title: Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva.
abstract: OBJECTIVE
  Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups.
  
  
  METHODS
  Tailored assays were developed for pharmacokinetic investigation of a drug in 100 μL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point.
  
  
  RESULTS
  The pharmacokinetic results of aliskiren and enalapril obtained by low-volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin-angiotensin-aldosterone system and to compare those results with the published literature.
  
  
  CONCLUSIONS
  These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy.
authors.affiliation: Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Bjoern B
authors.initials: BB
authors.lastname: Burckhardt
authors.affiliation: Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Tins
authors.affiliation: Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Ramusovic
authors.affiliation: Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Läer
keywords: aliskiren; child; enalapril; enalaprilat; pharmacokinetics; renin-angiotensin system; saliva