Compounding and quality control of two pediatric topiramate pharmaceutical preparations.

In pediatric wards, topiramate is prescribed as an antiepileptic at non-licensed dosages. Compounding is the best way to obtain topiramate drug adapted to pediatric patients, but this practice requires to control the quality of batches and to manage a stability study to establish a beyond-use-date. With this objective, 6 mg. mL 1 topiramate oral suspension and 9 mg capsules were realized, and our laboratory was mandated for their quality control. Previously described dosing methods did not allow us to determine topiramate content in prescribed preparations. An original HPLC-UV derivatization dosing method of topiramate was validated and was proved to be stability indicating. This derivatization methodology, but also total aerobic microbial count (TAMC) and total combined yeasts and mold count (TYMC) allowed the quality control of topiramate capsules and topiramate suspension. Beyond-use-dates can be attributed with regards to United States Pharmacopoeia recommendations, and a stability study was performed on 6 mg. mL-1 topiramate suspension to confirm empirical data. Topiramate pediatric suspension was found to be stable for two months at +2/+8 °C, one month after opening and one day at ambient temperature.

Monitoring topiramate concentrations at delivery and during lactation.

OBJECTIVE: To determine transplacental passage of topiramate and its transport to colostrum, mature maternal milk and breastfed infants, we examined data from 27 women treated with topiramate from 2004 to 2020. METHODS: In this cohort study, maternal serum, umbilical cord serum, milk and infant serum levels were measured by gas chromatography in the delivery subgroup, the colostrum subgroup (3-4 days postpartum) and the mature milk subgroup (7-30 days postpartum). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk levels were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum and infant/maternal serum levels. RESULTS: Topiramate levels varied from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum, and the mean umbilical cord/maternal serum ratio was 0.93 ± 0.11. At 3-4 days after delivery, topiramate concentrations were 1.4-8.4 mg/L in maternal serum, 1.5-8.6 mg/L in milk and 0.3-4.4 mg/L in infant serum. The mean milk/maternal serum ratio was 0.99 ± 0.45, and the mean infant/maternal serum ratio was 0.25 ± 0.15. At 7-30 days after delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. The mean milk/maternal serum ratio was 1.07 ± 0.31, and the mean infant/maternal serum ratio was 0.51 ± 0.27. CONCLUSIONS: We extended information about free transplacental passage of topiramate and its extensive transport to maternal milk with lower serum concentrations in breastfed infants in the largest group of patients ever reported to our knowledge. DATA AVAILABILITY STATEMENT: Authors declare that take full responsibility for the data, the analyses and interpretation, and the conduct of the research; that they have full access to all of the data; and that they have the right to publish all data. Authors were not participations in industry-sponsored research and corporate activities for evaluation of a manuscript.

Simultaneous determination of barbiturates, phenytoin and topiramate in hair by LC-MS/MS and application to real samples.

INTRODUCTION: Hair analysis is useful for monitoring exposure to drugs such as antiepileptics owing to long-term therapy and a high possibility of abuse of drugs, which could be fatal. An effective and rapid analytical method for the simultaneous determination of six barbiturates, as well as phenytoin and topiramate in hair samples was developed and validated by liquid-chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Three different extraction methods were investigated for the development of an appropriate analytical method. Hair was finely cut and then extracted with methanol, methanol containing 1% hydrochloric acid, and liquid-liquid extraction in acidic condition. RESULTS: There was no significant difference in the matrix effects among these three methods. Recoveries clearly declined in the extraction involving both acidic methanol extraction and a LLE in acidic condition. Methanol incubation was chosen as the appropriate extraction method with acceptable matrix effects and recoveries. After validating the methanol incubation, the limit of detection (LOD) and limit of quantification (LOQ) were determined as 0.01 and 0.02 ng/mg for topiramate and 0.25-0.5 and 0.5-1 ng/mg for the others in hair. The LC-MS/MS method was precise and accurate with a dynamic linear range of 0.02-5 ng/mg for topiramate and 0.5 or 1-50 ng/mg for others. This method was applied to authentic hair samples of two drug users. The hair concentrations of phenobarbital were 0.2-17.1 ng/mg in segmental analysis in one female subject and those of topiramate were 0.19-0.93 ng/mg in another female subject. DISCUSSION: The quantitative method was developed to determine 8 antiepileptics using LC-MS/MS. This method performed hair segmental analysis to provide useful informative and chronological data in both of the forensic and clinical toxicology fields.

Sensitive detection of topiramate degradation products by high-performance liquid chromatography/electrospray ionization mass spectrometry using ion-pairing reagents and polarity switching.

RATIONALE: The chromatographic analysis of topiramate and its degradation products is challenging due to the absence of chromophoric moieties in their structures, the wide polarity range of the compounds and their ionization differences. This work proposes two new mass spectrometry approaches for evaluating these analytes. METHODS: Based on the calculated experimental limit of detection (LOD), a highly sensitive high-performance liquid chromatography (HPLC) paired-ion electrospray ionization mass spectrometry (PIESI-MS) method was developed for the determination of topiramate inorganic degradation products. The influence of different solvent systems on the LODs for topiramate and its main degradation products was determined in both positive/negative ionization modes. In addition, a HPLC method to analyze both organic and inorganic degradation products was proposed by mass spectrometry with positive/negative ion switching electrospray ionization. RESULTS: A sensitive HPLC/PIESI-MS method was achieved for the efficient separation of topiramate inorganic degradation products. Both sulfate and sulfamate were detected in the positive selected ion monitoring (SIM) mode with an increased sensitivity compared with the negative SIM mode. The HPLC/ESI-MS analysis with positive/negative ion switching allowed the simultaneous separation and detection of the major degradation products of topiramate in a 10-min run using a single column and a single detector. CONCLUSIONS: Two new alternative MS approaches for analyzing the main degradation products of topiramate were developed. The proposed methods are considered advantageous over the existing methods and can be applied to quality control studies of topiramate.