Safety Study of Lisinopril in Children and Adolescents With a Kidney Transplant

Condition(s) targeted: Hypertension

Intervention: Lisinopril (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Uptal Patel

Official(s) and/or principal investigator(s):
Daniel Benjamin, MD, PhD, MPH, Study Director, Affiliation: Duke University
Howard Trachtman, MD, Study Chair, Affiliation: New York University Langone Medical Center
Uptal D Patel, MD, Principal Investigator, Affiliation: Duke University
Adam Frymoyer, MD, Principal Investigator, Affiliation: Stanford University

The drug lisinopril is approved by the U. S. Food and Drug Administration for the treatment of high blood pressure, heart failure, and acute heart attacks in adult patients. In children over 6 years of age, lisinopril is approved for the treatment of high blood pressure. Lisinopril is in a group of medications called angiotensin-converting enzyme inhibitors (ACE). ACE inhibitors such as lisinopril work by decreasing certain chemicals that tighten the blood vessels so blood flows more smoothly and the heart can pump blood more efficiently. There is some information available about how children with high blood pressure absorb, distribute, metabolize, and eliminate lisinopril (this information about medication processing by the body is called pharmacokinetic data). However, there is no information about how children with high blood pressure who have received a kidney transplant process lisinopril. In addition to decreasing blood pressure, investigators believe that lisinopril may help kidney transplants work longer by reducing the activity of chemicals made by cells in kidney transplants that can lead to inflammation and injury. Such benefits have not been found with another group of blood pressure medications called calcium channel blockers, which are the most commonly used medication group to control high blood pressure in children after a kidney transplant. A clinical trial will be conducted in the future to compare which medication group helps kidney transplants in children last longer. To guide the selection of the best dose to test in future studies, investigators in this study will try to determine the safety profile, dose tolerability, and pharmacokinetics of lisinopril in children and adolescents (2-17 years of age) who have received a kidney transplant and have high blood pressure.

Official title: Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Pharmacokinetics (PK) - Area Under the Plasma Concentration-time Curve (AUC)

PK - Maximum Observed Concentration of Drug in Plasma (Cmax)

PK - Time of the Maximum Observed Concentration in Plasma (Tmax)

PK - Oral Clearance (CL/F)

PK Renal Clearance (CLrenal)

Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) During/After Study Drug Administration

Secondary outcome:

Change in Potassium Level From Baseline in Lisinopril-naive Participants

Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants

Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants

Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants.

Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants

Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants

Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group

Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group

Minimum age: 2 Years. Maximum age: 17 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Kidney transplant recipient 2. Age 2-17 years, inclusive, at the time of first study dose 3. Estimated GFR (eGFR) ≥30 ml/min/1. 73m2, with stable allograft function as indicated by <20% change in serum creatinine in the previous 30 days 4. Stable immunosuppressive regimen, as indicated by <10% change in dosage (in mg/kg) in these medications, within the 14 days prior to enrollment 5. Systolic BP >90th percentile for age, gender, and height, necessitating initiation or addition of an antihypertensive medication 6. For females of child-bearing potential, a negative serum pregnancy test prior to initial dosing and agreement to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy testing through the remainder of the study (30 days after last administration of investigational agents). Exclusion Criteria: 1. History of anaphylaxis attributable to lisinopril or other angiotensin-converting enzyme inhibitor (ACEI) agents (e. g.,enalapril, ramipril, quinapril) 2. History of anaphylaxis attributable to iohexol or an iodine hypersensitivity 3. Use of an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker, or renin antagonist within 30 days prior to enrollment 4. Stage 2 hypertension defined as the >99th percentile for age, height and gender + 5 mm Hg 5. Blood Potassium value > 6. 0 milliequivalent / liter (mEq/L) (as determined at the screening visit) 6. Previous participation in this study 7. Physician concern that the participant may not adhere to the study protocol, based on prior behavior 8. Current plasmapheresis treatment 9. History of angioedema 10. Pregnancy

University of Alabama, Birmingham, Alabama 35233, United States

Arkansas Children's Hospital, Little Rock, Arkansas 72202, United States

Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia 30322, United States

University of Michigan, Ann Arbor, Michigan 48109, United States

Children's Mercy Hospitals & Clinics, Kansas City, Missouri 64108, United States

New York University Langone Medical Center, New York, New York 10016, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Pediatric Trials Network (PTN)

The Eunice Kennedy Shriver National Institute of Child Health and Human

Information about Lisinopril

Related publications:

National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004 Aug;114(2 Suppl 4th Report):555-76.

Knütter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M. Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. doi: 10.1124/jpet.108.143339. Epub 2008 Aug 19.

Lin JH, Chen IW, Ulm EH, Duggan DE. Differential renal handling of angiotensin-converting enzyme inhibitors enalaprilat and lisinopril in rats. Drug Metab Dispos. 1988 May-Jun;16(3):392-6.

Hogg RJ, Delucchi A, Sakihara G, Wells TG, Tenney F, Batisky DL, Blumer JL, Vogt BA, Lo MW, Hand E, Panebianco D, Rippley R, Shaw W, Shahinfar S. A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension. Pediatr Nephrol. 2007 May;22(5):695-701. Epub 2007 Jan 10.

Prinivil® (lisinopril tablets) package insert; Whitehouse Station, NJ: Merck & Co., Inc.; 2003

Mitsnefes MM, Khoury PR, McEnery PT. Early posttransplantation hypertension and poor long-term renal allograft survival in pediatric patients. J Pediatr. 2003 Jul;143(1):98-103.

Silverstein DM, Leblanc P, Hempe JM, Ramcharan T, Boudreaux JP. Tracking of blood pressure and its impact on graft function in pediatric renal transplant patients. Pediatr Transplant. 2007 Dec;11(8):860-7.

Mitsnefes MM, Omoloja A, McEnery PT. Short-term pediatric renal transplant survival: blood pressure and allograft function. Pediatr Transplant. 2001 Jun;5(3):160-5.

Cross NB, Webster AC, Masson P, O'connell PJ, Craig JC. Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized controlled trials. Transplantation. 2009 Jul 15;88(1):7-18. doi: 10.1097/TP.0b013e3181a9e960. Review.

Sorof JM, Goldstein SL, Brewer ED, Steiger HM, Portman RJ. Use of anti-hypertensive medications and post-transplant renal allograft function in children. Pediatr Transplant. 2000 Feb;4(1):21-7.

Hernández AA, Moreso F, Bayés B, Lauzurica R, Sánz-Guajardo D, Gómez-Huertas E, Pereira P, Paul J, Crespo J, Amenábar JJ, Oliver J, Serón D. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in renal transplantation between 1990 and 2002 in Spain. NDT Plus. 2010 Jun;3(Suppl_2):ii21-ii25.

Mitterbauer C, Heinze G, Kainz A, Kramar R, Hörl WH, Oberbauer R. ACE-inhibitor or AT2-antagonist therapy of renal transplant recipients is associated with an increase in serum potassium concentrations. Nephrol Dial Transplant. 2008 May;23(5):1742-6. doi: 10.1093/ndt/gfm864. Epub 2008 Jan 30.

Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant. 2007 Oct;7(10):2350-60. Review.

Morath C, Schmied B, Mehrabi A, Weitz J, Schmidt J, Werner J, Buchler MW, Morcos M, Nawroth PP, Schwenger V, Doehler B, Opelz G, Zeier M. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation. Clin Transplant. 2009 Dec;23 Suppl 21:33-6. doi: 10.1111/j.1399-0012.2009.01107.x. Review.

Iñigo P, Campistol JM, Lario S, Piera C, Campos B, Bescós M, Oppenheimer F, Rivera F. Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. J Am Soc Nephrol. 2001 Apr;12(4):822-7.

Nielsen SE, Schjoedt KJ, Astrup AS, Tarnow L, Lajer M, Hansen PR, Parving HH, Rossing P. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. Diabet Med. 2010 Oct;27(10):1144-50. doi: 10.1111/j.1464-5491.2010.03083.x.

Halimi JM, Giraudeau B, Buchler M, Al-Najjar A, Etienne I, Laouad I, Bruyère F, Lebranchu Y. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. Clin Transplant. 2007 Mar-Apr;21(2):277-84.

Spooner N, Lad R, Barfield M. Dried blood spots as a sample collection technique for the determination of pharmacokinetics in clinical studies: considerations for the validation of a quantitative bioanalytical method. Anal Chem. 2009 Feb 15;81(4):1557-63. doi: 10.1021/ac8022839.

Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.

Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S. A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens. 2003 Oct;16(10):795-800.

Thompson KC, Zhao Z, Mazakas JM, Beasley CA, Reed RA, Moser CL. Characterization of an extemporaneous liquid formulation of lisinopril. Am J Health Syst Pharm. 2003 Jan 1;60(1):69-74.

CDER Approval Package for Prinivil®: Application Number 19-558/S-043. Clinical Pharmacology and Biopharmaceutics Review. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/19-558S043_Prinivil.cfm. Last accessed Jan. 6, 2011.

Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76. doi: 10.1007/s00467-008-0997-5. Epub 2008 Oct 10.

Thomson AH, Kelly JG, Whiting B. Lisinopril population pharmacokinetics in elderly and renal disease patients with hypertension. Br J Clin Pharmacol. 1989 Jan;27(1):57-65.

Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002 May;(246):1-190.

Bazzoli C, Retout S, Mentré F. Design evaluation and optimisation in multiple response nonlinear mixed effect models: PFIM 3.0. Comput Methods Programs Biomed. 2010 Apr;98(1):55-65. doi: 10.1016/j.cmpb.2009.09.012. Epub 2009 Nov 4.

Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006 May 12;98(9):1123-33. Review.

Wühl E, Witte K, Soergel M, Mehls O, Schaefer F; German Working Group on Pediatric Hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens. 2002 Oct;20(10):1995-2007. Erratum in: J Hypertens. 2003 Nov;21(11):2205-6.

Soergel M, Kirschstein M, Busch C, Danne T, Gellermann J, Holl R, Krull F, Reichert H, Reusz GS, Rascher W. Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: a multicenter trial including 1141 subjects. J Pediatr. 1997 Feb;130(2):178-84.

ESCAPE Trial Group, Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Möller K, Wigger M, Peruzzi L, Mehls O, Schaefer F. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009 Oct 22;361(17):1639-50. doi: 10.1056/NEJMoa0902066.

Knoll GA, Cantarovitch M, Cole E, Gill J, Gourishankar S, Holland D, Kiberd B, Muirhead N, Prasad R, Tibbles LA, Treleaven D, Fergusson D. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation--study design. Nephrol Dial Transplant. 2008 Jan;23(1):354-8. Epub 2007 Sep 10.

Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006 Jun 8;354(23):2443-51.

Urbina E, Alpert B, Flynn J, Hayman L, Harshfield GA, Jacobson M, Mahoney L, McCrindle B, Mietus-Snyder M, Steinberger J, Daniels S; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the council on cardiovascular disease in the young and the council for high blood pressure research. Hypertension. 2008 Sep;52(3):433-51. doi: 10.1161/HYPERTENSIONAHA.108.190329. Epub 2008 Aug 4.

Starting date: June 2012
Last updated: June 15, 2015