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

Abstract

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.

Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function

“…Furthermore, Xie et al's model demonstrated nonlinear binding categorized under target-mediated drug disposition, which was more pronounced in children with renal impairment. 28 Limitation of this study is that we did not study the influence of morning vs. evening administration of the drug, neither on PK/PD characteristics, although some authors claim the superiority of evening administration in adults. 19,50 Main limitations of our analysis were primarily due to the sparsity of the data collected and the limited number of patients enrolled.…”

“…25 Furthermore, 3 physiologically based PK (PBPK) models have been published, primarily utilizing adult data. [26][27][28] One of these models incorporates peptide-1 transporter efflux found in the duodenum and jejunum, while another model takes into account intestinal peptide 1 through mRNA expression. 27,28 The FDA recommends paediatric dosing of lisinopril based on limited studies, with an initial dose ranging from 0.08 to 0.1 mg kg À1 /day up to a maximum of 5 mg day À1 or a maximum of 0.6 mg kg À1 day À1 for children older than 6 years.…”

“…[26][27][28] One of these models incorporates peptide-1 transporter efflux found in the duodenum and jejunum, while another model takes into account intestinal peptide 1 through mRNA expression. 27,28 The FDA recommends paediatric dosing of lisinopril based on limited studies, with an initial dose ranging from 0.08 to 0.1 mg kg À1 /day up to a maximum of 5 mg day À1 or a maximum of 0.6 mg kg À1 day À1 for children older than 6 years. European guidelines suggest an initial dose ranging from 0.05 mg kg À1 day À1 up to a maximum of 0.2 mg kg À1 for all age categories.…”

“…Additionally, the study did not account for factors such as compliance and the need for dose escalations 25 . Furthermore, 3 physiologically based PK (PBPK) models have been published, primarily utilizing adult data 26–28 . One of these models incorporates peptide‐1 transporter efflux found in the duodenum and jejunum, while another model takes into account intestinal peptide 1 through mRNA expression 27,28 …”

Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward

“…Kim et al., assuming involvement of novel transporters at the intestinal level, developed the PBPK model for bilastine (Kim et al., 2021). Other transporters, such as (peptide transporter 1) PEPT1 and (plasma membrane monoamine transporter) PMAT, were also being modeled, as they play a vital role for intestinal absorption of drugs such as cefadroxil, lisinopril, and metformin (Tan et al., 2021; Xie et al., 2021; Yang et al., 2021). Intestinal carnitine/organic cation transporter 2 and mono‐carboxylate transporter protein 1 that are distributed in gastrointestinal tract and brain are being explored, as they may aid in targeted drug delivery (Guo et al., 2020; Wang, Zhao, et al., 2020).…”