Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia

Abstract

Purpose

Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen.

Methods

Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated.

Results

The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy.

Conclusions

Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.

Appendix: differential equations of the final PK/PD model

PK:

$$\begin{array}{*{20}c} {\frac{{{\text{dA}}_{1} }}{{{\text{d}}t}} = - {\text{A}}_{1} \cdot K_{\text{A}} } \hfill & {\text{Gut}} \hfill \\ {\frac{{{\text{dA}}_{2} }}{{{\text{d}}t}} = {\text{A}}_{1} \cdot K_{\text{A}} - {\text{A}}_{2} \cdot K_{23} + {\text{A}}_{3} \cdot K_{32} - {\text{A}}_{2} \cdot K} \hfill & {\text{Central compartment}} \hfill \\ {\frac{{{\text{dA}}_{3} }}{{{\text{d}}t}} = {\text{A}}_{2} \cdot K_{23} - {\text{A}}_{3} \cdot K_{32} } \hfill & {\text{Peripheral compartment}} \hfill \\ {\frac{{{\text{dA}}_{4} }}{{{\text{d}}t}} = - {\text{A}}_{4} \cdot K_{\text{C}} } \hfill & {{\text{Carboplatin compartment }}\left( {\text{KPD}} \right)} \hfill \\ \end{array}$$

PD:

$$\begin{array}{*{20}c} {\frac{{{\text{dA}}_{5} }}{{{\text{d}}t}} = K_{\text{IN}} \cdot \left( {1 - {\text{EFFC}}} \right) \cdot \left( {1 + {\text{EFFE}}} \right){ - }K_{\text{T}} \cdot {\text{A}}_{5} } \hfill & {{\text{Precursor production compartment }}\left( {\text{BM1}} \right)} \hfill \\ {\frac{{{\text{dA}}_{6} }}{{{\text{d}}t}} = K_{\text{T}} \cdot {\text{A}}_{5} - K_{\text{T}} \cdot {\text{A}}_{6} } \hfill & {{\text{Transit/maturation compartment }}\left( {\text{BM2}} \right)} \hfill \\ {\frac{{{\text{dA}}_{7} }}{{{\text{d}}t}} = K_{\text{T}} \cdot {\text{A}}_{6} - K_{\text{T}} \cdot {\text{A}}_{7} } \hfill & {{\text{Transit/maturation compartment }}\left( {\text{BM3}} \right)} \hfill \\ {\frac{{{\text{dA}}_{8} }}{{{\text{d}}t}} = K_{\text{T}} \cdot {\text{A}}_{7} - K_{\rm deg} \cdot {\text{A}}_{8} } \hfill & {{\text{Platelet compartment }}\left( {\text{P}} \right)} \hfill \\ \end{array}$$

Where	Initial conditions
$\begin{aligned} K_{\text{A}} & = 0,\quad {\text{if}}\;t < t_{\text{LAG}} \\ & = K_{{{\text{A}}_{1} }} ,\quad {\text{if}}\;t_{\text{LAG}} \le t < t_{\text{LAG}} + t_{\text{M}} \\ & = K_{{{\text{A}}_{2} }} ,\quad {\text{if}}\;t > t_{\text{LAG}} + t_{\text{M}} \\ \end{aligned}$	A1(0) = Dose1 (eltrombopag) A2(0) = A3(0) = 0 A4(0) = Dose2 (carboplatin) A5(0) = A6(0) = A7(0) = K IN/K T A8(0) = K IN/K deg
$\begin{gathered} K_{ 2 3} = {\text{Q}}/{\text{V}}_{\text{C}} \hfill \\ K_{ 3 2} = {\text{Q}}/{\text{V}}_{\text{P}} \hfill \\ K = {\text{CL}}/{\text{V}}_{\text{C}} \hfill \\ \end{gathered}$
$\begin{gathered} K_{\rm deg } = K_{\text{IN}} /{\text{BASE}} \hfill \\ {\text{EFFC}} = {\text{SLPC}}\, \times \,{\text{A}}_{ 4} \hfill \\ {\text{SLPC}} = {\text{SLPC}}_{0} \, \times \,{\text{CYCLE}}^{\gamma 1} \hfill \\ {\text{EFFE}} = {\text{SLPE}}\, \times \,{\text{A}}_{ 2} /{\text{V}}_{\text{C}} \hfill \\ {\text{SLPE}} = {\text{SLPE}}_{0} \, \times \,{\text{CYCLE}}^{\gamma 2} \hfill \\ \end{gathered}$

1. K _A  First-order absorption rate constant, K elimination rate constant, CL/F oral clearance, Vc/F oral volume of distribution, Q/F distributional clearance, Vp/F peripheral volume, K _C  elimination rate constant from the hypothetical carboplatin compartment, K _IN  production rate of platelet precursors, K _T  maturation rate of platelet precursors, K _deg  first-order elimination rate of platelets, BASE baseline platelet count, SLPC linear proportionality constant of carboplatin effect, SLPE linear proportionality constant of eltrombopag effect, A _x  amount of drug (for PK compartments) or concentration of platelets/precursors (for PD compartments) in compartment x