Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection

H Trachtman, A Frymoyer, A Lewandowski, L A Greenbaum, D I Feig, D S Gipson, B A Warady, J W Goebel, G J Schwartz, K Lewis, R Anand, U D Patel, Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee, Daniel K Benjamin Jr, Katherine Y Berezny, Edmund Capparelli, Michael Cohen-Wolkowiez, Gregory L Kearns, Matthew Laughon, Andre Muelenaer, T Michael O'Shea, Winston Salem, Ian M Paul, P Brian Smith, John van den Anker, Kelly Wade, Thomas J Walsh, David Siegel, Perdita Taylor-Zapata, Anne Zajicek, Zhaoxia Ren, Katerina Tsilou, Alice Pagan, Gina Simone, H Trachtman, A Frymoyer, A Lewandowski, L A Greenbaum, D I Feig, D S Gipson, B A Warady, J W Goebel, G J Schwartz, K Lewis, R Anand, U D Patel, Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee, Daniel K Benjamin Jr, Katherine Y Berezny, Edmund Capparelli, Michael Cohen-Wolkowiez, Gregory L Kearns, Matthew Laughon, Andre Muelenaer, T Michael O'Shea, Winston Salem, Ian M Paul, P Brian Smith, John van den Anker, Kelly Wade, Thomas J Walsh, David Siegel, Perdita Taylor-Zapata, Anne Zajicek, Zhaoxia Ren, Katerina Tsilou, Alice Pagan, Gina Simone

Abstract

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

Trial registration: ClinicalTrials.gov NCT01491919.

Conflict of interest statement

CONFLICTS OF INTEREST/DISCLOSURES

Dr. Frymoyer received support from the National Institute of Child Health and Human Development (NICHD; 1K23HD079557 and HSSN275000002). Drs. Anand and Lewandowski receive support from Government Contract HHSN267200700051C (PI: Benjamin). Dr. Patel received support for research from NICHD contract HHSN27500007 and from industry for drug development in adults and children with kidney disease (www.dcri.duke.edu/research/coi.jsp). The remaining authors have no conflicts of interest to disclose.

© 2015 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Mean lisinopril concentration versus time after multiple dosing following once-daily dosing in patients who have received a kidney transplant. Patients were stratified by dose group: low dose = 0.1 mg/kg; middle dose = 0.2 mg/kg; and high dose = 0.4 mg/kg. One patient received twice-daily dosing and was not included.
Figure 3
Figure 3
Impact of eGFR on (A) oral clearance allometrically scaled to a 70 kg adult and (B) AUC0–24 dose adjusted to 0.1 mg/kg/day. The geometric mean AUC0–24 dose adjusted to 0.1 mg/kg in historical hypertensive children is shown for comparison.

Source: PubMed

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