Extensive review of pharmacokinetic and pharmacodynamic properties of ace-inhibitors and angiotensin receptor blockers in children with renal impairment

Abstract

Background/Aims: Childhood hypertension is affecting around 2 to 4% of the paediatric population, where 90% of the Western cases is caused by renal impairment. ACE-inhibitors (ACE-I) and Angiotensin Receptor Blockers (ARB’s) are most frequently prescribed for blood pressure reduction. Both therapeutics are currently being used off-label, despite being available for over three decades. The aim of this study is to retrospectively summarize and to compare findings of conducted pharmacokinetic (PK) and pharmacodynamic (PD) studies investigating all drugs of the ACE-I and ARB’s classes, including a potential recommendation for improved study design. Method: This review focused on the clinical trials investigating PK and PD properties of ACE-I and ARB’s. 60 studies were selected, including 19 randomized controlled trials. Analysis was conducted with a focus on trial design and endpoints, i.e. safety and efficacy. Results: Between ACE-I and ARB’s, geographical location, drug intake and formulations were comparable. Study population differed, for example studies on ARB’s focused on both primary and secondary hypertension, where studies on ACE-I focused on secondary hypertension. Sampling regimens varied, where studies investigating the PK of ARB’s were frequently based on single dosing at non-steady state. For both classes, low reporting of estimated glomerular filtration rate (eGFR) (23.3%) and the exclusion of participants with an eGFR under 30 was apparent. Individual antihypertensive effects of ACE-I could be verified in 77 children, where around 90% achieved a blood pressure decrease of ≥ 6 mmHg. ACE-I were generally well tolerated when considering safety parameters and serious adverse events. Limited studies investigated the long-term effects of ACE-I and ARB’s on cardiovascular morbidity and mortality. Conclusion: Standardization of methodology and reporting of results is imperative for PKPD studies, to allow a better comparison of results and to aim towards appropriate labelling. Inclusion across and stratification for age categories and eGFR ranges is recommended