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Background: Progesterone belongs to a class of neurosteroids used for the reduction of seizure frequency in patients with refractory epilepsy. However, the pharmacokinetics of progesterone and its active derivative, allopregnanolone, have never been studied in these patients. Objectives: This study was aim to explore the pharmacokinetic parameters of progesterone 400 mg every 12 h, for 3 months, in patients with refractory epilepsy as an add-on therapy to control seizures. Phoenix® WinNonlin® was used to analyse the pharmacokinetic parameters. Results: Twelve patients were recruited. From a therapeutic drug monitoring, the serum progesterone and allopregnanolone levels after taking the first dose of progesterone were characterised by a time to maximum concentration (Tmax) median of 1 and 2.5 h, a maximum concentration (Cmax) median of 274.97 and 3.81 ng/mL, and a minimum concentration (Cmin) median of 56.93 and 1.06 ng/mL, respectively. The median values of the pharmacokinetic parameters of progesterone and allopregnanolone during the steady state were as follows: t1/2 of 2.4 and 2.0 h, Cmax of 964.35 and 8.92 ng/mL, and Cmin of 64.67 and 1.86 ng/mL, respectively. By examining the relationship between the progesterone or allopregnanolone concentrations with seizure-controlling ability, we could identify a responder patient group with 6- to 7-fold higher serum concentrations of progesterone and allopregnanolone than the non-responders. Conclusions: We could establish higher serum levels of both progesterone and allopregnanolone, which could consequently relate to lowering the seizure frequency in patients with refractory epilepsy. The suggested progesterone dose was 400 mg orally every 12 h against refractory epilepsy Trial registration: This study has been registered on the Thai Clinical Trials Registry (No. TCTR20200710005, 10 July 2020)

Background: We aimed to study the efficacy and safety of allopregnanolone which convert from oral micronized progesterone as an adjunctive treatment for Thai patients with refractory status epilepticus.Methods: Adults 18–80 years old who diagnosed with either convulsive or non-convulsive refractory status epilepticus receiving standard AED treatment, intravenous midazolam, for longer than 60 minutes were included. The intervention group received Utrogestran® (micronized progesterone, 200 mg/capsule) via enteric feeding every 8 h for five days. Treatments for RSE were continuing along the clinical trial period. Serum allopregnanolone levels were measured by radioimmunoassay (DetectX® Allopregnanolone Immunoassay Kit; Arbor Assays, Michigan, United States). Control patients were randomly selected from our hospital RSE cohort during 2015–2019. Continuous data were presented as the mean and standard deviation. Discrete data were assessed by number and percentage. The changes in laboratories were analyzed by paired t-test. The difference between groups were compared by independent sample t-test. The Mann-Whitney U test, Chi-square test or Fisher’s exact test were used for non-parametric parameters. A p-value < 0.05 indicated statistical significance. All analyses were performed using SPSS version 26 software (IBM Corp., Armonk, NY).Results: The average duration of refractory status epilepticus after treatment with midazolam plus progesterone (intervention group) and without progesterone until status epilepticus termination was 25.5 and 58.4 hours, (p = 0.004), indicated that allopregnanolone significantly shortens the refractory status epilepticus duration in vivo.Conclusions: Allopregnanolone, produced from oral micronized progesterone, demonstrates efficacy and safety in treating refractory status epilepticus as an adjunctive treatment.Trial registration: This trial was registered in Thai Clinical Trials Registry (TCTR) database. The trial registration number was “TCTR20200717002”, 16 July 2020, retrospectively registered.