perturbed tumor growth. The meanings of the symbols and variables are explained in the model development section.</p

Model Comparison: Modeling Tumor Growth Inhibition by AZ968.

<p>A) Modeling of pharmacokinetic data after single i.p. dose of AZ968 at 10, 20 and 30 mg/kg. Data (symbols) was described with a 2 compartment model with dose-dependent elimination rate constant and central volume of distribution (model prediction in lines). B) Observed (symbols) and model predicted (lines) tumor volume using the lifespan model of tumor growth inhibition. Line style and color indicate unrestricted condition and oral treatment with AZ968 at 10, 20 and 30 mg/kg in mice xenograft. Symbols indicate control condition (black squares), 10 mg/kg AZ968 (black circles), 20 mg/kg (grey diamonds), and 30 mg/kg (grey triangles). Initial tumor volume was fixed at 180 mm³ as estimated from initial data points. C) Fitting of same AZ968 data using the Simeoni model.</p

Parameter Estimates for PK Fitting of AZ968.

<p>Parameter Estimates for PK Fitting of AZ968.</p

Parameter Estimates for Unperturbed Tumor Growth.

<p>Parameter Estimates for Unperturbed Tumor Growth.</p