Pharmacokinetics, Excretion, and Mass Balance of [14 C]-Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Abstract

Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [¹⁴ C]-radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2-period, open-label study, 6 healthy male subjects received a single IV microtracer 1-hour infusion of 4 μg [¹⁴ C]-batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 μg) followed by oral [¹⁴ C]-batefenterol (200 μg) in period 2 after a 14-day washout. The primary end points included: the area under the concentration-time curve from time zero to last time of quantifiable concentration (AUC_0-t ); maximum observed concentration (C_max ); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC_0-t of [¹⁴ C]-batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC_0-t ratio indicated that [¹⁴ C]-batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [¹⁴ C]-batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

Trial registration: ClinicalTrials.gov NCT02663089.

Keywords: batefenterol; chiral inversion; microtracer; pharmacokinetics.

Figure 1

Study design. IV indicates intravenous ^aThe follow‐up period was extended if radioactivity excretion was >1% upon discharge.

Figure 2

Arithmetic mean (SD) concentrations of (A) plasma batefenterol following IV administration (data provided by LC+AMS assay) with concomitant inhaled administration (data by LC/MS assay), and oral administration (data by LC+AMS assay of pooled samples) (PK population; oral and inhaled doses normalized to 4‐μg IV dose); (B) total radioactivity (data by AMS) and batefenterol in plasma following IV administration (data by LC+AMS); and (C) total radioactivity (data by AMS) and batefenterol in plasma following oral administration (data by LC+AMS of pooled samples). AMS indicates accelerator mass spectrometry; IV, intravenous; LC, liquid chromatography; MS mass spectrometry; PK, pharmacokinetic; PO, oral administration; SD, standard deviation.

Figure 3

Arithmetic mean (±SD) total radioactivity recovery over time following IV administration of [¹⁴C]‐batefenterol (PK population). IV indicates intravenous; PK, pharmacokinetic; SD, standard deviation.

Figure 4

Arithmetic mean (±SD) radioactivity recovery over time following oral administration of [¹⁴C]‐batefenterol (PK population). Data presented are those for which the subject, who exhibited abnormally low mass balance recovery following oral [¹⁴C]‐batefenterol dosing compared with the other subjects was excluded. PK indicates pharmacokinetic; SD, standard deviation.

Figure 5

(A) Representative LC‐MS/MS chromatogram of pooled human plasma samples from a single subject following administration of batefenterol (1200 μg) by inhalation; (B) LC‐MS/MS chromatogram of a human plasma sample spiked with batefenterol (150 pg/mL) and R‐batefenterol (at a 10% ratio; 15 pg/mL). cps indicates counts per second; LC‐MS/MS, liquid chromatography–tandem mass spectrometry.