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

The incidence of untreated or inadequately treated hypertension in pediatric kidney transplant recipients is nearly 60%, a figure that has been steady over the last 2 decades.1 Uncontrolled hypertension, beginning within the first year post-transplant, represents a modifiable risk factor that contributes to long-term graft loss.1,2 The requirement for treatment with antihypertensive medications at any time from 6 months to 3 years post-transplant is associated with graft dysfunction and a lower glomerular filtration rate (GFR).3 Calcium channel blockers are considered the preferred first-line agent in this circumstance,4 and they are the most commonly used drug class to control post-transplant hypertension in children.5 However, compared with calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs) may have additional beneficial effects for prolonging allograft survival in kidney transplant recipients by lowering intraglomerular hypertension and reducing the activity of profibrotic molecules such as TGF-β and inflammatory mediators.6 Recent reports in adults document an increased use of ACEI in the 2-year period after kidney transplantation between 1990 and 2002. By the end of this period, 45% of patients were receiving these agents, and their use was associated with a significantly higher graft survival.7 Despite greater potential benefits, there is a reluctance to use ACEIs in pediatric kidney transplant recipients who develop hypertension because this class of drugs may compromise the angiotensin II-dependent component of GFR in patients with a single transplanted kidney. In addition, they may cause clinically significant hyperkalemia.8 The low use of ACEI in pediatric kidney transplant patients is noteworthy because these drugs lower urinary protein excretion and are reno-protective in pediatric and adult patients with reduced kidney mass and/or diminished renal function.9 Lisinopril, a long-acting ACEI, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with essential hypertension. Based on recovery of the drug in the urine, the apparent extent of absorption of lisinopril is ~25% with large inter-patient variability. In adults, peak serum concentrations of lisinopril are seen approximately 7 hours after oral dosing.10 The disposition of lisinopril in children is similar to adults, with peak concentrations observed within 6 hours after dosing and the extent of drug absorption ~28%.11,12 The drug is not appreciably bound to plasma proteins and thus, its disposition appears to be unaltered by low serum albumin levels.13 Lisinopril is not appreciably metabolized, and it is excreted largely unchanged in the urine via glomerular filtration with no apparent contribution via active tubular secretion.14 Impaired renal function decreases the elimination of lisinopril, but this only becomes clinically relevant at a GFR below 30 mL/min/1.73m2. Compared to healthy children with essential hypertension, the disposition of and response to antihypertensive medications may be altered in pediatric patients with a renal transplant consequent to the presence of a solitary kidney, potential alterations in renal hemodynamics, renal effects of drugs used to prevent acute rejection, and extra-renal organ dysfunction secondary to chronic kidney disease (CKD) prior to receipt of the kidney allograft. Thus, it is important to understand if lisinopril disposition is altered in pediatric patients who receive a renal transplant. Given the widespread use of this drug in pediatrics, we conducted a clinical trial to evaluate the pharmacokinetics (PK) and safety/tolerability profile of lisinopril in children and adolescents with hypertension after kidney transplantation. The impact of lisinopril on blood pressure was also examined.