P347 Undetectable levels of adalimumab in clinical practice: Should we say goodbye to the drug?

Abstract Background Therapeutic drug monitoring (TDM) is used in inflammatory bowel disease to guide dosing of biologics to individualise drug exposure and optimise outcomes. In case of undetectable levels of Adalimumab (levels <1.6 μg/ml) some authors recommend to discontinue the treatment, although this strategy is not universally accepted. The aim of this study was to describe the evolution (recovery of levels and persistence of treatment) of patients with undetectable levels of ADA and its relationship with the different treatment strategies (dose escalation and/or addition of an immunosuppressant) Methods Since October 13 to August 19, 758 TDM were performed in 260 patients treated with ADA. We selected the patients who had at least a level <1.6 μg / ml. Patients with follow-up fewer than 90 days after level detection and those in whom the drug was withdrawn at that time were excluded Results We identified 46 patients with undetectable levels; 12 were excluded. Thirty-four patients were included, 29 (85.3%) with Crohn’s disease and 5 (14.7%) with ulcerative colitis. Ten (29.4%) patients had combined treatment and 17 (50%) had previously received another anti-TNF. In 24 (70.6%) TDM was performed proactively. After detection of levels <1.6 μg /ml, ADA was intensified in 20 patients (58.8%) either shortening the interval in 18 (90%), increasing the dose in 8 (40%) or with both interventions in 6 (30%). In 5 (14.7%) patients an immunomodulator was added and in 14 (41.2%) the treatment was not modified. At the end of the follow-up (mean 1101 days; SD 510) 61.8% (21/34) of the patients continued with ADA: 75% (15/20) in the intensified group and 42.9% (6/14) in the group of those who did not receive changes in treatment. Fourteen patients (41. 2%) recovered therapeutic levels (>5 μg/ml), 12 (60%) in the intensified-patient group and 2 (14.3%) in the group in whom the treatment was not modified. ADA was withdrawn in 13 patients (32.8%) after a mean time of 358 days (SD 258). The ADA maintenance rate (HR=3.88; 95% CI 1.2–12.4; p = 0.02) and the recovery ratio of ADA levels (HR = 6.75; 95% CI 1.1–39, 8; p = 0.03) was higher in the intensified group. Hypoalbuminemia was associated with an earlier withdrawal of ADA (p = 0.03) Conclusion The intensification of ADA in patients with IBD and undetectable plasma concentrations allows recovery of levels and maintenance of the drug in a high percentage of patients. The decision to withdraw treatment in patients with undetectable levels should be individualised.

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Abstract 14134: The Impact of Ablation for Atrial Fibrillation on Dementia Incidence in Patients With and Without Depression

Circulation ◽

10.1161/circ.142.suppl_3.14134 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Heidi T May ◽

Tami L Bair ◽

Stacey Knight ◽

Jeffrey L Anderson ◽

Joseph B Muhlestein ◽

...

Keyword(s):

Atrial Fibrillation ◽

Treatment Strategies ◽

Brain Perfusion ◽

Cardiovascular Comorbidities ◽

Incident Dementia ◽

History Of ◽

The Impact ◽

Mean Time ◽

History Of Depression

Introduction: Studies have previously shown that atrial fibrillation (AF) is associated with dementia. The mechanisms are likely multifactorial, but may involve treatment strategies that include anticoagulation use and rhythm management, particularly when used early. Patients that have earlier-life depression are at risk of dementia. However, depression diagnosis in AF patients may indicate a patient at higher risk of developing dementia and whether treatments ameliorate that risk is unknown. Methods: A total of 132,703 AF patients without a history of dementia were studied. History of depression was determined at the time of AF diagnosis. Patients were deemed as having a follow-up ablation if it occurred prior to a dementia diagnosis. Patients were stratified into 4 groups based on depression history and follow-up ablation status: no depression, ablation (n=5,960); no depression, no ablation (n=106,986); depression, ablation (n=923); and depression, no ablation (n=18,834). Patients were followed for 5-year incidence of dementia. Results: A total of 14.9% (n=19,757) pts had a history of depression at the time of AF diagnosis. The mean time between depression and AF diagnoses was 4.9±4.8 years. Patients with depression were younger (68±15 vs. 71±14 years), more likely to be female (62% vs. 44%), and had more cardiovascular comorbidities. Mean time to ablation was 1.3±1.4 days (median: 7.7 months) from AF diagnosis. Frequencies of 5-year dementia were: no depression, ablation=1.6%; no depression, no ablation=5.2%; depression, ablation=4.7%; and depression, no ablation=9.7%, p<0.0001. Multivariable comparisons between the groups are shown in the Figure. Conclusion: In AF patients with and without depression, ablation was associated with a lower risk of incident dementia. Rhythm control approaches that improve long-term brain perfusion may represent a means to impact cognitive declines in patients at higher risk because of earlier-life depression.

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P346 Single-centre experience of ustekinumab: Therapeutic drug monitoring in Crohn’s disease patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.475 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S331-S333

Author(s):

C Liefferinckx ◽

M Fassin ◽

D Thomas ◽

C Minsart ◽

A Cremer ◽

...

Keyword(s):

Crohn’S Disease ◽

Therapeutic Drug Monitoring ◽

Crohn's Disease ◽

Median Time ◽

Real World ◽

Drug Monitoring ◽

Drug Exposure ◽

Therapeutic Drug ◽

Loss Of Response

Abstract Background Therapeutic drug monitoring (TDM) is a diagnostic tool in the monitoring of anti-TNF therapies. Yet, the benefit for TDM of new biologics such as ustekinumab (USK) is still controversial in real-world experiences. Methods This monocentric retrospective study aims to correlate USK trough levels (TLs) with clinical and endoscopic data. All patients have given written consent to the Biobank (B2011/005). Endoscopic disease was defined as quiescent in absence of endoscopic lesions, mild disease in presence of few superficial ulcerations, moderate in presence of several ulcers and severe in presence of numerous deep ulcers and/or inflammatory stenosis. 313 serum USK samples from 67 Crohn’s disease patients were used to measure USK TL (USK ELISA, apDia) while 88 samples (at week 16, and before and after optimisation) were used to measure anti-drug antibody (ADA), using a drug-tolerant affinity capture elution anti-ustekinumab assay Results Demographic and baseline data of our population are presented in Table 1. The median follow-up was 73 weeks (IQR 39–92). An optimisation due to loss of response was required in 44.8% of patients (n = 30) after a median time of 38 weeks (IQR 24–55). To evaluate the drug efficacy, an endoscopy was performed in 61% of cases at a median time of 35 weeks (IQR 27–47). TLs were 5.2 µg/ml (IQR 2.1–8.8), 1.7 µg/ml (IQR 0.3–4.3) and 2.6 µg/ml (IQR 0.6–4.1) at week 8, 16 and 24, respectively. TLs at week 8 were correlated to the induction IV dose administrated (r = 0.3, p = 0.03). At week 16, low TLs were associated with higher endoscopic activity in the follow-up (p = 0.02), although this was not the case at week 8 (p = 0.5) (Figure 1). Patients not requiring an optimisation had higher TLs in maintenance than patients requiring optimisation (2.45 µg/ml (IQR 1.3–4.4) vs. 1.15 µg/ml (IQR 0.1–2.24), p = 0.008). Obviously, optimisation significantly increased TLs (1.15 µg/ml (IQR 0.1–2.24) vs. 6.6 µg/ml (IQR 2.3–11.3), p < 0.001). ADA were undetectable in all the measured samples in maintenance. Conclusion This real-world experience confirms a drug exposure-endoscopic response relationship. Week 16 seems to be an appropriate time point to monitor drug exposure. Earlier USK TLs, at week 8, appear less valuable to be monitored due to the influence of initial IV dose. The absence of immunogenicity suggests that it is not a key driver in the loss of response.

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Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02462-17 ◽

2018 ◽

Vol 62 (6) ◽

Cited By ~ 3

Author(s):

Charalampos Antachopoulos ◽

Stavroula Ilia ◽

Paschalis Kadiltzoglou ◽

Eirini Baira ◽

Aristides Dokoumetzidis ◽

...

Keyword(s):

Critically Ill ◽

Drug Exposure ◽

Pediatric Patients ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Burn Patients ◽

Time Curve ◽

Once Daily ◽

Concentration Time ◽

Optimal Drug

ABSTRACT The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) of plasma concentrations on day 1 ranged between 123.8 to 663.9 μg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

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Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01034-17 ◽

2017 ◽

Vol 61 (12) ◽

Cited By ~ 33

Author(s):

Amit V. Desai ◽

Laura L. Kovanda ◽

William W. Hope ◽

David Andes ◽

Johan W. Mouton ◽

...

Keyword(s):

Steady State ◽

Invasive Aspergillosis ◽

Filamentous Fungi ◽

Aspartate Aminotransferase ◽

Drug Exposure ◽

Fungal Infections ◽

Plasma Concentrations ◽

Water Soluble ◽

Therapeutic Drug ◽

Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

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P277 Frequency and effectiveness of empirical anti-TNF dose intensification in Inflammatory Bowel Disease: systematic review with meta-analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.402 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S309-S309

Author(s):

L Guberna Blanco ◽

O P Nyssen ◽

M Chaparro ◽

J P Gisbert

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Medical Condition ◽

Cochrane Library ◽

Therapeutic Drug ◽

Dose Intensification ◽

Loss Of Response ◽

Subgroup Analyses ◽

Inflammatory Bowel

Abstract Background Loss of response to anti-TNF (tumor necrosis factor) therapies in inflammatory bowel disease occurs in a high proportion of patients. However, the precise incidence of dose intensification (DI) and its effectiveness remains unclear. Our aims were: 1) To evaluate the need of DI of anti-TNF therapy either by increasing the dose or decreasing doses’ interval; 2) To evaluate possible variables influencing its requirement; 3) To assess the effectiveness of empirical DI. Methods Bibliographical searches were performed in Pubmed, Embase, the Cochrane Library and CINAHL. Selection: prospective and retrospective studies assessing loss of response to anti-TNF therapy, considered as the need of DI, in Crohn’s disease (CD) and ulcerative colitis (UC) patients treated for at least 12 weeks with an anti-TNF drug [infliximab (IFX), adalimumab (ADA), certolizumab or golimumab]. Exclusion criteria: studies using anti-TNF as prophylaxis for postoperative recurrence in CD or those where DI was based on therapeutic drug monitoring. Data synthesis: Effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (UC vs. CD), anti-TNF drug and follow-up. Subgroup analyses were performed to explore heterogeneity. Results In total, 174 studies (32,031 patients) were included. The overall rate of DI requirement after 12 months follow-up was 27% (95%CI 23-31, I2=96%, 51 studies) in naïve patients and 38% (95%CI 31-46, I2=87%, 18 studies) in non-naïve patients. The rate of DI requirement was higher in patients with prior anti-TNF exposure (c²=6.5, P=0.01) and in UC patients (c²=4.7, P=0.03). The rate of DI requirement in naïve patients after 36 months follow-up was 35% (95%CI 27-43%; I2=98%; 22 studies). The overall short-term response and remission rates to empirical DI in naïve patients were 66% (95%CI 61-71%; I2=81%; 35 studies) and 48% (95%CI 35-62%; I2=97%; 27 studies), respectively. Subgroup analyses are presented in the tables. Conclusion Loss of response to anti-TNF agents ―and consequent DI― occur frequently in IBD (approximately in 1/4 at one year and in 1/3 at 3 years). DI requirement is higher in UC patients and in those with prior anti-TNF exposure. Empirical DI is a relatively effective therapeutic option.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v2 ◽

2019 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

Abstract Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.

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Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Cancers ◽

10.3390/cancers13246281 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6281

Author(s):

Anna Mc Laughlin ◽

Eduard Schmulenson ◽

Olga Teplytska ◽

Sebastian Zimmermann ◽

Patrick Opitz ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Anticancer Drugs ◽

Drug Monitoring ◽

Drug Exposure ◽

Plasma Concentrations ◽

Blood Sampling ◽

Therapeutic Drug ◽

Study Phase ◽

Blood Samples ◽

Drug Concentrations

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v3 ◽

2020 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

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P093 IDENTIFICATION OF PATIENTS AT RISK OF SUBTHERAPEUTIC DRUG EXPOSURE PRIOR TO INITIATION OF CERTOLIZUMAB PEGOL THERAPY FOR THE TREATMENT OF CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.177 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S69-S70

Author(s):

Pavine Lefevre ◽

Leonardo Guizzetti ◽

Brian Feagan ◽

Anca Pop ◽

Mohamed Yassine ◽

...

Keyword(s):

At Risk ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Drug Exposure ◽

Certolizumab Pegol ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Clinical Variables ◽

Therapy Initiation ◽

Patients At Risk

Abstract Background Certolizumab pegol (CZP) is effective treatment for moderately-to-severely active Crohn’s disease (CD)1, 2 at approved subcutaneous doses of 400 mg on weeks 0, 2 and 4 (induction) and every 4 weeks thereafter (maintenance). Prior research has demonstrated a relationship between CZP drug exposure and outcomes, with higher plasma CZP concentrations during induction and maintenance therapy associated with more favorable clinical, endoscopic and biologic (C-reactive protein [CRP], fecal calprotectin [FC]) disease outcomes.3 Increased drug clearance is the driver of subtherapeutic CZP concentrations, although the identification of patients at risk for accelerated clearance prior to therapy initiation has not previously been possible. Methods A population pharmacokinetic model4 was used to estimate baseline CZP clearance (i.e., at the time of therapy initiation) using baseline clinical variables (i.e., gender, body weight, albumin and CRP concentration) available from patients with CD previously included in nine randomized, controlled, phase 2 and 3 trials (N=2157). Baseline CZP clearance was compared between patients who achieved observed Week 6 CZP plasma concentrations previously associated with meaningful clinical (>36 μg/mL for Crohn’s Disease Activity Index [CDAI] ≤ 150), biologic (>44 μg/mL for FC ≤ 250 μg/g) and composite clinical and biologic (>48 μg/mL for CDAI ≤ 150 and FC ≤ 250 μg/g) outcomes at Week 6. Receiver operating characteristic curve analysis identified baseline CZP clearance thresholds associated with effective CZP concentrations at Week 6. Results Baseline CZP clearance was significantly higher in patients not achieving effective Week 6 CZP plasma concentration thresholds of 36 μg/mL, 44 μg/mL and 48 μg/mL compared to patients who achieved these thresholds (Figure 1; p<0.0001 for all comparisons). Baseline CZP CL of ≥ 0.5 L/day was associated with subtherapeutic observed Week 6 CZP plasma concentrations. The sensitivity, specificity, likelihood ratios and area under the concentration curves for the association between baseline CZP clearance and observed Week 6 CZP concentration thresholds are shown in Table 1. Conclusion Patients with CD who have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Clearance can be calculated using baseline clinical variables and would allow for identification of patients for whom therapeutic CZP concentrations may be achieved with current approved dosing. Implementing therapeutic drug monitoring may increase the likelihood of achieving therapeutic drug exposure during induction as well as treatment success. References

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Advantages of everolimus therapeutic drug monitoring in oncology when drug–drug interaction is suspected: A case report

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220904761 ◽

2020 ◽

Vol 26 (7) ◽

pp. 1743-1749 ◽

Cited By ~ 1

Author(s):

Geoffrey Strobbe ◽

Diane Pannier ◽

Ilyes Sakji ◽

Alexandre Villain ◽

Frédéric Feutry ◽

...

Keyword(s):

Drug Interaction ◽

Case Report ◽

Therapeutic Drug Monitoring ◽

Drug Interactions ◽

Drug Monitoring ◽

Plasma Concentrations ◽

Response To Treatment ◽

Therapeutic Drug ◽

High Doses

Introduction Drug interactions involving everolimus are fairly well known because of its common use, primarily as an immunosuppressant. Several recommendations regarding therapeutic drug monitoring are also available for the use of everolimus-based immunosuppression regimens. However, everolimus use in oncology differs substantially, particularly because of the high doses involved. Therapeutic drug monitoring, although sometimes necessary, is not recommended as a routine in oncology. Thus, it was deemed inapplicable due to the lack of clear recommendations. Case report Here, we present a case where a patient was prescribed everolimus for renal cell carcinoma. The patient benefitted from a pharmaceutical consultation prior to treatment initiation, and a drug interaction with verapamil was suspected. Management and outcome: Therapeutic drug monitoring of everolimus was proposed. Based on the everolimus values reported in the literature, trough plasma concentration in the patient was greatly increased. The patient was then diagnosed with grade 4 oral mucositis, thereby requiring temporary suspension of everolimus treatment. Management of adverse effects was performed through multiple medicated mouthwashes. Discussion Therapeutic drug monitoring for everolimus is important for potential drug interactions or the occurrence of severe adverse events. In such cases, dose adjustments should be managed according to everolimus plasma concentrations. Clear oncological recommendations regarding plasma everolimus thresholds are required for a successful follow-up of the patient’s condition and to ensure adequate response to treatment.

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