Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers

Abstract

A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open‐label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed‐effect modeling. The plasma maximal concentrations (Cmax) showed striking nonlinear disposition of sultiame, with a 10‐fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two‐compartment model with first‐order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results.

Development and validation of an LC–MS/MS method for relevant drugs in epilepsy patients using dried blood spots

“…The mean ratio of 2.15 ± 0.78 for zonisamide concurs with the data by D'Urso et al (2.7 ± 0.8; D'Urso, Rudge, et al, 2019) and is also supported by the b/p ratio. For sultiame, to the best of our knowledge, no comparison data between DBS and serum samples are published so far, but it is described that this compound has a strong affinity for erythrocytes (Dao et al, 2020) so that the higher concentrations in DBS seem entirely plausible. For stiripentol, there is neither any comparison data nor information regarding the b/p ratio available, and also during our study period only two sample pairs were received.…”

Pharmacokinetic Drug–Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients

“…Data calculated using non-compartmental pharmacokinetic analysis showed that plasma clearance decreased several folds with increasing dose (after 50, 100 and 200 mg and amounted to 40.4, 11.7 and 8.3 L/h) (Table 1). Bioavailability after oral administration was complete and the protein binding was low [65].…”

“…CBZ, PRM and PHT increase the elimination of STM. Antacids with magnesium oxide or magnesium trisilicate and bismuth oxycarbonate decrease GI absorption of STM and, in consequence, decrease plasma levels of STM [19,65]. Serum PHT levels have been shown to increase when STM is added to PHT therapy.…”

New Methods Used in Pharmacokinetics and Therapeutic Monitoring of the First and Newer Generations of Antiepileptic Drugs (AEDs)

“…Interactions CBZ and PRM, PHT increase the elimination of STM. Antacids with magnesium and bismuth decrease gastrointestinal (GI) absorption [38,42]. Therapeutic reference range 2-10 mg/L (5-35 µmol/L) was established for STM [4].…”