The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab
Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn’s disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to recei...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/10/2408 |
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| author | Marla C. Dubinsky Shervin Rabizadeh John C. Panetta Elizabeth A. Spencer Annelie Everts-van der Wind Thierry Dervieux |
| author_facet | Marla C. Dubinsky Shervin Rabizadeh John C. Panetta Elizabeth A. Spencer Annelie Everts-van der Wind Thierry Dervieux |
| author_sort | Marla C. Dubinsky |
| collection | DOAJ |
| description | Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn’s disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (<i>p</i> < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (<i>p</i> < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = −19.2; <i>p</i> < 0.001), and the combination of both further minimized OFV (<i>p</i> < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone. |
| first_indexed | 2024-03-10T20:59:07Z |
| format | Article |
| id | doaj.art-dea09ccc678a456c878679f1158b2931 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T20:59:07Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-dea09ccc678a456c878679f1158b29312023-11-19T17:44:05ZengMDPI AGPharmaceutics1999-49232023-09-011510240810.3390/pharmaceutics15102408The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with InfliximabMarla C. Dubinsky0Shervin Rabizadeh1John C. Panetta2Elizabeth A. Spencer3Annelie Everts-van der Wind4Thierry Dervieux5Mount Sinai Medical Center, New York, NY 10029, USACedars Sinai Medical Center, Los Angeles, CA 90048, USASt. Jude Children’s Research Hospital, Memphis, TN 38105, USAMount Sinai Medical Center, New York, NY 10029, USAPrometheus Laboratories, San Diego, CA 92121, USAPrometheus Laboratories, San Diego, CA 92121, USAInfliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn’s disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction (<i>p</i> < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (<i>p</i> < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = −19.2; <i>p</i> < 0.001), and the combination of both further minimized OFV (<i>p</i> < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.https://www.mdpi.com/1999-4923/15/10/2408infliximabCrohn’s diseasepharmacokineticsclearancepredictive factors |
| spellingShingle | Marla C. Dubinsky Shervin Rabizadeh John C. Panetta Elizabeth A. Spencer Annelie Everts-van der Wind Thierry Dervieux The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab Pharmaceutics infliximab Crohn’s disease pharmacokinetics clearance predictive factors |
| title | The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab |
| title_full | The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab |
| title_fullStr | The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab |
| title_full_unstemmed | The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab |
| title_short | The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab |
| title_sort | combination of predictive factors of pharmacokinetic origin associates with enhanced disease control during treatment of pediatric crohn s disease with infliximab |
| topic | infliximab Crohn’s disease pharmacokinetics clearance predictive factors |
| url | https://www.mdpi.com/1999-4923/15/10/2408 |
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