0895 Pharmacokinetics of pitolisant in breast milk and serum of healthy lactating women

Abstract

Abstract Introduction Pitolisant is a potent and highly selective histamine-3-receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. A phase 4, open-label study was conducted to evaluate the pharmacokinetics (PK) of pitolisant and its major metabolite, BP1.3484, in breast milk and serum following a single dose of pitolisant administered to healthy lactating women. Methods In this study, eight healthy lactating women (aged 22-42 years) who met eligibility criteria were enrolled and received a single oral dose of pitolisant (35.6 mg). Serial breast milk samples were collected at pre-dose on Day 1 and at various intervals through 24 hours post-dose. Serial blood samples for PK analyses were collected at pre-dose and through 120 hours post-dose. Since the total infant dosage calculated from single dose data may be under-estimated, steady-state serum concentrations were predicted using noncompartmental methods and then multiplied by the 24-hour breast milk:serum ratio (AUCBM/S) to estimate a more appropriate total infant dose. Results Pitolisant was excreted in breast milk, with mean CmaxBM/S and AUCBM/S ratios of 85.2% and 123%, respectively. Concentrations of pitolisant in breast milk were only slightly lower than concentrations in serum. However, since the volume of breast milk was low, the percentage of the maternal dose expressed in breast milk was very low. Steady state calculations for a 6-month-old infant resulted in a mean total infant dosage of 0.005 mg/kg/day (SD 0.002), which is 1.15% of the maternal dose. For BP1.3484, maternal exposure and the calculated mean daily infant exposure were much lower than pitolisant. All subjects completed the study as planned. Five subjects (62.5%) reported a total of 8 treatment-emergent adverse events, which were mild in severity and resolved by end of the study. Conclusion Pitolisant is present in human milk, but the mean daily infant dosage in a 6-month-old infant after steady-state dosing of pitolisant in healthy lactating women was estimated to be very low. Overall, a single oral dose of pitolisant 35.6 mg was well-tolerated in healthy lactating women. Support (if any) The study was sponsored by Harmony Biosciences LLC.