Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context
Abstract
:1. Introduction
Quantitative Clinical Pharmacology Tools
2. Materials and Methods
3. Results and Discussion
3.1. PBPK Model Development for a Virtual Healthy Adult after Single Intravenous Administration of Infliximab (5 mg/kg)
3.2. PBPK Model Development for a Virtual Adult with IBD after Intravenous Administrations of Infliximab (5 mg/kg)
3.3. PBPK Modeling Exploration for Virtual Adults with IBD (Typical and Heavy) after Switching to Subcutaneous Infliximab
3.4. PBPK Modeling Exploration for an Older Virtual Child (14-Year-Old, 60 kg) with IBD after Intravenous Administrations of Infliximab (5 mg/kg)
3.5. PBPK Modeling Exploration for an Older Virtual Child (14-Year-Old, 60 kg) with IBD after Switching to a Flat-Fixed Dose of Subcutaneous Infliximab (120 mg)
3.6. PBPK Modeling Exploration for a Virtual Pediatric Population Stratified by Weight Bands after Switching to Subcutaneous Infliximab: A PBPK-Model-Informed Dose Suggestion
3.7. Limitations and Future Perspectives of the Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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1. Clinical trial in healthy adults, single intravenous dose 5 mg/kg [18] |
2. Clinical trial in adult patients with IBD [20] intravenous dose 5 mg/kg induction + maintenance up to week 54 subcutaneous switch, dose: 120 mg (skin of abdomen or upper thigh) subcutaneous switch, dose: 240 mg (skin of abdomen or upper thigh) |
3. Clinical trial in adult patients with IBD, population pharmacokinetic study (subcutaneous switch to 120 mg in adults with IBD) and simulations on smaller, average, and heavier adult patients [17] |
4. Clinical trial in pediatric population with IBD (intravenous route 5 mg/kg, ulcerative colitis) [14,21] |
5. Clinical trial in older pediatric population with IBD (post-switch to subcutaneous 120 mg, skin of abdomen or upper thigh) [22] |
TNF-α |
Reference concentration: 0.2 pm [16] |
Localization: plasma and interstitial space; relative expression: 1 [14] |
Infliximab |
Molecular weight: 149.9 kDa [1] |
Radius (solute): 5.18 nm [23] |
Kd (FcRn) in endosomal space: 0.73 µmol/L [24] |
Kd (FcRn) plasma/interstitial *: 4.54 mmol/L (i.e., negligible binding affinity [25])Kd (TNF-α) *: 120.17 pmol/L (100 pmol/L [26]) |
Koff (TNF-α) *: 1.331/ms (111/ms [27]) |
Kass (FcRn)*: 0.72 L/µmol/min (0.80 L/µmol/min [28]) |
Anatomy and physiology of a virtual healthy adult |
Fraction endosomal: 0.20 [28] |
Specific clearance in endosome *: 0.911/min |
Fraction recycled to plasma: 1 [28] |
Fraction of endosomal uptake from plasma *: 0.53 |
Rate constant for endosomal uptake: 0.291/min [28] |
Rate constant for recycling from endosomal space *: 0.301/min |
Kd (FcRn, endogenous IgG) in plasma/interstitial space: 10,000 µmol/L [28] |
Kd (FcRn, endogenous IgG) in endosome: 0.63 µmol/L [28] |
Kass (FcRn, endogenous IgG): 0.87 L/ µmol/min [28] |
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Petric, Z.; Gonçalves, J.; Paixão, P. Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context. Biomedicines 2024, 12, 1974. https://doi.org/10.3390/biomedicines12091974
Petric Z, Gonçalves J, Paixão P. Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context. Biomedicines. 2024; 12(9):1974. https://doi.org/10.3390/biomedicines12091974
Chicago/Turabian StylePetric, Zvonimir, João Gonçalves, and Paulo Paixão. 2024. "Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context" Biomedicines 12, no. 9: 1974. https://doi.org/10.3390/biomedicines12091974