title: Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.
abstract: Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Roozekrans
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Olofsen
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van der Schrier
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Gerven
authors.affiliation: Galleon Pharmaceuticals Corp., Horsham, Pennsylvania, USA.
authors.forename: S
authors.initials: S
authors.lastname: Peng
authors.affiliation: Galleon Pharmaceuticals Corp., Horsham, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: McLeod
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008954:Models, Biological; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy*; D014227:Triazines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D014227:Triazines; C000593146:GAL021