IMPAACT P1058A: Pharmacokinetic Effects of New Antiretroviral Drugs on Children, Adolescents and Young Adults

IMPAACT P1058A: Intensive Pharmacokinetic Studies of New Classes of Antiretroviral Drug Combinations in Children, Adolescents and Young Adults

This study will examine drug and body interactions in children receiving anti-HIV treatment regimens using new medications. Drug regimens to be examined will feature the medications raltegravir (RAL), maraviroc (MVC), and etravirine (ETV). These drugs will not be provided through the study.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Raltegravir (RAL); Drug: Atazanavir (ATV); Drug: Ritonavir (RTV); Drug: Tenofovir (TDF); Drug: Etravirine (ETV); Drug: Darunavir (DRV); Drug: Maraviroc (MVC); Drug: Lopinavir/ritonavir (LPV/r)

Detailed Description

Antiretroviral (ARV) medication regimens for children, adolescents and young adults are often prescribed based on drug resistance because of previous treatment history. In order to find an effective regimen, clinicians must often turn to newer drugs before they have been fully tested in adolescent or pediatric clinical trials. One of the first steps in testing these drugs is to assess the drug pharmacokinetics (PK), or interaction between drugs and body. This study, a follow-on protocol to the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1058 study, will test children, adolescents and young adults who have already been prescribed treatment regimens with new drugs. The study will examine the PK of medication combinations featuring raltegravir, a new drug in the new ARV class of entry inhibitors (EIs); maraviroc, a new drug in the new class of fusion inhibitors (FIs); and etravirine, a new drug in the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Older medications may also be used to complete these regimens.

Participation in this study will last between 1 and 7 weeks and involve at least two clinic visits. The first is a screening and entry visit at which a medical history will be taken and a physical exam and blood test will be completed. The second visit will measure PK of the medications. During this visit, participants will complete the same measures as before-medical history, physical exam, blood test-and then be given a dose of their anti-HIV medication regimen. After receiving the medications, participants will be monitored and give blood samples after 1, 2, 4, 6, 8, and 12 hours. For Groups G, H, I, J, K and L an intensive 12-hour PK study will be scheduled after at least 30 days on the combination of interest. For all Groups, the intensive 12-hour PK study should be performed within 35 days (5 weeks) of screening/entry evaluations. Medications will not be provided through this study.

Results of the 12-hour medication monitoring tests will be delivered to participants' physicians within 6 weeks. If, based on these results, a physician decides to change the dosage of a participant's medication, that participant may be asked to complete a second PK visit. Participants must have received the revised dose for at least 14 days before the PK study can be repeated.

• Study Type: Observational
• Enrollment (Actual): 168

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • San Juan City Hosp. PR NICHD CRS (5031)
  • San Juan, Puerto Rico, 00936-5067
    • University of Puerto Rico Pediatric HIV/AIDS Research (6601)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ. of Alabama Birmingham NICHD CRS (5096)
  • California
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital Long Beach, CA NICHD CRS (5093)
    • Los Angeles, California, United States, 90033
      • Usc La Nichd Crs (5048)
    • San Diego, California, United States, 92103
      • UCSD Mother, Child & Adolescent HIV Program(4601)
    • San Francisco,, California, United States, 94117
      • Univ. of California San Francisco NICHD CRS (5091)
    • Torrance, California, United States, 90509
      • Harbor (UCLA) Medical Center NICHD CRS (5045)
    • Torrance, California, United States, 90509
      • Harbor Univeristy of California, Los Angeles (UCLA) Medical Center (603)
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Childrens Hospital (U. Colorado, Denver) NICHD CRS (5052)
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center (5015)
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • South Florida CDC Ft Lauderdale NICHD CRS (5055)
    • Miami, Florida, United States, 33136
      • University of Miami Pediatric Perinatal HIV/AIDS CRS (4201)
    • Tampa, Florida, United States, 33620
      • University of South Florida Tampa (5018)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Cook County (5083)
    • Chicago, Illinois, United States, 60614
      • Chicago Children's CRS (4001)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland NICHD CRS (5094)
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University NICHD CRS (5092)
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital of Boston NICHD CRS (5009)
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center Ped. HIV Program NICHD CRS (5011)
    • Worcester, Massachusetts, United States, 01605
      • WNE Maternal Pediatric Adolescent AIDS CRS (7301)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School (NJ) (2802)
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hospital (6901)
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center Bronx (5013)
    • New York, New York, United States, 10016
      • New York University NY (5012)
    • New York, New York, United States, 10029
      • Metropolitan Hospital (5003)
    • New York, New York, United States, 10032
      • Columbia IMPAACT CRS (4101)
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook NICHD CRS (5040)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center (DUMC) (4701)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hosp. of Philadelphia IMPAACT CRS (6701)
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude/UTHSC CRS (6501)
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hosp. CRS (3801)
  • Washington
    • Seattle, Washington, United States, 98105
      • Harborview Medical Center NICHD CRS (5027)
    • Seattle, Washington, United States, 98105
      • Univ of Washington Children's Hospital Seattle (5017)
    • Seattle, Washington, United States, 98105
      • University of Washington NICHD CRS (5029)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

HIV infected children, adolescents and young adults who are receiving a regimen of antiretroviral drugs prescribed by their physician that includes one of the target combinations.

Description

Inclusion Criteria:

• Certain laboratory values received within 5 weeks of the date of the screening or entry evaluations
• HIV infected
• Stable on the specified antiretroviral (ARV) regimen for 30 days prior to screening and entry. ARVs will not be provided through this protocol.
• Prescribed one of the regimens described in the study details by clinician on the basis of clinical need (although the availability of drug levels may have been a factor in clinical decision-making). The decision to initiate the regimen must have been solely that of the prescribing physician.
• On the ARV combination of interest for at least 14 days and within 5 weeks (35 days) of the date of screening results
• Body surface area (BSA) of at least 0.85 m2
• Participants in P1058 Version 1.0 and Version 2.0 who have switched to a regimen specified in the entry criteria are eligible for P1058A.
• Any licensed formulation that achieves these dosages, but without including a disallowed drug, may be used.
• Participants who have enrolled in P1058A (Groups G-L) and who subsequently switch to a different regimen specified in the entry criteria are eligible to re-register to a subsequent step of P1058A (re-consent required)
• Females must agree to use two reliable methods of contraception, one of which must be a barrier method, while taking study medications and for 6 weeks after study testing
• Documentation of presence of an R5-tropic virus at the start of treatment with maraviroc (MVC)

Exclusion Criteria:

• Pregnant or breastfeeding
• Hemoglobin level less than 8.5 g/dL
• Clinical evidence of pancreatitis as defined by moderate clinical symptoms
• Treatment with any anti-HIV or non-ARV drug that could interact with drugs under pharmacokinetic (PK) study in the 14 days prior to study entry
• Known allergy, sensitivity, or hypersensitivity to components of two or more study-specified drugs or their formulation

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

11

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group G; Participants will receive a medication regimen including RAL + ATV + RTV.	Drug: Raltegravir (RAL); 400 mg twice daily (BID); Other Names: Isentress; Drug: Atazanavir (ATV); 300 mg daily; Other Names: Reyataz; Drug: Ritonavir (RTV); 100 mg daily, dosing by weight in Group I; Other Names: Norvir
Group H; Participants will receive a medication regimen including RAL + TDF.	Drug: Raltegravir (RAL); 400 mg twice daily (BID); Other Names: Isentress; Drug: Tenofovir (TDF); 300 mg daily; Other Names: Viread
Group I; Participants will receive a medication regimen including ETV + DRV + RTV.	Drug: Ritonavir (RTV); 100 mg daily, dosing by weight in Group I; Other Names: Norvir; Drug: Etravirine (ETV); 200 mg BID; Other Names: Intelence; Drug: Darunavir (DRV); Dosing by weight; Other Names: Prezista
Group J; Participants will receive a medication regimen including MVC + ATV + RTV.	Drug: Atazanavir (ATV); 300 mg daily; Other Names: Reyataz; Drug: Ritonavir (RTV); 100 mg daily, dosing by weight in Group I; Other Names: Norvir; Drug: Maraviroc (MVC); 150 mg BID in groups J and K; 600 mg BID in group L; Other Names: Selzentry
Group K; Participants will receive a medication regimen including MVC + LPV + RTV.	Drug: Ritonavir (RTV); 100 mg daily, dosing by weight in Group I; Other Names: Norvir; Drug: Maraviroc (MVC); 150 mg BID in groups J and K; 600 mg BID in group L; Other Names: Selzentry; Drug: Lopinavir/ritonavir (LPV/r); Coformulation of 400 mg lopinavir and 100 mg ritonavir, taken twice daily; Other Names: Kaletra
Group L; Participants will receive a medication regimen including MVC + RAL + ETV.	Drug: Raltegravir (RAL); 400 mg twice daily (BID); Other Names: Isentress; Drug: Etravirine (ETV); 200 mg BID; Other Names: Intelence; Drug: Maraviroc (MVC); 150 mg BID in groups J and K; 600 mg BID in group L; Other Names: Selzentry
Arm M; Participants will receive a medication regimen of DRV
Arm N; Participants will receive a medication regimen of DRV
Arm O; Participants will receive a medication regimen of unboosted ATV
Arm P; Participants will receive a medication regimen of RPV
Arm Q; Participants will receive a medication regimen of RPV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Steady state pharmacokinetics (PK) of raltegravir administered in combination with atazanavir/ritonavir or tenofovir or maraviroc/etravirine to older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing
Steady state PK of etravirine administered to older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing
Steady state PK of maraviroc administered in combination with atazanavir/ritonavir or lopinavir/ritonavir to older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing
Steady state PK of maraviroc (600 mg twice daily [BID]) given in combination with raltegravir and etravirine (a protease inhibitor [PI]-sparing regimen) to older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing

Secondary Outcome Measures

Outcome Measure	Time Frame
Relationship between Tanner stage and the PK of the regimens of interest in children and adolescents	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing
Relationships between the PK parameters and polymorphisms that may affect the antiretrovirals (ARVs) of interest in older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing
Adverse events associated with the ARVs of interest	Measured throughout
Steady state PK of darunavir/ritonavir administered to older children, adolescents and young adults	Measured at baseline and 1, 2, 4, 6, 8, and 12 hours after dosing

Collaborators and Investigators

• Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Jennifer R. King, PharmD, University of Alabama at Birmingham; Study Chair: Ram Yogev, MD, Northwestern University Feinberg School of Medicine

Publications and helpful links

General Publications

• Guidelines for the use of antiretroviral agents in pediatric HIV infection. Center for Disease Control and Prevention. MMWR Recomm Rep. 1998 Apr 17;47(RR-4):1-43. Erratum In: MMWR Morb Mortal Wkly Rep 1998 Apr 24;47(15):315.
• Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Breidinger SA, Mangin EC, Azrolan N, Greenberg HE, Haazen W, Stone JA, Gottesdiener KM, Wagner JA. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008 Dec;52(12):4338-43. doi: 10.1128/AAC.01543-07. Epub 2008 Oct 6.
• Wenning LA, Friedman EJ, Kost JT, Breidinger SA, Stek JE, Lasseter KC, Gottesdiener KM, Chen J, Teppler H, Wagner JA, Stone JA, Iwamoto M. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother. 2008 Sep;52(9):3253-8. doi: 10.1128/AAC.00005-08. Epub 2008 Jul 14.
• Cressey TR, Hazra R, Wiznia A, Foca M, Jean-Philippe P, Graham B, King JR, Britto P, Carey VJ, Acosta EP, Yogev R; IMPAACT P1058A Team. Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults. Pediatr Infect Dis J. 2016 Dec;35(12):1333-1335. doi: 10.1097/INF.0000000000001320.

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: September 15, 2009
• First Submitted That Met QC Criteria: September 15, 2009
• First Posted (Estimate): September 16, 2009

Study Record Updates

• Last Update Posted (Estimate): August 7, 2015
• Last Update Submitted That Met QC Criteria: August 5, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Treatment; Children; Treatment Experienced; Integrase Inhibitors; Entry Inhibitors
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Tenofovir; Raltegravir Potassium; Ritonavir; Lopinavir; Maraviroc; Darunavir; Etravirine; Atazanavir Sulfate
• Other Study ID Numbers: IMPAACT P1058A; U01AI068632 (U.S. NIH Grant/Contract)