Case Report of Novel Genetic Variant in KCNT1 Channel and Pharmacological Treatment With Quinidine. Precision Medicine in Refractory Epilepsy

Case introduction: In this work we present a female infant patient with epilepsy of infancy with migrating focal seizures (EIMFS). Although many pharmacological schemes were attempted, she developed an encephalopathy with poor response to antiepileptic drugs and progressive cerebral dysfunction.Aim: To present the pharmacological response and therapeutic drug monitoring of a paediatric patient with a severe encephalopathy carrying a genetic variant in KCNT1 gene, whose identification led to include quinidine (QND) in the treatment regimen as an antiepileptic drug.Case report: Patient showed slow rhythmic activity (theta range) over left occipital areas with temporal propagation and oculo-clonic focal seizures and without tonic spasms three months after birth. At the age of 18 months showed severe impairments of motor and intellectual function with poor eye contact. When the patient was 4 years old, a genetic variant in the exon 24 of the KCNT1 gene was found. This led to the diagnosis of EIMFS. Due to antiepileptic treatment failed to control seizures, QND a KCNT1 blocker, was introduced as a therapeutic alternative besides topiramate (200 mg/day) and nitrazepam (2 mg/day). Therapeutic drug monitoring (TDM) of QND plasma levels needed to be implemented to establish individual therapeutic range and avoid toxicity. TDM for dose adjustment was performed to establish the individual therapeutic range of the patient. Seizures were under control with QND levels above 1.5 mcg/ml (65–70 mg/kg q. i.d). In addition, QND levels higher than 4.0 mcg/ml, were related to higher risk of suffering arrhythmia due to prolongation of QT segment. Despite initial intention to withdrawal topiramate completely, QND was no longer effective by itself and failed to maintain seizures control. Due to this necessary interaction between quinidine and topiramate, topiramate was stablished in a maintenance dose of 40 mg/day.Conclusion: The implementation of Precision Medicine by using tools such as Next Generation Sequencing and TDM led to diagnose and select a targeted therapy for the treatment of a KCNT1-related epilepsy in a patient presented with EIMFS in early infancy and poor response to antiepileptic drugs. QND an old antiarrhythmic drug, due to its activity as KCNT1 channel blocker, associated to topiramate resulted in seizures control. Due to high variability observed in QND levels, TDM and pharmacokinetic characterization allowed to optimize drug regimen to maintain QND concentration between the individual therapeutic range and diminish toxicity.

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Optimum Use of Therapeutic Drug Monitoring and Pharmacokinetics-Pharmacodynamics in the NICU

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-14.2.66 ◽

2009 ◽

Vol 14 (2) ◽

pp. 66-74

Author(s):

Peter Gal

Keyword(s):

Drug Therapy ◽

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Therapeutic Range ◽

Drug Monitoring ◽

Population Based ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Patient Response ◽

Drug Concentrations

Therapeutic drug monitoring is increasingly giving way to dosing drugs based on population-based pharmacokinetic parameters, even when pharmacokinetic values vary quite a bit in individual patients. Further, drug concentrations are often considered appropriate if they are within a defined therapeutic range, even if the patient response is suboptimal. This lecture discusses the limitations of therapeutic ranges in neonates, and proposes greater emphasis on pharmacodynamic curves to individualize drug therapy. Examples are provided using methylxanthines, indomethacin, antiepileptic drugs and aminoglycosides. The potential to use pharmacokinetic findings to describe physiologic changes and occasionally assist with diagnosis is also discussed.

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DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report

Pharmaceutics ◽

10.3390/pharmaceutics11050199 ◽

2019 ◽

Vol 11 (5) ◽

pp. 199 ◽

Cited By ~ 9

Author(s):

Theodore J. Wigle ◽

Elena V. Tsvetkova ◽

Stephen A. Welch ◽

Richard B. Kim

Keyword(s):

Case Report ◽

Therapeutic Drug Monitoring ◽

Precision Medicine ◽

Drug Monitoring ◽

Dihydropyrimidine Dehydrogenase ◽

Systemic Exposure ◽

Standard Of Care ◽

Hepatic Metabolism ◽

Relevant Information ◽

Therapeutic Drug

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

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1 Case report: Major depression and Therapeutic Drug Monitoring in patient with CYP2C19 genetic polymorphism

10.1055/s-0040-1710109 ◽

2020 ◽

Author(s):

I Adamovic ◽

S Michaelis ◽

F Streit ◽

L Binder ◽

D Degner

Keyword(s):

Case Report ◽

Genetic Polymorphism ◽

Major Depression ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Therapeutic Drug

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Feasibility of Using Oral Fluid for Therapeutic Drug Monitoring of Antiepileptic Drugs

European Journal of Drug Metabolism and Pharmacokinetics ◽

10.1007/s13318-020-00661-1 ◽

2021 ◽

Author(s):

Morgan Patrick ◽

Samuel Parmiter ◽

Sherif Hanafy Mahmoud

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

Oral Fluid ◽

Therapeutic Drug

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Therapeutic Drug Monitoring of Antiepileptic Drugs in a Tertiary Care Hospital in India

Clinical Neuropharmacology ◽

10.1097/wnf.0000000000000057 ◽

2015 ◽

Vol 38 (1) ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Natarajan Harivenkatesh ◽

Natarajan Haribalaji ◽

Darling Chellathai David ◽

C. M. Prabu Kumar

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Therapeutic Drug ◽

Care Hospital

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Pharmacist-Provider Immunosuppression Collaborative Practice Agreement for Post-Transplant Therapeutic Drug Monitoring Increases Time in Therapeutic Range

Transplantation and Cellular Therapy ◽

10.1016/s2666-6367(21)00595-9 ◽

2021 ◽

Vol 27 (3) ◽

pp. S458

Author(s):

Cameron Ninos ◽

Sydney Stiener ◽

Lauren McGinty ◽

Larissa Hacker ◽

Mark B. Juckett

Keyword(s):

Therapeutic Drug Monitoring ◽

Therapeutic Range ◽

Drug Monitoring ◽

Collaborative Practice ◽

Therapeutic Drug ◽

Post Transplant ◽

Time In Therapeutic Range ◽

Collaborative Practice Agreement

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Therapeutic Drug Monitoring of Second- and Third-Generation Antiepileptic Drugs: Insights From a College of American Pathologists Proficiency Testing Survey

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2020-0562-cp ◽

2021 ◽

Author(s):

Matthew D. Krasowski ◽

Thomas A. Long ◽

Christine L. H. Snozek ◽

Annabel Dizon ◽

Barbarajean Magnani ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Proficiency Testing ◽

Drug Monitoring ◽

First Generation ◽

Therapeutic Drug ◽

Third Generation ◽

Enzyme Immunoassays ◽

Steady Growth ◽

Survey Results

Context.— Therapeutic drug monitoring has traditionally been widely used for first-generation antiepileptic drugs (AEDs) such as carbamazepine and phenytoin. The last 2 decades have seen the introduction of second- and third-generation AEDs (eg, lamotrigine, levetiracetam, and topiramate) into clinical practice. Objective.— To use data from the College of American Pathologists Therapeutic Drug Monitoring, Extended proficiency testing survey to determine the performance of assays used for therapeutic drug monitoring of newer AEDs, including comparison of enzyme immunoassay and chromatographic techniques. Design.— Six years of proficiency testing surveys were reviewed (2013–2018). Results.— Steady growth was seen in participant volumes for newer AEDs. The analytical performance of automated enzyme immunoassays for lamotrigine, levetiracetam, and topiramate was similar to that of chromatographic methods, consistent with published literature using patient samples for comparisons. The majority of participating laboratories now use enzyme immunoassays to measure levetiracetam. Conclusions.— Survey results reflect steadily growing interest in therapeutic drug monitoring of newer AEDs. The increasing availability of robust immunoassays for new AEDs should facilitate their clinical utility, especially for clinical laboratories that do not perform chromatographic assays for therapeutic drug monitoring.

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