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Agonists can bind with and activate receptors, resulting in the formation of drug-receptor complexes. Once formed, these complexes catalyze many biochemical processes at the cellular level and subsequently induce a pharmacologic response. The degree of response is directly proportional to the fraction of activated receptors, which in turn, depends on the concentration of the drug at the receptor site as well as the sensitivity of the receptor. An increase in the administered dose contributes to...
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Exposure-response modeling for nausea incidence for cotadutide using a Markov modeling approach.

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Cotadutide, a dual GLP-1/glucagon receptor agonist, can cause nausea. A biweekly, twofold dose escalation strategy minimizes nausea, reaching therapeutic doses faster with better tolerability.

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Area of Science:

  • Pharmacology
  • Clinical Pharmacology
  • Drug Development

Background:

  • Cotadutide is a dual glucagon-like peptide-1 (GLP-1)/glucagon receptor agonist.
  • Gastrointestinal adverse effects, particularly nausea, are common with GLP-1 receptor agonists.
  • Gradual dose titration is a strategy to mitigate these effects and improve patient tolerance.

Purpose of the Study:

  • To characterize the exposure-nausea relationship for cotadutide.
  • To optimize cotadutide titration schemes for improved tolerability.
  • To simulate nausea event rates under different dosing strategies.

Main Methods:

  • Pooled data from cotadutide studies were used.
  • Three modeling approaches were employed: proportional odds, discrete-time Markov, and two-stage discrete-time Markov models.
  • Nausea severity was modeled (non-nausea, mild, moderate/severe), and covariate analysis identified influencing factors.

Main Results:

  • Markov models outperformed the proportional odds model in characterizing the exposure-nausea relationship.
  • Disease indications (NASH, obesity) and sex were identified as covariates affecting nausea.
  • Biweekly titration with twofold dose escalation showed a lower predicted nausea rate (25% at 600 μg) and faster achievement of therapeutic dose.

Conclusions:

  • A biweekly, twofold dose escalation titration scheme is superior for cotadutide administration.
  • This optimized titration strategy can minimize nausea and improve the risk-benefit balance.
  • The developed model can inform titration strategies for other therapeutics in clinical trials.