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Results: 5

1.
Figure 2

Figure 2. From: Demonstration of the Equivalent Pharmacokinetic/Pharmacodynamic Dosing Strategy in a Multiple-Dose Study of Gefitinib.

The PK model-predicted (―――) and mean (n = 3–4) observed (●) gefitinib concentrations for plasma (A), tumor (C) of LN229-wild-type EGFR tumor bearing group and plasma (B), tumor (D) of LN229-EGFRvIII mutant group, respectively. Bars = ± 1 SD. The multiple dose regimens consisted of 55 mg/kg/d PO × 15 days and 30 mg/kg/d PO × 15 in LN229-wild-type EGFR and LN229-EGFRvIII mutant tumor-bearing groups, respectively. Physiologically-based hybrid PK models were fitted to the observed plasma and tumor gefitinib concentrations from both Day l and Day 15.

Shining Wang, et al. Mol Cancer Ther. ;8(6):1438-1447.
2.
Figure 3

Figure 3. From: Demonstration of the Equivalent Pharmacokinetic/Pharmacodynamic Dosing Strategy in a Multiple-Dose Study of Gefitinib.

The PK/PD model-predicted (―――) and mean (n = 3–4) observed (●) fractional inhibition of pERK for wild-type tumor group (A) and vIII mutant tumor group (B), respectively. Bars = ± 1 SD. Once the hybrid PK models were finalized, the associated PK variables were held constant and linked to a 2-compartment target-response model, consisting of a target compartment representing pEGFR, and a response compartment representing pERK, which was applied to the PD observations on both Day 1 and Day 15.

Shining Wang, et al. Mol Cancer Ther. ;8(6):1438-1447.
3.
Figure 5

Figure 5. From: Demonstration of the Equivalent Pharmacokinetic/Pharmacodynamic Dosing Strategy in a Multiple-Dose Study of Gefitinib.

Clinical PK/PD model simulations. Model simulations of gefitinib brain tumor concentration-time profiles (left y-axis) and corresponding tumor pERK inhibition-time profiles (right y-axis) following 1000 mg/d PO × 15 days in patients bearing intracerebral wild-type EGFR tumors (―――) and 500 mg/d PO × 15 days in patients bearing intracerebral EGFRvIII mutant tumors (―――). The brain tumor partition coefficient, Rbt, was set to 10 (A). The effects of the brain tumor partition coefficient (Rbt) on the steady-state maximum brain tumor concentration (i.e. Cbtmax, ―――) and the percent inhibition of pERK at the nadir in patients bearing either intracerebral wild-type EGFR (―――) or EGFRvIII mutant (······) tumors following 500 mg/d of gefitinib for 15 days (B).

Shining Wang, et al. Mol Cancer Ther. ;8(6):1438-1447.
4.
Figure 4

Figure 4. From: Demonstration of the Equivalent Pharmacokinetic/Pharmacodynamic Dosing Strategy in a Multiple-Dose Study of Gefitinib.

The PK/PD/tumor growth model-predicted (―――, gefitinib-treated group; ―――, vehicle control group) and mean observed (●, gefitinib-treated group, n = 23; ○, vehicle control group, n = 9) tumor sizes are presented for wild-type tumor group (A) and vIII mutant tumor group (B), respectively. Bars = ± 1 SD. Once the hybrid PK/PD models were finalized, a Gompertz tumor growth model was linked to the final PD model for each tumor group by using pERK as the biomarker. The tumor growth models for each tumor group were derived in a sequential manner by fitting to the control groups first, and then fitting to the gefitinib-treated groups.

Shining Wang, et al. Mol Cancer Ther. ;8(6):1438-1447.
5.
Figure 1

Figure 1. From: Demonstration of the Equivalent Pharmacokinetic/Pharmacodynamic Dosing Strategy in a Multiple-Dose Study of Gefitinib.

Schematic representation of a hybrid PK/PD/tumor growth model consisting of a 2-compartment systemic disposition model, a 1-compartment tumor model, a 2-compartment target-response model and a Gompertz tumor growth model. The model was developed based on a sequential modeling approach of first defining the PK model, then the PD model, and finally the tumor growth model. The PK model variables included the elimination rate constant (K10), volume of distribution in the plasma compartment (Vc), inter-compartment transfer rate constants (K12, K21), absorption rate constant (Ka), bioavailability (F), blood flow rate (Q), tumor to plasma partition coefficient (Ri). The tumor volume (Vt) was represented by an exponential equation describing the actual mean tumor volumes during the 15 days treatment. The PD model variables included tumor drug concentration for 50% inhibition of pEGFR (IC50), the zero-order rate constant for the formation of pEGFR (Kin), the rate constant from the drug target compartment (pEGFR) to the response compartment (pERK) (Ktr), and a first-order rate constant for degradation and dephosphorylation of pERK (Kout), which was expressed by an exponential equation Kout = Kout (0) (−r·time) in order to describe the change of Kout during the 15 days treatment, in which Kout(0) represents the baseline Kout level and r is the arbitrary constant associated with the reduction of Kout. The pEGFR0 and Imax were fixed as 1. The tumor growth model included the rate constants for exponential and linear tumor growth (Kgexp and Kgzero), a first-order rate constant representing the signal propagation between the inhibitory compartments (Ksp), and γ, a variable that mediates the switch from the exponential to linear tumor growth.

Shining Wang, et al. Mol Cancer Ther. ;8(6):1438-1447.

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