Precision therapy for epilepsy due to KCNT1 mutations

ObjectiveTo evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1.MethodsA single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial.ResultsProlonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3–5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10–18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval −1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction.ConclusionQuinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks.Clinical trials registrationAustralian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151).Classification of evidenceThis study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.

Serum Quinidine Concentrations and Effect on QT Dispersion and Interval

OBJECTIVE: To establish a relationship between serum quinidine concentrations (SQCs) and QT interval dispersion, compared with corresponding QT intervals, in order to identify a reason why many reports describe torsade de pointes as occurring at subtherapeutic concentrations. DESIGN: Retrospective study. SETTING: University teaching hospital. PARTICIPANTS: Eleven patients with atrial arrhythmias managed with quinidine therapy. MAIN OUTCOME MEASURES: Patients with subtherapeutic (<2 μg/mL) and therapeutic (2–5 μg/mL) SQCs with corresponding 12-lead electrocardiograms (ECGs) (25 mm/sec) and baseline ECG were evaluated for QT interval dispersion, calculated as the maximum minus the minimum QT interval on the 12-lead ECG. RESULTS: Mean ± SD subtherapeutic and therapeutic SQCs were 1.48 ± 0.39 μg/mL and 3.78 ± 0.88 μg/mL (p < 0.001). Baseline values for QT/QTc intervals were 376.4 ± 59.2/429.5 ± 57.3 msec. At subtherapeutic and therapeutic SQCs, mean QT/QTc intervals were 403.6 ± 59.9/450.5 ± 38.5 msec and 439.1 ± 48.9/472.4 ± 44.6 msec, respectively. Mean QT dispersion was 47 ± 16.2 msec at baseline, 98.2 ± 27.5 msec at subtherapeutic SQC, and 70.9 ± 33.9 msec at therapeutic SQCs (p = 0.001 for overall analysis; p < 0.001 for baseline vs. subtherapeutic concentrations; p = NS for therapeutic vs. subtherapeutic in post hoc comparison). CONCLUSIONS: Despite QT interval lengthening with increasing SQCs, QT dispersion was numerically greatest at subtherapeutic SQCs. Further study is required to determine the value of QT dispersion as a tool for identifying proarrhythmic risk with drugs that prolong the QT interval.

Comparison of Assay Procedures Used to Measure Total and Unbound Concentrations of Quinidine

Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03 · HPLC +0.96, r=0.93;EMIT= 1.08 · HPLC + 0.38, r=0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT + 35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11 · QFF(E) + 0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 ± 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations. The EMIT procedure on average produces acceptable error for the measurement of total quinidine concentrations; however, errors greater than 100 percent do occur. Thus, caution should be used when interpreting the results of the EMIT procedure. For determining unbound concentrations the EMIT produces unacceptable error and the HPLC method should be used to obtain reliable estimates of free quinidine concentrations.

Serum Quinidine Determination: Comparison of Mass-Spectrometric and Extraction-Fluorescence Methods

A comparison of two analytical methods of quinidine plasma determination—the modified extraction fluorometric method and the mass spectrometric method—was made. Plasma supplies collected at steady state from normal human volunteers participating in a bioavailability study were analyzed, using both methods. A total of 359 samples were analyzed. Comparison of both sets of values, by linear regression, yielded an r2 value of 0.84. The results of this comparison were consistent with the results reported by others, confirming that the commonly used extraction fluorometric method of quinidine determination is sufficiently accurate for monitoring quinidine plasma concentrations in the patient care setting, as well as for bioavailability comparisons between products.