Estimation of Equipotent Doses for Anti-Inflammatory Effects of Prednisolone and AZD9567, an Oral Selective Nonsteroidal Glucocorticoid Receptor Modulator

Abstract

AZD9567 is a potent and selective nonsteroidal oral glucocorticoid receptor modulator. It is developed as an anti-inflammatory drug with improved safety profile compared with steroids like prednisolone. Throughout the clinical development of AZD9567, dose selection and data interpretation require a method for determining doses with the same anti-inflammatory effect as prednisolone. Equipotent doses of AZD9567 and prednisolone were defined by the same average inhibition of TNFα release, a biomarker of anti-inflammatory effect, measured in a lipopolysaccharide-stimulated whole blood ex vivo assay. Based on pharmacokinetic-pharmacodynamic models, TNFα dose-response relationships for AZD9567 and prednisolone were established. A comparison of the dose-response curves enabled estimation of an equipotency relationship. Specifically, 20 mg prednisolone was estimated to be equipotent to 40 mg AZD9567 (95% confidence interval: 29-54 mg). Static concentration-response analyses showed that the relative potencies for inhibition of TNFα release of AZD9567 and prednisolone were well aligned with several other pro-inflammatory cytokines.

Figure 1

Visual predictive checks on a logarithmic scale, stratified on dose for the AZD9567 pharmacokinetic (PK) model (a) and the prednisolone PK model (b). Plots are showing the 95% confidence interval for the model median (blue for AZD9567, red for prednisolone), observed individual data (gray dots) and their median (solid black line), and the lower limit of quantification (dashed black line). Insets are showing a magnification of the first 4 hours after dose. The y‐scale of the insets are different but always show a 10‐fold range for AZD9567 and a 1,000‐fold range for prednisolone.

Figure 2

The total concentration AZD9567 producing half‐maximal inhibition of cytokine release (IC₅₀) plotted against the corresponding total concentration prednisolone ${\text{IC}}_{50}$. Uncertainties of the ${\text{IC}}_{50}$ pairs are shown as 95% confidence regions around the point estimates. A reference line (dashed) is defined by the axes origin and the pair of ${\text{IC}}_{50}$ point estimates for TNFα inhibition. The ${\text{IC}}_{50}$ estimates for the other cytokines line up along the reference line, showing that the relative potency is similar across the set of cytokines. IFN‐ γ, interferon‐γ; IL, interleukin; MIP, macrophage inflammatory protein.

Figure 3

Visual predictive checks on a logarithmic scale for the TNFα pharmacokinetic/pharmacodynamic model for AZD9567 (a), prednisolone (b), baseline (c), and placebo (d). a and b are stratified on dose. Plots are showing the 95% confidence interval for the model median (blue for AZD9567, red for prednisolone, green for baseline, and yellow for placebo), observed individual data (gray dots) and their median (solid black line).

Figure 4

Simulation on a linear scale of the pharmacokinetic (a) and TNFα (expressed as percent of baseline) (b) profiles in a typical individual following the fifth dose of once daily dosing of either 40 mg AZD9567 (blue) or 20 mg prednisolone (red). Drug concentrations in the plasma, transduction, and weighted transduction compartment are scaled with the respective half‐maximal inhibitory concentration (${\text{IC}}_{50}$) to facilitate a comparison between the two compounds. The estimated ${\text{IC}}_{50}$ is shown as reference (dashed line). The transduction compartment concentration profile has a delayed maximum compared to the plasma concentration. The weighted concentration always lies in between the plasma and transduction compartment concentration. The main difference compared with the transduction compartment is a more rapid increase just after dosing. Ex vivo TNFα is shown relative to the estimated baseline. The onset of effect on TNFα is slightly faster for AZD9567 due to its somewhat more rapid absorption, but prednisolone reaches its maximal level of inhibition faster than AZD9567. Prednisolone also achieves a higher maximal reduction of TNFα, but AZD9567 compensates by a slower return toward the baseline.

Figure 5

Dose‐response curves with 95% confidence intervals for AZD9567 (blue) and prednisolone (red). Response is defined as the average TNFα inhibition over 24 hours following 5 consecutive daily doses.

Figure 6

The point estimate (black) and the 95% confidence interval (gray) of the equipotency relationship between AZD9567 and prednisolone. Illustration of a dose‐to‐dose translation shows that 20 mg prednisolone (red line) is equipotent to 40 mg AZD9567 (blue line), with a 95% confidence interval (CI) of 29–54 mg (blue shaded region). Similarly, 40 mg AZD9567 is equipotent to 20 mg prednisolone, with a 95% CI of 14–29 mg (red shaded region).