Exposure-driven tolerance modeling of efpeglenatide-induced nausea or vomiting using repeated time-to-event analysis: implications for dose-escalation strategies.

Seo J, Choi S, Kim N, Kim H, Lim HS

Frontiers in pharmacology22 Sept 2026

PMID42840589DOI10.3389/fphar.2026.1846164PepBankPUB-42840589

Publisher page PubMedAsk about this study

Summary

IntroductionNausea or vomiting are common adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists and often decline over time despite continued exposure, suggesting tolerance development. However, the longitudinal dynamics of recurrent events and tolerance have not been quantitatively characterized for efpeglenatide. This study aimed to characterize efpeglenatide-induced nausea/vomiting in non-diabetic patients with obesity using repeated time-to-event (RTTE) modeling and to explore its implications for dose-escalation strategies.MethodsData from six clinical trials were pooled, and 678 participants with obesity and/or type 2 diabetes mellitus were included in the analysis. A total of 672 nausea or vomiting events were analyzed using a sequential PK-AE approach based on a previously developed population pharmacokinetic model. Separate RTTE models were developed for an obesity population and a pooled total population. The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC). Model performance was evaluated using bootstrap and visual predictive checks, and Monte Carlo simulations were performed to assess nine dose-escalation scenarios. The obesity model served as the primary model for predicting dosing regimen-dependent AE patterns, whereas the pooled total model was used as an exploratory model to assess the concentration-AE response relationship.ResultsAmong the 678 participants, 247 (36.4%) experienced at least one episode of nausea or vomiting. In the obesity model, the exposure-hazard relationship was best described by a log-linear function. The estimated AUC associated with 50% tolerance development was 109,872 h ng/mL in the obesity model. Among the nine dosing scenarios, the Case 1-4 titration regimens achieved approximately 50% tolerance within 3-4 weeks while maintaining a lower early AE burden than high fixed-dose regimens. Low fixed-dose regimens delayed tolerance development, whereas high fixed-dose regimens increased the early AE burden.ConclusionEfpeglenatide-associated nausea or vomiting was well characterized using an exposure-driven RTTE framework, and early cumulative exposure appeared to play a central role in tolerance development. These findings suggest that, in non-diabetic patients with obesity, stepwise titration of efpeglenatide may help optimize tolerability by mitigating early AE burden while allowing sufficient cumulative exposure for tolerance development.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study6

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone6

In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Efpeglenatide.

01Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In the obesity model, efpeglenatide's exposure-hazard relationship for nausea or vomiting followed a log-linear function.
In plain wordsThe computer model described efpeglenatide exposure and nausea or vomiting risk with a log-linear relationship.
Peptide
Efpeglenatide
Outcome
Not applicableExposure-hazard relationship for nausea or vomiting
Study
n: not reported in source
repeated time-to-event obesity model
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Source sentences
Summary
In the obesity model, the exposure-hazard relationship was best described by a log-linear function.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058901
02Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In the obesity model, the estimated exposure associated with 50% tolerance to efpeglenatide-associated nausea or vomiting was 109,872 h ng/mL.
In plain wordsThe computer model estimated 50% tolerance to efpeglenatide-associated nausea or vomiting at an exposure of 109,872 h ng/mL.
Peptide
Efpeglenatide
Outcome
Not applicableExposure for tolerance development
Study
n: not reported in source
repeated time-to-event obesity model
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
AUC for 50% tolerance
109,872 h ng/mL
obesity model
Source sentences
Summary
The estimated AUC associated with 50% tolerance development was 109,872 h ng/mL in the obesity model.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058902
03Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In simulations, efpeglenatide Case 1-4 titration regimens achieved approximately 50% tolerance within 3-4 weeks.
In plain wordsComputer simulations predicted approximately 50% tolerance within 3-4 weeks with the efpeglenatide titration regimens.
Peptide
Efpeglenatide
Outcome
Not applicableTime to tolerance with titration
Study
n: not reported in source
repeated time-to-event obesity model
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Tolerance
≈ 50%
Case 1-4 titration
Time to tolerance
3 to 4 weeks
Case 1-4 titration
Source sentences
Summary
Among the nine dosing scenarios, the Case 1-4 titration regimens achieved approximately 50% tolerance within 3-4 weeks while maintaining a lower early AE burden than high fixed-dose regimens.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058903
04Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In simulations, efpeglenatide titration regimens maintained lower early adverse-event burden than high fixed-dose regimens.
In plain wordsComputer simulations predicted fewer early nausea or vomiting events with efpeglenatide titration than with high fixed doses.
Peptide
Efpeglenatide
Outcome
DecreaseEarly nausea or vomiting burden with titration
Study
n: not reported in source
repeated time-to-event obesity model
Comparator
high fixed-dose regimens
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Source sentences
Summary
Among the nine dosing scenarios, the Case 1-4 titration regimens achieved approximately 50% tolerance within 3-4 weeks while maintaining a lower early AE burden than high fixed-dose regimens.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058904
05Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In simulations, low fixed-dose efpeglenatide regimens delayed tolerance development.
In plain wordsComputer simulations predicted slower tolerance development with low fixed efpeglenatide doses.
Peptide
Efpeglenatide
Outcome
DecreaseTolerance development with low fixed doses
Study
n: not reported in source
repeated time-to-event obesity model
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Source sentences
Summary
Low fixed-dose regimens delayed tolerance development, whereas high fixed-dose regimens increased the early AE burden.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058905
06Computer modelNot a test of Efpeglenatide aloneIn silicoSafety outcome
In simulations, high fixed-dose efpeglenatide regimens increased early adverse-event burden.
In plain wordsComputer simulations predicted more early nausea or vomiting events with high fixed efpeglenatide doses.
Peptide
Efpeglenatide
Outcome
IncreaseEarly nausea or vomiting burden with high fixed doses
Study
n: not reported in source
repeated time-to-event obesity model
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Source sentences
Summary
Low fixed-dose regimens delayed tolerance development, whereas high fixed-dose regimens increased the early AE burden.
2 context sentences(design, population, supporting numbers)
Summary · context
Separate RTTE models were developed for an obesity population and a pooled total population.
Summary · context
The models incorporated baseline hazard, a time-decaying non-drug effect, and an exposure-driven drug effect with tolerance linked to cumulative exposure (AUC).
In this study, Efpeglenatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Efpeglenatide.
Show in the study text Report a problemFND-4284058906

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

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Version 2Current
27 Oct 2026, 18:20 UTC
Study results updated
Version 1
27 Oct 2026, 16:32 UTC
First added · source update from Europe PMC

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