title: Safety and pharmacokinetics of oral lansoprazole in preadolescent rats exposed from weaning through sexual maturity.
abstract: Proton pump inhibitors, the reference standard in adults with acid-related disorders, are increasingly being used in children despite limited pediatric safety and pharmacokinetic data. This study evaluated these parameters in rats aged 21-60 days, which approximately correlates with children aged 2-11 years. Lansoprazole at doses of 0, 5, 15, 50, or 150 mg/kg per day was administered to Sprague-Dawley rats from weaning through sexual maturity. Safety assessments included clinical, neurobehavioral, ophthalmologic, and gender-specific developmental milestones, clinical pathology including urinalysis, organ weight (at necropsy), and histopathologic evaluation. Blood samples for pharmacokinetics were collected on the first and last days of treatment. After the end of dosing, decreases in body weight gain, serum total protein and albumin (males), and microcytic hypochromic anemia were observed at doses of > or =50mg/kg per day, and hypoglycaemia (females) at 150 mg/kg per day. Selected groups exhibited increases in absolute and relative duodenal and stomach weights (> or =15 mg/kg per day), decreases in absolute and relative thymus weights (> or =50 mg/kg per day), increased relative liver weights (> or =50 mg/kg per day), and chronic adhesions to the spleen (> or =15 mg/kg per day). No other changes were observed. The area under the curve values in 60-day-old rats was less than those observed in 21-day-old rats. Areas under the curve values for lansoprazole were higher in female than male 60-day-old rats. No unexpected signs of toxicity were observed in the current preadolescent rats relative to those observed in adult rats in previous studies. The NOEL in preadolescent rats was similar to adults and gives a safety margin of one- to five-fold relative to the pediatric dose (0.87 mg/kg in 2-11-year-olds). These results provide comparative evidence for the value of studies in rats to support safety in a pediatric population.
authors.affiliation: Department of Drug Safety, TAP Pharmaceutical Products, Inc, 675 North Field Dr, Lake Forest, IL 60045, USA. ashraf.yousse@tap.com
authors.forename: Ashraf F
authors.initials: AF
authors.lastname: Youssef
authors.forename: Pat
authors.initials: P
authors.lastname: Turck
authors.forename: Farrel L
authors.initials: FL
authors.lastname: Fort
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000747:Anemia, Hypochromic / Q000139:chemically induced; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007003:Hypoglycemia / Q000139:chemically induced; D064747:Lansoprazole; D023421:Models, Animal; D019055:No-Observed-Adverse-Effect Level; D009853:Omeprazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects* / Q000502:physiology; D014886:Weaning
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D012709:Serum Albumin; D064747:Lansoprazole; D009853:Omeprazole