Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach

Abstract

Aims: Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate.

Methods: Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation.

Results: A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h).

Conclusions: The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol.

Keywords: NONMEM; inhalation; olodaterol; pharmacometrics; population pharmacokinetics; pulmonary absorption.

Figure 1

Semi‐logarithmic plot of olodaterol plasma and urine data, including a colour grading for the different dosing regimens. (A) Plasma concentrations after intravenous administration (trial 1). (B) Plasma concentrations after oral inhalation (single and multiple rising‐dose trials, trial 2 and trial 3). (C) Cumulative amount of drug excreted into the urine after intravenous administration (trial 1). (D) Cumulative amount of drug excreted into the urine after inhalation (single and multiple rising‐dose trials, trial 2 and trial 3)

Figure 2

Schematic representation of the best pharmacokinetic (PK) model. Pulmonary PK box: Pulmonary PK model; systemic PK box: systemic disposition model; rhombus: calculated values; rectangles: model compartments; arrows from the absorption compartments to the central systemic compartment represent the absorption processes. CL_R, renal clearance; CL_NR, nonrenal clearance; FF1, first proportionality parameter; FF2, second proportionality parameter; k_{a_slow}, slow absorption rate constant; k_{a_int}, intermediate absorption rate constant; k_{a_fast}, fast absorption rate constant; ND, nominal dose (ex‐mouthpiece); PBIO, pulmonary bioavailable fraction; Q₂–Q₄: inter‐compartmental clearances; V_C–V₄, volumes of distribution. Whenever the next dose was inhaled, the calculation of the cumulative amount of drug excreted into the urine was restarted

Figure 3

Standard goodness‐of‐fit plots for plasma pharmacokinetic (PK) data after olodaterol inhalation, including a colour grading for the different dosing regimens. (A) Logarithmic plot of olodaterol observations vs. predictions. (B) Logarithmic plot of observations vs. individual predictions. (C) Semi‐logarithmic plot of absolute individual weighted residuals (IWRES) vs. individual predictions. (D) Semi‐logarithmic plot of conditional weighted residuals (CWRES) vs. time after last dose. In (A) and (B), the thick black line represents the line of identity and the thin black line represents the lower limit of quantification. In (C) and (D), the thick black line represents the reference line

Figure 4

Standard goodness‐of‐fit plots for urine data after olodaterol inhalation, including a colour grading for the different dosing regimens. (A) Logarithmic plot of observations vs. predictions. (B) Logarithmic plot of observations vs. individual predictions. (C) Semi‐logarithmic plot of absolute individual weighted residuals (IWRES) vs. individual predictions. (D) Semi‐logarithmic plot of conditional weighted residuals (CWRES) vs. time after last dose. In (A) and (B), the thick black line represents the line of identity and the thin black line represents the lower limit of quantification; in (C) and (D), the black line represents the reference line

Figure 5

Dose‐normalized visual predictive checks (VPC) to evaluate model performance. (A) Semi‐logarithmic VPC for plasma concentrations after single‐dose inhalation. (B) Semi‐logarithmic VPC for plasma concentrations after multiple‐dose inhalation (n_dose = 14). (C) VPC for plasma concentrations below the lower limit of quantification (LLOQ) after a single dose. (D) VPC for plasma concentrations below the LLOQ after multiple doses (n_dose = 14). (E) Semi‐logarithmic VPC for the cumulative amount of olodaterol excreted into the urine after single‐dose inhalation. (F) Semi‐logarithmic VPC for the cumulative amount of olodaterol excreted into the urine after multiple‐dose inhalation (n_dose = 14). The orange line represents the median of the observed data, the blue dashed lines represent the 5^th and 95^th percentiles of the observed data, the orange shaded area represents the 95% confidence interval around the median of the simulated data, the blue shaded area represents the 95% confidence interval around the 5^th and 95^th percentile of the simulated data and the blue points represent the measured concentrations

Figure 6

Simulations of different time profiles after inhalation of 5 μg olodaterol performed using the combined pharmacokinetic model. (A) Sum of drug amount in all depot (lung) compartments. (B) Sum of drug amount in all body compartments. (C) Plasma concentration–time profile. (D) Cumulative drug amount eliminated into the urine (calculated per dose). Blue profiles represent simulations performed in smokers, orange profiles represent simulations performed in nonsmokers, and blue and orange shaded areas represent 90% prediction intervals