Drug Levels of Tablet and Liquid Forms of Lamivudine, Nevirapine, and Stavudine in HIV Infected Thai Children

A Phase I/II Comparative Pharmacokinetic Study of the Fixed-Dose Combination (FDC) of Stavudine (d4T), Lamivudine (3TC), and Nevirapine (NVP) as GPO-VIR Pediatric Chewable Tablets Versus the Individual Liquid Formulations in HIV Infected Children 6 Months and Older to Less Than 13 Years of Age in Thailand

The purpose of this study is to compare the blood levels, absorption, and breakdown of lamivudine (3TC), nevirapine (NVP), and stavudine (d4T) in a fixed-dose tablet to that of the individual liquid formulations of the same anti-HIV drugs in HIV infected Thai children.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Lamivudine, nevirapine, and stavudine fixed-dose tablet; Drug: Lamivudine; Drug: Nevirapine; Drug: Stavudine

Detailed Description

The Thai Ministry of Public Health strives to provide the HIV infected people of Thailand with affordable antiretrovirals (ARVs). A fixed-dose combination tablet of 3TC, NVP, and d4T is recommended as first-line treatment in HIV infected adults in Thailand. There has been no similar product developed for children for several reasons: pediatric dosing is based on age, weight, or body surface area; developmental changes may influence the bioavailability and pharmacokinetics (PK) of ARVs; and medication adherence may also be a problem. The purpose of this study is to gather bioavailability and PK data in children taking a fixed-dose tablet of 3TC, NVP, and d4T. This information will then be compared to the bioavailability and PK of the individual liquid formulations of these ARVs.

This study has two stages. Stage 1 will last a minimum of 4 weeks; Stage 2 will last a minimum of 8 weeks. In Stage 1, patients will be randomly assigned to one of two arms. Arm A will receive the fixed-dose tablet twice daily for 2 weeks, then switch to the individual liquid formulations twice daily for 2 weeks. Arm B will receive the individual liquid formulations twice daily for 2 weeks, then switch to the fixed-dose tablet twice daily for 2 weeks. To encourage medication adherence, study staff will make home visits and phone calls to each patient's parent or guardian the first week of each treatment regimen. Medical history, a physical exam, and urine collection will occur on Days 11 and 25. Also on Days 11 and 25, patients will be admitted to the hospital to ensure 100% medication adherence and to provide blood for PK studies.

Stage 1 patients are not eligible for Stage 2. In Stage 2, patients will be stratified by body weight, then randomly assigned to one of two arms. Arm A will receive the fixed-dose tablet twice daily for 4 weeks, then switch to the individual liquid formulations twice daily for 4 weeks. Arm B will receive the individual liquid formulations twice daily for 4 weeks, then switch to the fixed-dose tablet twice daily for 4 weeks. To encourage medication adherence, study staff will make home visits and phone calls to each patient's parent or guardian the first week of each treatment regimen. Medical history, documentation of direct observation of therapy (DOT), a physical exam, and urine collection will occur on Days 25 and 53. Also on Days 25 and 53, patients will be admitted to the hospital to ensure 100% medication adherence and to provide blood for PK studies.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Thailand
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University Pediatrics-Obstetrics CRS
  • Chonburri, Thailand, 20000 TH
    • Chonburi Hosp. CRS
  • Ratchathewi
    • Bangkok, Ratchathewi, Thailand, 10400
      • Queen Sirikit National Institute of Child Health, Pediatric Infectious Unit
    • Bangkok, Ratchathewi, Thailand, 10700
      • Siriraj Hospital Mahidol University CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Stages 1 and 2:

• HIV infected
• On a highly active antiretroviral regimen (HAART) including NVP and 2 nucleoside reverse transcriptase inhibitors and receiving a maintenance of NVP for at least 4 weeks prior to study entry and taking the current recommended oral dose every 12 hours
• Willing to swallow or chew study drugs
• Willing to be hospitalized for the 12 hour PK studies
• Willing to use acceptable forms of contraception
• Parent or guardian willing to provide informed consent

Inclusion Criteria for Stage 1:

• Between 12 to 30 kg (26.5 to 66.1 lbs)

Inclusion Criteria for Stage 2:

• Between 6 to 30 kg (13.2 to 66.1 lbs)

Exclusion Criteria:

• Certain abnormal laboratory values
• Require certain medications
• Grade 2 or greater vomiting within 30 days prior to study entry
• Grade 2 or greater diarrhea within 30 days prior to study entry
• History of immunological failure (CD4 percentage decrease of more than 30% within a 6-month period for children 6 years or younger OR CD4 cell count decrease of more than 30% within a 6-month period for children older than 6 years)
• Current treatment for acute serious bacterial, viral, or opportunistic infection
• History of dose-limiting toxicity requiring treatment discontinuation of any of the study drugs
• Known hypersensitivity to any of the study drugs
• Current surgical or medical problem affecting gastrointestinal motility or absorption (e.g., ileus, ulcerative colitis) or liver function
• Treatment with immune modulators or myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic, or cytotoxic drugs within 30 days prior to study entry. Patients who have received therapeutic vaccines are not excluded.
• Treatment with experimental drugs within 30 days of study entry
• Acute inflammation of the liver
• Chemotherapy for active cancer
• Any clinically significant diseases other than HIV infection or clinically significant findings that, in the investigator's opinion, may interfere with the study
• Inability to provide a reliable means of contact (e.g., telephone number)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A, Stage 1; Tablet containing d4T, 3TC, and NVP taken orally twice daily for the first 4 weeks, then liquid formulations of d4T, 3TC, and NVP taken orally twice daily for the final 4 weeks	Drug: Lamivudine, nevirapine, and stavudine fixed-dose tablet; 7 mg d4T, 30 mg 3TC, 50 mg NVP tablet; Other Names: GPO-Vir; d4T/3TC/NVP; Drug: Lamivudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Nevirapine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Stavudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.
Experimental: A, Stage 2; Tablet containing d4T, 3TC, and NVP taken orally twice daily for 4 weeks, then liquid formulations of d4T, 3TC, and NVP taken orally twice daily for 4 weeks	Drug: Lamivudine, nevirapine, and stavudine fixed-dose tablet; 7 mg d4T, 30 mg 3TC, 50 mg NVP tablet; Other Names: GPO-Vir; d4T/3TC/NVP; Drug: Lamivudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Nevirapine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Stavudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.
Experimental: B, Stage 1; Liquid formulations of d4T, 3TC, and NVP taken orally twice daily for 2 weeks, then tablet containing d4T, 3TC, and NVP taken orally twice daily for 2 weeks	Drug: Lamivudine, nevirapine, and stavudine fixed-dose tablet; 7 mg d4T, 30 mg 3TC, 50 mg NVP tablet; Other Names: GPO-Vir; d4T/3TC/NVP; Drug: Lamivudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Nevirapine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Stavudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.
Experimental: B, Stage 2; Liquid formulations of d4T, 3TC, and NVP taken orally twice daily for 4 weeks, then tablet containing d4T, 3TC, and NVP taken orally twice daily for 4 weeks	Drug: Lamivudine, nevirapine, and stavudine fixed-dose tablet; 7 mg d4T, 30 mg 3TC, 50 mg NVP tablet; Other Names: GPO-Vir; d4T/3TC/NVP; Drug: Lamivudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Nevirapine; Dosage dependent on weight. More information on this criterion can be found in the protocol.; Drug: Stavudine; Dosage dependent on weight. More information on this criterion can be found in the protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Comparative bioavailability	Throughout study
therapeutic adequacy	Throughout study

Secondary Outcome Measures

Outcome Measure	Time Frame
Drug absorption from standard pharmacokinetic (PK) analyses	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Investigators: Study Chair: Nirun Vanprapar, MD, Pediatric Infectious Unit, Department of Pediatrics, Siriraj Hopstial, Mahidol University

Publications and helpful links

General Publications

• Chokephaibulkit K, Plipat N, Cressey TR, Frederix K, Phongsamart W, Capparelli E, Kolladarungkri T, Vanprapar N. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS. 2005 Sep 23;19(14):1495-9. doi: 10.1097/01.aids.0000183625.97170.59.
• Hoody DW, Fletcher CV. Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children. Semin Pediatr Infect Dis. 2003 Oct;14(4):286-94. doi: 10.1053/j.spid.2003.09.004.
• King JR, Kimberlin DW, Aldrovandi GM, Acosta EP. Antiretroviral pharmacokinetics in the paediatric population: a review. Clin Pharmacokinet. 2002;41(14):1115-33. doi: 10.2165/00003088-200241140-00001.
• Vanprapar N, Cressey TR, Chokephaibulkit K, Muresan P, Plipat N, Sirisanthana V, Prasitsuebsai W, Hongsiriwan S, Chotpitayasunondh T, Eksaengsri A, Toye M, Smith ME, McIntosh K, Capparelli E, Yogev R; IMPAACT P1056 Team. A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand. Pediatr Infect Dis J. 2010 Oct;29(10):940-4. doi: 10.1097/INF.0b013e3181e2189d.

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: April 5, 2006
• First Submitted That Met QC Criteria: April 5, 2006
• First Posted (Estimate): April 7, 2006

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 29, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Treatment Experienced
• 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; Antimetabolites; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nevirapine; Lamivudine; Stavudine
• Other Study ID Numbers: P1056; 10139 (Other Identifier: CTEP); PACTG P1056; IMPAACT P1056