Therapeutic Drug Monitoring Of Captopril In Pediatric Patients With Heart Failure Diagnosis And Its Relationship With Functional Class and Functional Capacity

Introduction. Heart Failure (HF) in children can be defined as the failure of the heart to supply blood to either systemic or pulmonary circulation at an appropriate rate of flow, or to receive venous return at an appropriate filling pressure, resulting in adverse effects on the heart, the circulation, and the patient. (1) When making the diagnosis of HF, patients are categorized as belonging to one of four Functional Classes (FC), originally established by the New York Heart Association (NYHA) for adult patients, and later adapted for paediatric patients by Ross et al. Among the instruments implemented to evaluate the clinical repercussion of HF there is the 6 Minute Walk Test (6MWT), a submaximal exercise test which assesses the integrated functional capacity of pulmonary, cardiovascular, and muscular systems. Whereas clinical studies support the use of captopril in the HF treatment in adults, recommendations on its used in paediatric patients are largely based on extrapolations from studies carried out with adult subjects. Plasma concentrations of 50-500 pg/mL are generally considered therapeutic. Objective. The aim of this study is to determine the therapeutic plasma captopril concentrations for HF treatment in paediatric patients with regard to FC, and the 6MWT for objective quantification of functional capacity. Method. Patients in this study met the following characteristics: Mexican, age 1-17 years, diagnosed as with HF, with indicated therapy with captopril, who had never consumed the drug, with no concomitant pulmonary, hepatic, or renal disease. Patients received 1 mg/kg/day captopril doses in 8 h intervals. They were assessed on days 1, 11, and 22 of treatment, when FC was determined with the NYHA scale for children 3 years of age or older, and with the Ross scale for those 1-2 years old. Children 2 years of age or older performed 6MWT as described by the ATS (2), supervised by a competent practitioner. The expected distance to walk was calculated for each patient with the formula described by Priesnitz et al (3) for Latin American children, and considered as 100%; net results were considered as percentages of this. On days 11 and 22, 3 mL blood samples were drawn for plasma captopril determination before the first morning dose of captopril, and 40 minutes thereafter. Captopril concentrations were determined by high performance liquid chromatography. Data were analysed with Student’s t test using JMP 12 software from SAS Institute, Inc. Results. 27 patients participated in the study, with ages 1-16 years. All patients attended their follow-up visits; none presented captopril-related adverse effects. Plasma captopril concentrations were 1,65 (0-173,2) pg/mL before and 74,5 (2,6-506,9) pg/mL after drug administration on day 11, and 1,3 (0-64,1) pg/mL before and 28,8 (2,8-509,79)pg/mL after drug administration on day 22. Patients on FC I amounted to 3,7% on day 1, 16% on day 11, and 69,23% on day 22. Patients on FC III amounted to 29,63% on day 1, 20% on day 11, and 7,69% on day 22. There were no patients on FC IV. There was a statistically significant difference between the FCs of children on days 1 and 11, and on days 11 and 22 (p<0,01). There was no significant difference between FC improvement in children with post-dose plasma concentrations within 50!500pg/mL and children with concentrations of 2,6-50 pg/mL. 23 patients performed the 6MWT. The distance they walked was 67(30-107)% on day 1, 77(38-114)% on day 11, and 86(45-172)% on day 22.There was a statistically significant difference between the metres walked by children on days 1 and 11, and on days 11 and 22 (p<0,01). There was a trend to faster recovery with higher captopril plasma concentrations, although by day 22 of monitoring all children had reached a similar recovery state. There was a trend for children in better FC to walk longer distances. Conclusion. Plasma captopril concentrations between 2,6 and 509,7 pg/mL showed a trend to clinical efficacy, reflected in FC improvement and functional capacity. This suggests a therapeutic range for paediatric populations that should be pursued in further studies.

References

(1) Kantor PF et al. (2013). Canadian Journal of Cardiology. 29: 1535-1552.

(2) ATS Statement. (2002). Am J Crit Care Med. 166: 111-7.

(3) Priesnitz CV et al. (2009). PediatrPulmonol. 44:1174-9.