Bridging population pharmacokinetic and semimechanistic absorption modeling of APX3330

Abstract

APX3330 ((2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid), a selective inhibitor of APE1/Ref-1, has been investigated in treatment of hepatitis, cancer, diabetic retinopathy, and macular edema. APX3330 is administered orally as a quinone but is rapidly converted to the hydroquinone form. This study describes the pharmacokinetics of APX3330 and explores effect of food on absorption. Total plasma quinone concentrations of APX3330 were obtained following oral administration from studies in healthy Japanese male subjects (single dose-escalation; multiple-dose; food-effect) and patients with cancer patients. Nonlinear mixed effects modeling was performed using Monolix to estimate pharmacokinetic parameters and assess covariate effects. To further evaluate the effect of food on absorption, a semi-physiologic pharmacokinetic model was developed in Gastroplus to delineate effects of food on dissolution and absorption. A two-compartment, first order absorption model with lag time best described plasma concentration-time profiles from 49 healthy Japanese males. Weight was positively correlated with apparent clearance (CL/F) and volume. Administration with food led to an 80% higher lag time. CL/F was 41% higher in the cancer population. The semi-physiologic model indicates a switch from dissolution-rate control of absorption in the fasted-state to gastric emptying rate determining absorption rate in the fed-state. Oral clearance of APX3330 is higher in patients with cancer than healthy Japanese males, possibly due to reduced serum albumin in patients with cancer. Delayed APX3330 absorption with food may be related to higher conversion to the more soluble but less permeable hydroquinone form in the gastrointestinal tract. Future work should address pharmacokinetic differences between APX3330 quinone and hydroquinone forms.

FIGURE 1

Relationship between pharmacokinetic parameters and influential covariates for the base and final model from combined data from Japanese healthy volunteer and patients with cancer. Interindividual variability on CL/F (η _CL/F ) versus subject source and versus body weight (kg); inter‐individual variability on V ₁/F (η _V1/F ) versus body weight (kg) and interindividual variability on t _lag (η _Tlag) versus food, represented by fasted or fed states, are shown. These relationships are illustrated for estimates of η prior to incorporation of covariates effect in the model (left column – base model) or after adjusting for these covariates (right column – final model). The boxes represent the 25th, 50^th, and 75th percentiles; the whiskers represent the lowest datum still within 1.5 interquartile ranges (IQRs) of the lower quartile, and the highest datum still within 1.5 IQRs of the upper quartile range; the dots represent observed data, and blue lines represent the result of loess smoother with fitting by weighted least‐squares. CL/F, apparent clearance; t _lag, time lag; V1/F, volume of distribution of the central compartment; WT, weight.

FIGURE 2

Visual predictive checks of APX3330 plasma concentrations including combined data and stratified by single or multiple doses, fasted, or fed state, and subjects’ source. The circles represent the observations; the black lines denote the 5^th, 50^th, and 95^th percentiles of the prediction‐corrected observed data, the shaded areas denote the confidence interval of the 5^th, 50^th, and 95^th percentiles of the prediction‐corrected simulated data. IWRES, individual weighted residuals; PWRES, populational weighted residuals.

FIGURE 3

Absorption (gray lines) and dissolution (black lines) profile of APX3330 after an oral administration of 120 mg immediate release tablet under fasted (solid lines) and fed (dashed lines) states to a healthy volunteer.