1. Academic Validation
  2. GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers

  • Br J Anaesth. 2014 Nov;113(5):875-83. doi: 10.1093/bja/aeu182.
J F McLeod 1 J M Leempoels 2 S X Peng 3 S L Dax 3 L J Myers 4 F J Golder 3
Affiliations

Affiliations

  • 1 Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA [email protected] [email protected].
  • 2 SGS Life Science Services, Lange Beeldekensstraat 267, Antwerpen B-2060, Belgium.
  • 3 Galleon Pharmaceuticals Corporation, 213 Witmer Road, Horsham, PA 19044, USA.
  • 4 Vivonoetics, 27 Dorian, Newport Coast, CA, 92657, USA.
Abstract

Background: Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers.

Methods: Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h.

Results: Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h).

Conclusions: GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.

Keywords

BKCa channel; EudraCT: 2011-003371-11; KCNMA1; breathing; carotid body; pharmacokinetics; potassium channel; respiratory stimulant; ventilatory function.

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