Clinical trial NCT00260078: Blood Levels of Anti-HIV Drugs Used in Combination Regimens in HIV Infected Children
Official title: Intensive Pharmacokinetic Studies of Antiretroviral Drug Combinations in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: Treatment Experienced
Pharmacokinetics
PK
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2005-12-01
Enrollment: 75
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Limited data exist about combination anti-HIV treatment regimens in children, including how those drugs are cleared by the body in children. The purpose of this study is to measure the blood levels of the following combinations of anti-HIV drugs in HIV infected chilren: tenofovir disoproxil fumurate (TDF) and efavirenz (EFV) or nevirapine (NVP); TDF and darunavir (DRV) with or without EFV; and TDF and ritonavir (RTV) with or without EFV.

Detailed description: Because all of the available non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are metabolized by and affect hepatic cytochrome enzymes, combinations of two or more of these drugs produce complex pharmacokinetic (PK) interactions. However, little data exist regarding PK of anti-HIV drug combinations in the pediatric population. The purpose of this study is to assess steady-state PK of the following anti-HIV regimens: TDF and EFV or NVP; TDF and DRV with or without EFV; and TDF and RTV with or without EFV. In addition, this study will evaluate how age, length of treatment, adverse effects, and genes affect children's response to different anti-HIV combinations.

This study will last between 1 and 7 weeks. Participants in this study will be grouped based on the treatment regimen they are receiving or about to initiate. There are three groups in this study. Group D participants will receive TDF and EFV or NVP; Group E participants will receive TDF and DRV with or without EFV; and Group F participants will receive TDF and RTV with or without EFV. The inclusion of EFV or NVP will be dependent on each participant's prescribed regimen. Participants within each group will be stratified by age and how long they have been receiving their anti-HIV regimens. Antiretrovirals will not be provided by this study.

Most participants will have two study visits. The first visit will occur at study entry. Medical history, a physical exam, and blood collection will occur. The second visit will occur within 35 days of study entry and will take approximately 24 hours. Blood collection for PK studies, a physical exam, and medical history will be done at this visit. Urine collection will occur at all visits for female participants.

Participants will undergo PK testing at least 14 days after initiating their study regimens. Participants will be given a dose of their anti-HIV medications with food. A blood sample will be taken before dosing. Blood samples will also be taken at 1, 2, 4, 6, 8, 12, and 24 hours after dosing. Participants in Groups E and F may need to repeat PK testing within 6 weeks of initial PK testing at the discretion of the investigator.

Eligibility criteria: Note: The original Groups A, B, and C have been removed, and Groups D, E, and F have been added per protocol amendment dated 11/16/07.

Inclusion Criteria:

* HIV infected
* Currently receiving or about to initiate one of the following anti-HIV regimens: TDF with EFV or NVP, TDF and DRV/r with or without EFV, or TDF with ATV/r with or without EFV
* Body surface area at least 0.85 m2
* Parent or guardian willing and able to provide signed informed consent
* Willing to use acceptable forms of contraception

Exclusion Criteria:

* Liver disease that may affect the metabolism of study drugs
* Certain abnormal laboratory values
* Require certain medications
* Treatment with any anti-HIV or nonantiretroviral drug that could interact with drugs under PK study in the 14 days prior to study entry
* Any clinical or laboratory toxicity of Grade 4 or higher at screening. More information on this criterion can be found in the protocol.
* Pregnant or breastfeeding

Primary outcomes:
measure: Predosage concentration (C0 and C12) and area under the concentration-time curve (AUC)
timeFrame: Over the dosing interval
Secondary outcomes:
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Torrance
country: United States
facility: Harbor UCLA Medical Ctr. NICHD CRS
state: California
city: Hartford
country: United States
facility: Connecticut Children's Med. Ctr.
state: Connecticut
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Chicago
country: United States
facility: Rush Univ. Cook County Hosp. Chicago NICHD CRS
state: Illinois
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) CRS
state: Illinois
city: Baltimore
country: United States
facility: Univ. of Maryland Baltimore NICHD CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Univ. Baltimore NICHD CRS
state: Maryland
city: Boston
country: United States
facility: Children's Hosp. of Boston NICHD CRS
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Health, Baystate Med. Ctr.
state: Massachusetts
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan NICHD CRS
state: Michigan
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School CRS
state: New Jersey
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital CRS
state: Tennessee
city: Seattle
country: United States
facility: Seattle Children's Hospital CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham
name: Jennifer King, PharmD
role: STUDY_CHAIR
affiliation: Section of Pediatrics and Maternal HIV Infection, Children's Memorial Hospital, Northwestern University Medical School
name: Ram Yogev, MD
role: STUDY_CHAIR
References:
citation: Kiser JJ, Fletcher CV, Flynn PM, Cunningham CK, Wilson CM, Kapogiannis BG, Major-Wilson H, Viani RM, Liu NX, Muenz LR, Harris DR, Havens PL; Adolescent Trials Network for HIV/AIDS Interventions. Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2008 Feb;52(2):631-7. doi: 10.1128/AAC.00761-07. Epub 2007 Nov 19.
citation: Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, Worrell CJ, Steinberg SM, Flaherty J, Yale K, Kearney BP, Zeichner SL. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005 Dec;116(6):e846-54. doi: 10.1542/peds.2005-0975. Epub 2005 Nov 15.