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17 pages, 2252 KiB

Open AccessArticle

Trends in Targeted Therapy Usage in Inflammatory Bowel Disease: TRENDY Study of ENEIDA

by Celia Gómez-Labrador, Elena Ricart, Marisa Iborra, Eva Iglesias, María Dolores Martín-Arranz, Luisa de Castro, Ruth De Francisco, Francisco Javier García-Alonso, Ana Sanahuja, Carla J. Gargallo-Puyuelo, Francisco Mesonero, María José Casanova, Míriam Mañosa, Montserrat Rivero, Marta Calvo, Mónica Sierra-Ausin, Carlos González-Muñoza, Xavier Calvet, Santiago García-López, Jordi Guardiola, Lara Arias García, Lucía Márquez-Mosquera, Ana Gutiérrez, Yamile Zabana, Mercè Navarro-Llavat, Rufo Lorente Poyatos, Marta Piqueras, Leyanira Torrealba, Fernando Bermejo, Ángel Ponferrada-Díaz, José L. Pérez-Calle, Manuel Barreiro-de Acosta, Coral Tejido, José Luis Cabriada, Ignacio Marín-Jiménez, Óscar Roncero, Yolanda Ber, Luis Fernández-Salazar, Blau Camps Aler, Alfredo J. Lucendo, Jordina Llaó, Luis Bujanda, Carmen Muñoz Villafranca, Eugeni Domènech, María Chaparro and Javier P. Gisbert Show full author list Hide full author list

Pharmaceutics 2024, 16(5), 629; https://doi.org/10.3390/pharmaceutics16050629 - 8 May 2024

Viewed by 2103

Abstract

Markers that allow for the selection of tailored treatments for individual patients with inflammatory bowel diseases (IBD) are yet to be identified. Our aim was to describe trends in real-life treatment usage. For this purpose, patients from the ENEIDA registry who received their [...] Read more.

Markers that allow for the selection of tailored treatments for individual patients with inflammatory bowel diseases (IBD) are yet to be identified. Our aim was to describe trends in real-life treatment usage. For this purpose, patients from the ENEIDA registry who received their first targeted IBD treatment (biologics or tofacitinib) between 2015 and 2021 were included. A subsequent analysis with Machine Learning models was performed. The study included 10,009 patients [71% with Crohn’s disease (CD) and 29% with ulcerative colitis (UC)]. In CD, anti-TNF (predominantly adalimumab) were the main agents in the 1st line of treatment (LoT), although their use declined over time. In UC, anti-TNF (mainly infliximab) use was predominant in 1st LoT, remaining stable over time. Ustekinumab and vedolizumab were the most prescribed drugs in 2nd and 3rd LoT in CD and UC, respectively. Overall, the use of biosimilars increased over time. Machine Learning failed to identify a model capable of predicting treatment patterns. In conclusion, drug positioning is different in CD and UC. Anti-TNF were the most used drugs in IBD 1st LoT, being adalimumab predominant in CD and infliximab in UC. Ustekinumab and vedolizumab have gained importance in CD and UC, respectively. The approval of biosimilars had a significant impact on treatment. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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13 pages, 1247 KiB

Open AccessArticle

The Impact of Inflammation on the In Vivo Activity of the Renal Transporters OAT1/3 in Pregnant Women Diagnosed with Acute Pyelonephritis

by Jhohann Richard de Lima Benzi, Patrícia Pereira dos Santos Melli, Geraldo Duarte, Jashvant D. Unadkat and Vera Lucia Lanchote

Pharmaceutics 2023, 15(10), 2427; https://doi.org/10.3390/pharmaceutics15102427 - 5 Oct 2023

Cited by 2 | Viewed by 1499

Abstract

Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the [...] Read more.

Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the probe drug furosemide. Pregnant women (second or third trimester) received a single oral dose of furosemide 40 mg during acute pyelonephritis (Phase 1; n = 7) and after its resolution (Phase 2; n = 7; by treatment with intravenous cefuroxime 750 mg TID for 3–7 days), separated by 10 to 14 days. The IL-6, IFN-γ, TNF-α, MCP-1, and C-reactive protein plasma concentrations were higher in Phase I vs. Phase II. The pregnant women had a lower geometric mean [CV%] furosemide CLsecretion (3.9 [43.4] vs. 6.7 [43.8] L/h) and formation clearance to the glucuronide (1.1 [85.9] vs. 2.3 [64.1] L/h) in Phase 1 vs. Phase 2. Inflammation reduced the in vivo activity of renal OAT1/3 (mediating furosemide CL_secretion) and UGT1A9/1A1 (mediating the formation of furosemide glucuronide) by approximately 40% and 54%, respectively, presumably by elevating the plasma cytokine concentrations. The dosing regimens of narrow therapeutic window OAT drug substrates may need to be adjusted during inflammatory conditions. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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15 pages, 2515 KiB

Open AccessArticle

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn’s Disease with Infliximab

by Marla C. Dubinsky, Shervin Rabizadeh, John C. Panetta, Elizabeth A. Spencer, Annelie Everts-van der Wind and Thierry Dervieux

Pharmaceutics 2023, 15(10), 2408; https://doi.org/10.3390/pharmaceutics15102408 - 30 Sep 2023

Cited by 2 | Viewed by 1326

Abstract

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 [...] Read more.

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 (p < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance (p < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = −19.2; p < 0.001), and the combination of both further minimized OFV (p < 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. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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11 pages, 1088 KiB

Open AccessArticle

Therapeutic Drug Monitoring of Anti-TNFα Inhibitors: A Matter of Cut-Off Ranges

by Stefania Cheli, Diego Savino, Francesca Penagini, Gianvincenzo Zuccotti, Giovanna Zuin, Emilio Clementi and Dario Cattaneo

Pharmaceutics 2023, 15(7), 1834; https://doi.org/10.3390/pharmaceutics15071834 - 27 Jun 2023

Cited by 2 | Viewed by 1462

Abstract

Therapeutic drug monitoring (TDM) is a useful tool for optimising the use of anti-TNFα inhibitors in patients with inflammatory bowel diseases (IBDs). Recently, point-of-care methods for the quantification of drug levels and anti-drug antibodies (ADAs) have been developed to overcome the limitations of [...] Read more.

Therapeutic drug monitoring (TDM) is a useful tool for optimising the use of anti-TNFα inhibitors in patients with inflammatory bowel diseases (IBDs). Recently, point-of-care methods for the quantification of drug levels and anti-drug antibodies (ADAs) have been developed to overcome the limitations of conventional enzyme-linked immunoabsorbent assays (ELISAs). Here, we evaluated the performance, interchangeability, and agreement between an automated ELISA-based immunoassay (CHORUS Promonitor) and the lateral flow assay (RIDA^®QUICK) for the quantification of infliximab (IFX, n = 65) and adalimumab (ADM, n = 58) plasma levels in IBD patients. Thirty-two samples for IFX and twenty-three samples for ADM that tested positively for the presence of ADAs were also used. Overall, data analysis showed a good agreement of ADM trough concentrations (R² = 0.75) between the two assays as well as for ADA measurement (K > 0.8). However, IFX levels highlighted a weak correlation (R² = 0.58) between the two kits, with the RIDA^®QUICK assay overestimating IFX plasma values by 30% when compared to the CHORUS Promonitor kit. Results from this study show that the two assays are not quantitatively and qualitatively interchangeable due to substantial discrepancies in some results. Accordingly, the same assay should be used for the longitudinal follow-up of IBD patients. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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14 pages, 1765 KiB

Open AccessArticle

Optimization of a Quantitative Anti-Drug Antibodies against Infliximab Assay with the Liquid Chromatography-Tandem Mass Spectrometry: A Method Validation Study and Future Perspectives

by Erin H. Smeijsters, Kim C. M. van der Elst, Amy Visch, Camiel Göbel, Floris C. Loeff, Theo Rispens, Alwin D. R. Huitema, Matthijs van Luin and Mohsin El Amrani

Pharmaceutics 2023, 15(5), 1477; https://doi.org/10.3390/pharmaceutics15051477 - 12 May 2023

Cited by 1 | Viewed by 2666

Abstract

Monoclonal antibodies (mAbs), such as infliximab, are important treatment options for different diseases. Immunogenicity is a major risk, resulting in anti-drug antibodies (ADAs), being associated with adverse events and loss of response, influencing long-term outcomes. The development of ADAs against infliximab is primarily [...] Read more.

Monoclonal antibodies (mAbs), such as infliximab, are important treatment options for different diseases. Immunogenicity is a major risk, resulting in anti-drug antibodies (ADAs), being associated with adverse events and loss of response, influencing long-term outcomes. The development of ADAs against infliximab is primarily measured by immunoassays like radioimmunoassay (RIA). Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) is increasingly utilized across different fields, this technique is currently not used for ADAs against infliximab measurements. Therefore, we developed the first LC-MS/MS method. Stable isotopically labeled infliximab antigen-binding fragments (SIL IFX F(ab’)₂) were used to bind and measure ADAs indirectly. Protein A magnetic beads were used to capture IgG, including ADAs, whereafter SIL IFX F(ab’)₂ was added for labeling. After washing, internal standard addition, elution, denaturation and digestion samples were measured by LC-MS/MS. Internal validation showed good linearity between 0.1 and 16 mg/L (R² > 0.998). Sixty samples were used for cross-validation with RIA, and no significant difference between ADA concentrations was found. The methods had high correlation (R = 0.94, p < 0.001) and excellent agreement, intraclass correlation coefficient = 0.912 (95% confidence interval 0.858–0.947, p < 0.001). We present the first ADA against the infliximab LC-MS/MS method. The method is amendable for quantifying other ADAs, making it applicable as a template for future ADA methods. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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11 pages, 1781 KiB

Open AccessArticle

Therapeutic Drug Monitoring of Vedolizumab in Inflammatory Bowel Disease Patients during Maintenance Treatment—TUMMY Study

by Merve Sivridaş, Rob H. Creemers, Dennis R. Wong, Paul J. Boekema, Tessa E. H. Römkens, Lennard P. L. Gilissen, Adriaan A. van Bodegraven, Floris C. Loeff, Theo Rispens and Luc J. J. Derijks

Pharmaceutics 2023, 15(3), 972; https://doi.org/10.3390/pharmaceutics15030972 - 17 Mar 2023

Cited by 3 | Viewed by 2179

Abstract

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure–response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim [...] Read more.

There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure–response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn’s disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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Review

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24 pages, 372 KiB

Open AccessReview

Personalized Use of Disease-Modifying Therapies in Multiple Sclerosis

by Chi-Yan Lee and Koon-Ho Chan

Pharmaceutics 2024, 16(1), 120; https://doi.org/10.3390/pharmaceutics16010120 - 17 Jan 2024

Cited by 9 | Viewed by 2601

Abstract

Multiple sclerosis is an important neurological disease affecting millions of young patients globally. It is encouraging that more than ten disease-modifying drugs became available for use in the past two decades. These disease-modifying therapies (DMTs) have different levels of efficacy, routes of administration, [...] Read more.

Multiple sclerosis is an important neurological disease affecting millions of young patients globally. It is encouraging that more than ten disease-modifying drugs became available for use in the past two decades. These disease-modifying therapies (DMTs) have different levels of efficacy, routes of administration, adverse effect profiles and concerns for pregnancy. Much knowledge and caution are needed for their appropriate use in MS patients who are heterogeneous in clinical features and severity, lesion load on magnetic resonance imaging and response to DMT. We aim for an updated review of the concept of personalization in the use of DMT for relapsing MS patients. Shared decision making with consideration for the preference and expectation of patients who understand the potential efficacy/benefits and risks of DMT is advocated. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

17 pages, 678 KiB

Open AccessReview

Interpreting the Benefit and Risk Data in Between-Drug Comparisons: Illustration of the Challenges Using the Example of Mefenamic Acid versus Ibuprofen

by André Farkouh, Margit Hemetsberger, Christian R. Noe and Christoph Baumgärtel

Pharmaceutics 2022, 14(10), 2240; https://doi.org/10.3390/pharmaceutics14102240 - 20 Oct 2022

Cited by 5 | Viewed by 9873

Abstract

Evidence-based pain therapy should rely on precisely defined and personalized criteria. This includes balancing the benefits and risks not only of single drugs but often requires complex between-drug comparisons. Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for several decades and their use is [...] Read more.

Evidence-based pain therapy should rely on precisely defined and personalized criteria. This includes balancing the benefits and risks not only of single drugs but often requires complex between-drug comparisons. Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for several decades and their use is described in an abundance of guidelines. Most of these guidelines recommend that ‘the selection of a particular NSAID should be based on the benefit-risk balance for each patient’. However, head-to-head studies are often lacking or of poor quality, reflecting the lower standards for clinical research and regulatory approval at the time. The inconsistency of approved indications between countries due to national applications adds to the complexity. Finally, a fading research interest once drugs become generic points to a general deficit in the post-marketing evaluation of medicines. Far from claiming completeness, this narrative review aimed to illustrate the challenges that physicians encounter when trying to balance benefits and risks in a situation of incomplete and inconsistent data on longstanding treatment concepts. Ibuprofen and mefenamic acid, the most frequently sold NSAIDs in Austria, serve as examples. The illustrated principles are, however, not specific to these drugs and are generalizable to any comparison of older drugs in daily clinical practice. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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