title: Clinical utility of topiramate extended-release capsules (USL255): Bioequivalence of USL255 sprinkled and intact capsule in healthy adults and an in vitro evaluation of sprinkle delivery via enteral feeding tubes.
abstract: OBJECTIVE
  The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinkled onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes.
  
  
  METHODS
  Bioequivalence of 200-mg USL255 (Qudexy XR [topiramate] extended-release capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N=36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 0.80 and 1.25, AUC and Cmax were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg/15 mL-25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested.
  
  
  RESULTS
  Area under the curve and Cmax for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC0-t 1.01 [0.97-1.04], AUC0-∞ 1.02 [0.98-1.05]; Cmax 1.09 [1.03-1.14]). Median Tmax was 4h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p=0.0018), and t1/2 was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus deionized water. Recovery of USL255 beads diluted in deionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr J-tubes.
  
  
  CONCLUSIONS
  For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once-daily option for taking topiramate. USL255 beads were also successfully delivered in vitro through ≥14-Fr G- or J-tubes, with tube clogging minimized by portioning the dose and using glidant diluents for smaller tubes.
authors.affiliation: Upsher-Smith Laboratories, Inc., Maple Grove, MN, United States. Electronic address: Annie.Clark@upsher-smith.com.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Clark
authors.affiliation: Virginia Commonwealth University, Division of Child Neurology, Richmond, VA, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Pellock
authors.affiliation: Upsher-Smith Laboratories, Inc., Maple Grove, MN, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Holmay
authors.affiliation: Upsher-Smith Laboratories, Inc., Maple Grove, MN, United States.
authors.forename: Bob
authors.initials: B
authors.lastname: Anders
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, United States.
authors.forename: James
authors.initials: J
authors.lastname: Cloyd
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004750:Enteral Nutrition; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D002214:Capsules; D003692:Delayed-Action Preparations; D000077236:Topiramate; D005632:Fructose
keywords: Antiepileptic drug; Bioequivalence; Epilepsy; Feeding tubes; Qudexy XR; Sprinkle