Population and Noncompartmental Pharmacokinetics of Sodium Oxybate Support Weight‐Based Dosing in Children and Adolescents With Narcolepsy With Cataplexy

Abstract

The pharmacokinetics (PKs) of sodium oxybate (SXB) was evaluated in a subset of participants from a study of SXB treatment in children (aged 7–11 years; n = 11) and adolescents (aged 12–17 years; n = 18) with narcolepsy with cataplexy. PK evaluation was conducted over 2 nights during the period when participants received a stable nightly SXB dose. The SXB dose on night 1 was half of night 2 and was administered in two equally divided doses: dose 1 was administered > 2 hours after the evening meal, and dose 2 was administered ≥ 4 hours after dose 1. Noncompartmental PK analysis demonstrated higher plasma concentrations post‐dose 2 vs. post‐dose 1, higher than dose‐proportional increases in area under the concentration‐time curve from 0 to 4 hours (AUC0–4h) after dose 1, indicating nonlinear clearance, and better correlation between exposure and mg/kg than exposure and gram dose. To confirm the noncompartmental findings, identify factors affecting SXB PK, and compare with prior results in adults, a population PK (PopPK) model was established combining PK data from the current study with prior data from adults (132 healthy volunteers and 13 with narcolepsy). A two‐compartment PopPK model with first‐order absorption and nonlinear clearance from the central compartment described the data well. PopPK identified weight as the main intrinsic factor and food as the main extrinsic factor affecting SXB PK, and predicts similar PK profiles on a mg/kg basis across ages. These results, along with previously reported efficacy and safety outcomes, support weight‐based SXB dose initiation in pediatric patients.

Calcium, Magnesium, Potassium, and Sodium Oxybates Oral Solution: A Lower-Sodium Alternative for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy

“… 20 The PK properties of SXB also were determined to be similar in both adults and children with narcolepsy based on 2 additional PK studies. 94 , 95 A population PK model previously developed to support the SXB pediatric regulatory filing was then adapted to include data from LXB 95 ; this model identified that weight was the major contributing factor to oxybate PK for both SXB and LXB, and showed that a similar dose-exposure relationship existed for SXB and LXB in both adult and pediatric participants with narcolepsy.…”

Pharmacokinetics, bioavailability, and bioequivalence of lower‐sodium oxybate in healthy participants in two open‐label, randomized, crossover studies

“…4 The safety and efficacy of SXB for the treatment of cataplexy and EDS in adults and children/adolescents with narcolepsy have been established in randomized controlled trials; commonly observed adverse events included nausea and vomiting. [5][6][7][8][9] The therapeutic effects of SXB in narcolepsy are hypothesized to be mediated through effects at gamma-aminobutyric acid B (GABA B ) receptors on noradrenergic, dopaminergic, and thalamocortical neurons. 4 SXB is administered orally as a solution, diluted before ingestion with 60 mL water, with the total nightly dose typically divided into 2 doses, the first at bedtime and the second 2.5-4 hours later.…”

“…In pediatric patients, dosing is based on weight, with an effective dose range of 3–9 g/night 4,5 . The pharmacokinetics (PK) of SXB has been characterized in adult and pediatric populations 6 . SXB is rapidly absorbed (average time to reach maximum plasma concentration [T max ], 0.5–1.25 h) and quickly metabolized and eliminated from the body (average half‐life, 0.5–1 h) 4 .…”

“…4 , 5 The pharmacokinetics (PK) of SXB has been characterized in adult and pediatric populations. 6 SXB is rapidly absorbed (average time to reach maximum plasma concentration [T max ], 0.5–1.25 h) and quickly metabolized and eliminated from the body (average half‐life, 0.5–1 h). 4 Dosing recommendations include the instruction to allow 2 h after eating before dosing due to the known effect of food, which causes a reduction in exposure with administration immediately following ingestion of a high‐fat meal, compared with the fasted state.…”

“…SXB is approved in the United States for cataplexy or EDS in patients greater than or equal to 7 years of age with narcolepsy 4 . The safety and efficacy of SXB for the treatment of cataplexy and EDS in adults and children/adolescents with narcolepsy have been established in randomized controlled trials; commonly observed adverse events included nausea and vomiting 5–9 . The therapeutic effects of SXB in narcolepsy are hypothesized to be mediated through effects at gamma‐aminobutyric acid B (GABA B ) receptors on noradrenergic, dopaminergic, and thalamocortical neurons 4…”