P28 Pharmacokinetics and implications for drug dosing in children with sickle cell disease: a systematic review
BackgroundChildren with sickle cell disease (SCD) are at high risk of intractable pain and severe infections despite early and aggressive drug treatment. SCD is a multisystemic disease potentially leading to liver and renal dysfunction. Altogether, those may lead to pharmacokinetic (PK) alterations, which may contribute to therapeutic failure or drug toxicity. We performed a systematic literature review to describe the current evidence on the effect of SCD on drug disposition in children.MethodsA systematic literature search was conducted by a librarian on 5 databases until 08.2018 and independently assessed by two reviewers. All full-text articles, containing PK data in children, were included. The reported differences in PK parameters between SCD and non-SCD children were examined.ResultsAmong 4213 retrieved abstracts, 50 full-text articles were assessed and 27 studies were included (13 exclusively children). Data on 15 drugs was available from which 5 were exclusively developed for SCD (impeding any comparison). From the remaining 10 drugs, a comparison of PK parameters was available in 8. Six were investigated in adults and children. Three (37.5%) showed significant PK alterations (morphine, cefotaxime,lidocaine) while 5 did not (hydroxyurea, sulfadoxine-pyrimethamine, methadone, rofecoxib,arginine butyrate). In children with SCD, clearance was higher by 42–61% for IV morphine, and by 24–62% for cefotaxime, compared with non-SCD controls. This difference led to a new dosing recommendation only for cefotaxime (400 mg/kg/day). Hepatic drug metabolism assessed by lidocaine was impaired in children with SCD compared to healthy controls.ConclusionSCD alters drug disposition of commonly used drugs but data is scarce. A significant increase in clearance of morphine and cefotaxime, two commonly used drugs in patients with SCD, suggests that recommended doses may not be sufficient to provide adequate analgesia and antimicrobial control. PK data is urgently needed to ensure adequate drug efficacy and safety in this high-risk population.ReferencesDong M, McGann PT, Mizuno T, et al. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Brit J Clin Pharmacol. 2016;81:742–52.Gremse DA, et al. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998;132:989–93.Dampier CD, et al. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.Kopecky EA, et al. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004;75:140–6.Maksoud E, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother. 2018;62: e00637–1.Disclosure(s)Nothing to disclose