Module 4.2.2 — Pharmacokinetic Study Reports — GLPI-103
| Field | Value |
|---|---|
| Document ID | M4-2.2 |
| Version | 2.0 (expanded) |
| Compound | GLPI-103 (GLP-1/APJ dual agonist) |
| Standard | ICH M4S; M3(R2); S3A; GLP (toxicokinetics) |
| Confidentiality | Confidential |
[MOCK — deep-knowledge assumption]Nonclinical PK/ADME study reports; data illustrative but technically representative of a C18-diacid-acylated, albumin-binding peptide.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-06-29 | Nonclinical / DMPK | Initial reports |
| 2.0 | 2026-06-30 | Nonclinical / DMPK | Expanded — cross-species PK parameters, albumin-binding half-life mechanism, metabolism/excretion, human projection |
4.2.2.1 Analytical Methods
Validated LC-MS/MS for GLPI-103 in plasma across species (selectivity, calibration range, accuracy/precision, dilution linearity, matrix and freeze-thaw stability), with an orthogonal ligand-binding assay for cross-validation; a tiered anti-drug-antibody (ADA) assay (screen → confirm → titre, with a neutralising-antibody assay) supports immunogenicity. [MOCK]
4.2.2.2 Absorption — Report PK-ADME-01 (non-GLP) + integrated GLP toxicokinetics
Mechanistic basis: the C18 fatty-diacid acylation drives strong, reversible binding to serum albumin (>99%), which (with the Aib protease-resistance substitutions) gives low clearance and a long half-life — the molecular basis for once-weekly IV dosing. Oral absorption is enabled transiently by the SNAC permeation enhancer.
Parameter (single dose) [MOCK] |
Rat | Monkey | Human (projected) |
|---|---|---|---|
| Clearance (CL) | low | low | ~0.04 L/h |
| Volume of distribution (Vss) | ~0.1 L/kg | ~0.08 L/kg | ~7–10 L |
| Terminal half-life (t½) | 24–48 h | 60–90 h | ~5–7 days |
| Plasma protein binding | >99% | >99% | >99% |
| Oral bioavailability (with SNAC) | — | ~1–2% | ~1% (basis for 8 mg oral vs 4 mg IV) |
| Dose proportionality | linear | linear | linear (Phase 1) |
Toxicokinetics integrated into the GLP repeat-dose studies (TOX-RD-01/02; M4-2.3) showed approximately dose-proportional AUC, minimal accumulation (~1.3×), and no relevant sex difference; these data define the exposure margins in M4-2.3.
4.2.2.3 Distribution
Low volume of distribution consistent with confinement to plasma and extracellular fluid by high albumin binding; tissue distribution (quantitative whole-body autoradiography, rat) consistent with a peptide with no unexpected accumulation; placental transfer low.
4.2.2.4 Metabolism
GLPI-103 is metabolised by proteolytic catabolism (endopeptidases and neprilysin) to small peptide fragments and amino acids, with β-oxidation and ω-oxidation of the fatty-diacid side chain; the Aib²/Aib¹³ substitutions confer resistance to DPP-4. No meaningful cytochrome-P450 metabolism was observed. No human-specific or disproportionate metabolites were identified (MIST not triggered).
4.2.2.5 Excretion
Elimination is predominantly via catabolism; intact GLPI-103 is a minor component of urinary/biliary excretion. Metabolite-related material is recovered in urine and faeces.
4.2.2.6 Pharmacokinetic Drug Interactions
Low metabolic drug-interaction potential: not a substrate/inhibitor/inducer of major CYP enzymes or principal transporters at clinically relevant concentrations; no relevant interaction with metformin. As a high-albumin-binder, displacement interactions were assessed and judged not clinically meaningful. [MOCK]
4.2.2.7 Immunogenicity
Anti-drug antibodies were low-titre and non-neutralising, without meaningful impact on PK, PD, or safety in repeat-dose studies — consistent with a largely human-sequence peptide.
Conclusion
The nonclinical DMPK profile — albumin-binding-driven low clearance and long half-life, proteolytic (non-CYP) metabolism, low drug-interaction potential, and SNAC-enabled oral absorption — supports the once-weekly IV and once-daily oral clinical regimens and underpins the exposure-margin and human-dose projections (M2.4; M2.7.2).