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

Claire Ambery, Graeme Young, Teresa Fuller, Aili L Lazaar, Adrian Pereira, Adam Hughes, David Ramsay, Frans van den Berg, Peter Daley-Yates, Claire Ambery, Graeme Young, Teresa Fuller, Aili L Lazaar, Adrian Pereira, Adam Hughes, David Ramsay, Frans van den Berg, Peter Daley-Yates

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 (AUC0-t ); maximum observed concentration (Cmax ); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0-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 AUC0-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.

© 2018, The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Study design. IV indicates intravenous aThe follow‐up period was extended if radioactivity excretion was >1% upon discharge.
Figure 2
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
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
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
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.

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