Key result
Doxapram-induced increases in cardiac output significantly increased alfentanil distribution and elimination clearances, reducing plasma alfentanil concentrations and antinociception.
Why the study?
Does doxapram-mediated increase in cardiac output alter the pharmacokinetics and pharmacodynamics of alfentanil in healthy volunteers?
RCT
Does doxapram-mediated increase in cardiac output alter the pharmacokinetics and pharmacodynamics of alfentanil in healthy volunteers?
Doxapram-induced increases in cardiac output significantly reduce plasma concentrations and antinociceptive effects of alfentanil, highlighting the impact of physiological changes on opioid pharmacokinetics.
May require alfentanil dose titration with CO changes; extends human PK evidence linking cardiac output to opioid disposition.
-channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.
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Roozekrans et al. (2016) conducted an RCT in Healthy Volunteers. Doxapram was evaluated on alfentanil distribution and elimination clearances, plasma alfentanil concentration, and antinociception. Doxapram-induced increases in cardiac output significantly increased alfentanil distribution and elimination clearances, reducing plasma alfentanil concentrations and antinociception.
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