Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.

Bolognani F, Kruithof AC, Schulthess P, Machacek M, de Kam ML, Bergmann KR, van Gent M, Moerland M, Crenn P, Greig G, Gal P

The Journal of pharmacology and experimental therapeutics14 Jun 2023Cited by 7 (Europe PMC)

PMID37316329DOI10.1124/jpet.123.001582PepBankPUB-37316329

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Summary

Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults. Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo. PK and citrulline (an enterocyte mass PD marker) samples were collected at multiple time points. Kinetic parameters of apraglutide and citrulline were calculated using noncompartmental analysis; repeated PD measures were analyzed with a mixed model of covariance. A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers. Twenty-four subjects were randomized; 23 received all study drug administrations. Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters. A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo. PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response. Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration. Apraglutide displays predictable dose-dependent PK and PD profiles, with a 5-mg dose showing significant PD effects. Results suggest that apraglutide has early and enduring effects on enterocyte mass and supports the continued development of weekly subcutaneous apraglutide for SBS-IF and GvHD patient populations. SIGNIFICANCE STATEMENT: Once-weekly subcutaneous apraglutide results in dose-dependent elevations of plasma citrulline (an enterocyte mass pharmacodynamic marker) with parameters suggesting that apraglutide has lasting effects on enterocyte mass and the potential to provide therapeutic benefits. This is the first report of a model relating glucagon-like peptide-2 (GLP-2) agonism and its effects in intestinal mucosa, affording not only the ability to predict pharmacologic effects of GLP-2 analogs but also the exploration of optimal dosing regimens for this drug class across populations with different body weights.

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

Results from this study8

7 results from studies that gave the peptide. 7 results from people.

01HumanRandomized controlled trialPharmacokinetics
In healthy adults, mean estimated apraglutide clearance was 16.5-20.7 l/day.
In plain wordsIn healthy adults, estimated apraglutide clearance averaged 16.5-20.7 l/day.
Peptide
Apraglutide
Outcome
Not applicableClearance
Study
n: not reported in source
Outcome group
Pharmacokinetics · Pharmacology
Studied dose
1, 5, or 10 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Measurements
Clearance
16.5 to 20.7 l/day
healthy adults
Source sentences
Summary
Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632901
02HumanRandomized controlled trialPharmacokinetics
In healthy adults, mean apraglutide volume of distribution was 55.4-105.0 liters.
In plain wordsIn healthy adults, apraglutide's average distribution volume was 55.4-105.0 liters.
Peptide
Apraglutide
Outcome
Not applicableVolume of distribution
Study
n: not reported in source
Outcome group
Pharmacokinetics · Pharmacology
Studied dose
1, 5, or 10 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Measurements
Volume of distribution
55.4 to 105 liters
healthy adults
Source sentences
Summary
Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632902
03HumanRandomized controlled trialActivity measurement
In healthy adults, 5-mg apraglutide produced higher citrulline levels than 1-mg apraglutide.
In plain wordsIn healthy adults, 5-mg apraglutide raised citrulline more than 1-mg apraglutide.
Peptide
Apraglutide
Outcome
IncreasePlasma citrulline
Study
n: not reported in source
Comparator
1 mg apraglutide
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
5 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Source sentences
Summary
A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632903
04HumanRandomized controlled trialActivity measurement
In healthy adults, 5-mg apraglutide produced higher citrulline levels than placebo.
In plain wordsIn healthy adults, 5-mg apraglutide raised citrulline more than placebo.
Peptide
Apraglutide
Outcome
IncreasePlasma citrulline
Study
n: not reported in source
Comparator
placebo
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
5 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Source sentences
Summary
A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632904
05HumanRandomized controlled trialActivity measurement
In healthy adults, 10-mg apraglutide produced higher citrulline levels than 1-mg apraglutide.
In plain wordsIn healthy adults, 10-mg apraglutide raised citrulline more than 1-mg apraglutide.
Peptide
Apraglutide
Outcome
IncreasePlasma citrulline
Study
n: not reported in source
Comparator
1 mg apraglutide
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
10 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Source sentences
Summary
A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632905
06HumanRandomized controlled trialActivity measurement
In healthy adults, 10-mg apraglutide produced higher citrulline levels than placebo.
In plain wordsIn healthy adults, 10-mg apraglutide raised citrulline more than placebo.
Peptide
Apraglutide
Outcome
IncreasePlasma citrulline
Study
n: not reported in source
Comparator
placebo
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
10 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Source sentences
Summary
A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632906
07HumanRandomized controlled trialActivity measurement
In healthy adults, elevated plasma citrulline persisted for 10-17 days after the final apraglutide administration.
In plain wordsIn healthy adults, raised blood citrulline persisted for 10-17 days after the last apraglutide dose.
Peptide
Apraglutide
Outcome
IncreasePersistence of citrulline elevation
Study
n: not reported in source
Outcome group
Gastrointestinal protection · Gastrointestinal
Studied dose
1, 5, or 10 mg weekly · subcutaneous · 6 weekly administrationsAs given in this study (human).
Measurements
Duration of increased plasma citrulline after final dose
10 to 17 days
after final apraglutide administration
Source sentences
Summary
Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration.
2 context sentences(design, population, supporting numbers)
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
Show in the study text Report a problemFND-3731632908

Studies that did not test the peptide alone1

In this study, Apraglutide 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 Apraglutide.

08Computer modelNot a test of Apraglutide aloneIn silicoActivity measurement
In a healthy-volunteer PK/PD analysis, weekly 5-mg apraglutide induced the maximal citrulline response.
In plain wordsIn a model using healthy-volunteer data, weekly 5-mg apraglutide produced the largest citrulline response.
Peptide
Apraglutide
Outcome
Not applicableMaximal citrulline response
Study
humann: not reported in source
population PK/PD model using healthy volunteer data
Outcome group
Gastrointestinal protection · Gastrointestinal
Source sentences
Summary
PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response.
3 context sentences(design, population, supporting numbers)
Summary · context
A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers.
Summary · context
This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults.
Summary · context
Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo.
In this study, Apraglutide 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 Apraglutide.
Show in the study text Report a problemFND-3731632907

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

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

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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