Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies

Abstract

Purpose

To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients.

Methods

Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5–32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model.

Results

HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment model. HM781-36 oral absorption was characterized by first-order input (absorption rate constant: 1.45 ± 0.23 h⁻¹). The central volume of distribution (185 ± 12.7 L) was influenced significantly by body weight. The absorption rate constant was influenced by food. The typical HM781-36 apparent clearance was 34.5 L/h (29.4 %CV), with an apparent peripheral volume of distribution of 164 L (53.5 %CV). Other covariates did not significantly further explain the PKs of HM781-36.

Conclusions

The proposed model suggests that HM781-36 PKs are consistent across most solid tumor types, and that the absorption process of HM781-36 is affected by the fed state before dosing. HM781-36 PKs are not complicated by patient factors, other than body weight.

Appendices

Appendix 1

HM781-36 Pharmacokinetic model (parent molecule only).

$$Ka_{i} = \theta_{1} \cdot \exp \left( {\eta_{{1,Ka_{i} }} } \right)\quad [{\text{fasting state}}]$$

$$Ka_{i} = \theta_{2} \cdot \exp \left( {\eta_{{2,Ka_{i} }} } \right)\quad [{\text{if dosed in fed state}}]$$

$${\text{CL}}/F_{i} = \theta_{2} \cdot \exp \left( {\eta_{{{\text{CL}}/F_{i} }} } \right)$$

$$V_{\text{c}} /F_{i} = \theta_{3} \cdot \exp \left( {\eta_{{Vc/F_{i} }} } \right)$$

$$Q/F_{i} = \theta_{4}$$

$$V_{\text{p}} /F_{i} = \theta_{5} \cdot \exp \left( {\eta_{{Vp/F_{i} }} } \right)$$

$$K_{i} = \left( {\frac{{{\text{CL}}/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$K_{23i} = \left( {\frac{{Q/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$K_{32i} = \left( {\frac{{Q/F_{i} }}{{V_{\text{p}} /F_{i} }}} \right)$$

$$C_{ij} = \hat{C}_{ij} \cdot \left( {1 + \varepsilon_{pij} } \right)$$

where all parameters are as defined in the text and individual PK parameters are denoted by the subscript i.

Appendix 2

Combined HM781-36 and HM781-36-M1/-M2 Pharmacokinetic parent-metabolite model.

$$Ka_{i} = \theta_{1} \cdot \exp \left( {\eta_{{1,Ka_{i} }} } \right)\quad [{\text{fasting state}}]$$

$$Ka_{i} = \theta_{2} \cdot \exp \left( {\eta_{{2,Ka_{i} }} } \right)\quad [{\text{if dosed in fed state}}]$$

$${\text{CL}}/F_{i} = \theta_{3} \cdot \exp \left( {\eta_{{{\text{CL}}/F_{i} }} } \right)$$

$$Vc/F_{i} = \theta_{4} \cdot \exp \left( {\eta_{{Vc/F_{i} }} } \right)$$

$$Q/F_{i} = \theta_{5}$$

$$V_{\text{p}} /F_{i} = \theta_{6} \cdot \exp \left( {\eta_{{Vp/F_{i} }} } \right)$$

$$K_{i} = \left( {\frac{{{\text{CL}}/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$K_{23i} = \left( {\frac{{Q/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$K_{32i} = \left( {\frac{{Q/F_{i} }}{{V_{\text{p}} /F_{i} }}} \right)$$

$$V_{4i} = V_{5i} = V_{\text{c}} /F_{i}$$

$${\text{fm}}_{1i} = \exp \left( { - \left( {\theta_{7} + \eta_{{{\text{fm}}_{1i} }} } \right)} \right)/\left( {1 + \exp \left( { - \left( {\theta_{7} + \eta_{{{\text{fm}}_{1i} }} } \right)} \right)} \right)$$

$${\text{fm}}_{2i} = 1 - {\text{fm}}_{1i}$$

$${\text{CLm}}_{1} /{\text{fm}}_{1i} = \theta_{9} \cdot \exp \left( {\eta_{{{\text{CLm}}_{1} /{\text{fm}}_{1i} }} } \right)$$

$${\text{CLm}}_{2} /{\text{fm}}_{2i} = \theta_{10} \cdot \exp \left( {\eta_{{{\text{CLm}}_{2} /{\text{fm}}_{2i} }} } \right)$$

$${\text{ERm}}_{1i} = \exp \left( { - \left( {\theta_{11} + \eta_{{{\text{ERm}}_{1i} }} } \right)} \right)/\left( {1 + \exp \left( { - \left( {\theta_{11} + \eta_{{{\text{ERm}}_{1i} }} } \right)} \right)} \right)$$

$${\text{ERm}}_{2i} = \exp \left( { - \left( {\theta_{12} + \eta_{{{\text{ERm}}_{2i} }} } \right)} \right)/\left( {1 + \exp \left( { - \left( {\theta_{12} + \eta_{{{\text{ERm}}_{2i} }} } \right)} \right)} \right)$$

$$K_{24i} = {\text{fm}}_{1i} \cdot \left( {\frac{{{\text{CL}}/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$K_{25i} = {\text{fm}}_{2i} \cdot \left( {\frac{{{\text{CL}}/F_{i} }}{{V_{\text{c}} /F_{i} }}} \right)$$

$$C1_{ij} = \hat{C}1_{ij} \cdot \left( {1 + \varepsilon 1_{pij} } \right)$$

$$C2_{ij} = \hat{C}2_{ij} \cdot \left( {1 + \varepsilon 2_{pij} } \right)$$

$$C3_{ij} = \hat{C}3_{ij} \cdot \left( {1 + \varepsilon 3_{pij} } \right)$$

where all parameters are as defined in the text, and individual PK parameters are denoted by the subscript i.

Appendix 3

See Table 4 and Figs. 4, 5 and 6.

Table 4 HM781-36 population pharmacokinetic (PK) parent-only model (n = 72)