Physiologically based pharmacokinetic modelling of lisinopril in children: A case story of angiotensin converting enzyme inhibitors

AIMS: Lisinopril is an angiotensin converting enzyme inhibitor to treat hypertension. It shows complex pharmacokinetics (PK), and its PK behaviour in paediatric populations is not well characterized. The aim of this study was to develop a physiologically based PK (PBPK) model for lisinopril to describe the drug's PK in children. METHODS: The PBPK model development was performed in a step-wise manner. An adult model was initially developed to characterize lisinopril's disposition and absorption and verified using literature data. Subsequently, the adult PBPK model was extrapolated to the paediatric population (0.5-18 years old) by accounting for age-dependent physiological and anatomical changes. Model performance was evaluated by comparing the PK profiles and drug exposures of observed vs predicted data. RESULTS: The disposition of lisinopril was well described by a minimal PBPK model-an effective strategy to capture the biphasic elimination of the drug. The absorption of lisinopril was described by the intestinal peptide transporter-mediated uptake. The adult model adequately described the literature data with predictions within a twofold range of clinical observations. Good model predictivity was also observed in children older than 6 years of age. The model overpredicted the drug exposure in children under 6 years, probably due to not incorporating the actual, unknown ontogeny of the intestinal peptide transporter. CONCLUSIONS: The PBPK model predicted the PK of lisinopril in adults and children above 6 years of age well. Model refinement in children under 6 years warrants future informative ontogeny data of the intestinal peptide transporter.