scholarly journals Closed-loop Neuropharmacology for Epilepsy: Distant Dream or Future Reality?

2019 ◽  
Vol 17 (5) ◽  
pp. 447-458
Author(s):  
Irene Aicua-Rapun ◽  
Pascal André ◽  
Jan Novy
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Disease Activity ◽  
Drug Monitoring ◽  
Closed Loop ◽  
Therapeutic Drug ◽  
Efficient Treatment ◽  
Treatment Regimens ◽  
Epilepsy Treatment ◽  
Monitoring Treatment ◽  
Potential Biomarkers

Epilepsy is considered the most frequent severe neurological condition but most patients treated with medication become seizure free. The management of treatment, however, is highly empirical, mainly relying on observation. A closed-loop therapy for epilepsy would be very valuable for more efficient treatment regimens. Here we discuss monitoring treatment (therapeutic drug monitoring) and the potential developments in this field, as well as providing a review of potential biomarkers that could be used to monitor the disease activity. Finally, we consider the pharmacogenetic input in epilepsy treatment.

Management of Chronic Myelogenous Leukemia Using Therapeutic Drug Monitoring of Imatinib: The French Experience of a Centralized Laboratory

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3222-3222
Author(s):  
Mathieu Molimard ◽  
Stephane Bouchet ◽  
Gabriel Etienne ◽  
Laurence Legros ◽  
Delphine Rea ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Therapeutic Drug Monitoring ◽  
Sex Ratio ◽  
Chronic Myelogenous Leukemia ◽  
Drug Monitoring ◽  
Individual Variability ◽  
Myelogenous Leukemia ◽  
Therapeutic Drug ◽  
Efficient Treatment ◽  
Trough Plasma

Abstract Pharmacokinetic monitoring is widely used in different medical specialities, but it has been rarely applied in clinical oncology practice. The current gold standard treatment of chronic myelogenous leukemia (CML) is imatinib, a tyrosine kinase inhibitor. We have previously shown the necessity to obtain a trough plasma threshold of 1000 ng/mL for efficient treatment with imatinib. We routinely perform centralized quantification for patients in France and this has allowed the assessment of imatinib therapeutic monitoring and its use in a real-life setting. After 16 months of data collection, we had gathered 1607 samples for 1044 CML patients (mean age 55 years, F/M sex ratio 0.67) treated with imatinib 400 mg (median) range (100–800mg). We received only one sample for 739 patients and more than one sample for 305 patients. The mean trough plasma concentration of imatinib (Cmin) was 1043 ng/mL (median: 876 ng/mL) and 596 of the 1044 CML patients (57%) had a Cmin <1000ng/ml at first determination. Plasma concentration increased with dose, but there was a large inter-individual variability (64%) and intra-individual variability was twice as small. For plasma concentrations < 1000 ng/mL, mean dose was 420 mg and for those ≥ 1000 ng/mL, this was 510 mg. For the 189 patients having had at least 2 correct Cmin determination, 70% had initial Cmin< 1000 ng/mL (mean concentration of 1st determination: 583 ng/mL). Among the 62 patients who initially had a Cmin below 1000 ng/mL that subsequently rose above this threshold, 63% had their imatinib dose increased; the rest did not have a dose modification. For the latter, it is probable in view of low intra-individual variability that this was due to enhanced compliance. For the 32 patients with a first Cmin <1000 and no CCyR, none of those with Cmin remaining below 1000 ng/mL achieved CCyR, wheras 5 (28%) achieved CCyR when Cmin rose above 1000 ng/mL. In cases where there was suspicion of a drug–drug interaction, the most frequently combined drugs were proton pump inhibitors (such as omeprazole), diuretics, allopurinol and NSAIDs. The most recurrent adverse effects were digestive, hematological and muscular. Although the studied population had characteristics generally described for this pathology (age, sex ratio), there was probably selection bias at the beginning of study: we received first and foremost the patients having an insufficient response, and therefore low plasma concentration. Therapeutic drug monitoring of imatinib appears to be helpful for the management of CML patients and the resulting database allows a better understanding and use of this treatment.

MicroRNAs as novel biomarkers for rivaroxaban therapeutic drug monitoring

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Eric Rytkin ◽  
Irina V. Bure ◽  
Pavel O. Bochkov ◽  
Kristina A. Akmalova ◽  
Karin B. Mirzaev ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
High Performance ◽  
Allelic Variant ◽  
Therapeutic Drug ◽  
Nonvalvular Atrial Fibrillation ◽  
Expression Levels ◽  
Micro Rnas ◽  
Potential Biomarkers

Abstract Objectives The aim of this study is to assess micro-RNAs miR-142 and miR-39 as potential biomarkers for drug-monitoring of rivaroxaban among elderly patients with atrial fibrillation. Methods The study involved 57 patients with median (ME) age 87 years [80–94 years old] with nonvalvular atrial fibrillation admitted to a multidisciplinary hospital in Moscow. High-performance liquid chromatography with mass-spectrometry detection (HPLC-MS) was carried out to measure rivaroxaban concentrations. Carriership of CYP3A4 and ABCB1 was detected. MiRNA expression levels were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of 6β-hydroxycortisol and cortisol. Results The miR-142 expression levels of patients with CC allelic variant polymorphism ABCB1 3435 C>T (rs1045642) were significantly higher compared to CT and TT variants 31.69 ± 1.60 vs. 34.06 ± 1.66 vs. 33.16 ± 1.77 (p=0.021). Carriers of TT allelic variant polymorphism ABCB1 rs4148738 had a higher concentration of the 6-beta-hydroxycortisol in urine compared to CC and CT variants 3,467.35 ± 1,055.53 vs. 3,453.52 ± 1,516.89 vs. 2,593.30 ± 1,172.52 (p=0.029). As for CYP3A4*22, the carriers of CC allelic variant had higher prothrombin time 14.10 ± 2.17 vs. 11.87 ± 0.60 and INR 1.31 ± 0.20 vs. 1.1 ± 0.06 but lower Quick’s value 74.52 ± 16.84 vs. 97.55 ± 10.54 (p=0.059). A positive correlation between the Ct miR-142 and the aPTT p=0.019 was noted. Also miR-142 has a correlation with Quick’s value p=0.095. There is no statistically significant connection between miR-142 and miR-39 expression levels and the plasma concentration of rivaroxaban (b coefficient=−2.055, SE 3.952, p=0.605 and b coefficient=1.546, SE 9.887, p=0.876 in the linear regression model respectively). Conclusions This study has assessed new potential biomarkers for rivaroxaban therapeutic drug monitoring: miR-142 and miR-39.

scholarly journals P441 Clinical efficacy, drug sustainability and results from therapeutic drug monitoring in Crohn’s disease patients treated with ustekinumab – 1-year follow-up of a prospective, nationwide, multicenter cohort from Hungary

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S441-S441
Author(s):  
L Gonczi ◽  
K Szanto ◽  
K Farkas ◽  
T Molnar ◽  
T Szamosi ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Therapeutic Drug Monitoring ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Clinical Efficacy ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Disease Phenotype ◽  
Dose Intensification

Abstract Background Although efficacy and safety of ustekinumab (UST) in the treatment of inflammatory bowel disease have been demonstrated through randomized trials, data from real-life prospective cohorts are still of great interest. Our aim was to evaluate the clinical efficacy, drug sustainability, frequency of dose intensification, and results from therapeutic drug monitoring in UST treated Crohn’s disease (CD) patients using a prospective, nationwide, multicenter cohort from Hungary. Methods Patients were consecutively enrolled in this cohort between 2019 January and 2020 May from 5 academic centers and 5 county hospitals. Data from patient demographics, disease phenotype, treatment history (surgical history, prior and present medical therapies), clinical disease activity (using the Crohn’s Disease Activity Index (CDAI), Harvey Bradshaw Index (HBI)), biomarkers (C-reactive protein – CRP), and therapeutic drug monitoring were captured. Evaluations were performed at week8 (post-induction), w16-20, w32-36, and w52-56 follow-up visits. Results N=142 CD patients were included with a median follow-up time of 60 weeks (IQR:47.5–79.5w) [57.4% female; age 38.4±13.0 years]. Based on the Montreal classification, complicated disease behavior (B2orB3) was 48.2%, whereas ileocolonic disease location(L3) 55.7%. Perianal manifestation was present in 46.8% of the patients. Previous anti-TNF exposition was 97.2%, while previous vedolizumab failure was 25.5%. 66.2%/ 66.9% of the patients had moderate-to-sever clinical disease activity at baseline (CDAI>220/HBI>7). Clinical response and remission rates were 78.1% and 57.7% using CDAI, and 82.5% and 51.8% based on HBI scores after induction treatment (w8). One year clinical remission rates were 58% / 57.3% (CDAI/HBI) Composite clinical and biomarker remission (CDAI<150 and CRP<10mg/L) rates were 35.4%; 33.3%; 38.6% and 36.6% at w8/w16-20/w32-36 and w52-56. Parallel corticosteroid use was 34%/26.3%/16.5%/21%/16.9% at baseline and w8/w16-20/w32-36/w52-56. Drug sustainability was high with 81.9% (SD: 3.4) of patients remaining on treatment at one year.(Figure1) Probability of dose intensification was high and introduced early in the treatment, 42.2% (SD: 4.2) at ~w32 and 51.9% (SD: 4.4%) at 1y.(Figure2) Patients with complex disease phenotype (B2/B3) had higher probability for dose intensification (log-rank: p=0.042). Mean serum trough levels of UST were 4,28±3,35/ 1,35±1,42/ 0,82±0,65 and 1,13±0,74µg/mL measured at w8/w16-20/w32-36 and w52-56. ADAs were exceeding 1AU/mL in only 2 patients. Conclusion Ustekinumab showed good drug sustainability and clinical efficacy in a population with severe disease phenotype and high rates of previous anti-TNF failure, however frequent and early dose intensification was required.

scholarly journals P428 Early and Late Fecal Calprotectin Remission - Analysis of a proactive Therapeutic Drug Monitoring Treatment Protocol

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S432-S432
Author(s):  
J Pedro ◽  
I Rodrigues ◽  
F Damião ◽  
S Fernandes ◽  
A R Gonçalves ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Clinical Outcomes ◽  
Drug Monitoring ◽  
Clinical Remission ◽  
Treatment Protocol ◽  
Surrogate Marker ◽  
Fecal Calprotectin ◽  
Therapeutic Drug ◽  
Monitoring Treatment

Abstract Background Fecal calprotectin (Fc) is an adequate surrogate marker for endoscopic activity in inflammatory bowel disease. The timing of Fc remission may have prognostic implications in patients under biologic therapy. Methods Using a prospectively maintained database we followed 135 patients under a proactive therapeutic drug monitoring (pTDM) protocol aiming at an Infliximab trough level (IFXTL) between 5-10 µg/mL with sequential measurements of Fc. We evaluated the rates of early (at week 14) and late (after week 14) Fc remission (<250 µg/g) and associated clinical outcomes at 2-years of follow up. Results 77 patients (57.0%) reached early Fc remission and 30 patients (22.2%) reached late Fc remission. Patients with late Fc remission presented higher Fc at baseline (1708.5 μg/g [681-3483] vs 803 μg/g [339-1477], P=0.006) and lower IFXTL at week 14 (2.71 µg/mL [1.24-6.30] vs 6.59 µg/mL [3.41-10.63], P=0.001) than patients with early Fc remission. However, by the end of follow-up, IFXTL were similar in both groups: 7.94 µg/mL (4.79-11.25) vs 8.54 µg/mL (6.49-11.07), P=0.514. In patients without early Fc remission, week 14 IFXTL did not differ between those with and without late Fc remission (2.71 µg/mL [1.24-6.30] vs 3.47 µg/mL [0.945-6.94], P=0.957), but significantly increased in late responders by the end of follow-up: 8.54 µg/mL (6.49-11.07) vs 4.37 µg/mL (1.77-7.49), P=0.002. Patients with early and late Fc remission presented similar rates of clinical remission (88.3% vs 83.0%, P=0.493), steroid-free clinical remission (79.1% vs 92.9% P=0.239), lower rates of IFX discontinuation (14.3% vs 16.7%, P=0.756), hospitalization (11.7% vs 13.3%, P=0.815), and surgery (1.3% vs 3.3%, P=0.485). Conclusion The magnitude of Fc at baseline and IFXTL at week 14 significantly influence the timing of Fc remission. The use of PTDM results in similar pharmacokinetics and clinical outcomes in both groups.

Diagnose und Monitoring bei chronisch-entzündlicher Darmerkrankung

2018 ◽  
Vol 75 (5) ◽  
pp. 316-328
Author(s):  
Christian Ansprenger ◽  
Emanuel Burri
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Morbus Crohn ◽  
Therapeutic Drug ◽  
Körperliche Untersuchung

Zusammenfassung. Die Diagnose und auch die Überwachung von chronisch entzündlichen Darmerkrankungen ruht auf mehreren Säulen: Anamnese, körperliche Untersuchung, Laborwerte (im Blut und Stuhl), Endoskopie, Histologie und Bildgebung. Die Diagnose kann nicht anhand eines einzelnen Befundes gestellt werden. In den letzten Jahren hat sich das Therapieziel weg von klinischen Endpunkten hin zu endoskopischen und sogar histologischen Endpunkten entwickelt. Für einige dieser neuen Therapieziele existiert allerdings noch keine allgemein gültige Definition. Regelmässige Endoskopien werden von Patienten schlecht toleriert, weshalb Surrogat-Marker wie Calprotectin untersucht wurden und eine gute Korrelation mit der mukosalen Entzündungsaktivität nachgewiesen werden konnte. Entsprechend zeigte sich bei Morbus Crohn eine Algorithmus-basierte Therapiesteuerung – unter anderem basierend auf Calprotectin – einer konventionellen Therapiesteuerung überlegen. Die Überwachung der medikamentösen Therapie («Therapeutic Drug Monitoring» [TDM]) ist ein zweites Standbein des Monitoring von chronisch entzündlichen Darmerkrankungen. Mit zunehmendem Einsatz vor allem der Biologika-Therapien wurden sowohl reaktives TDM (in Patienten mit klinischem Rezidiv) als auch proaktives TDM (in Patienten in Remission / stabiler Erkrankung) untersucht und haben (teilweise) Eingang in aktuelle Richtlinien gefunden. Zukünftige Studien werden die vorgeschlagenen Therapieziele besser definieren und den Nutzen der medikamentösen Therapieüberwachung auf den Krankheitsverlauf weiter untersuchen müssen.

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