Clinical trial NCT00014014: Zidovudine and Lamivudine Given Once Versus Twice Daily
Official title: A Phase I Pharmacokinetic Study of Once Versus Twice Daily Dosing With Zidovudine and Lamivudine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Zidovudine
Phosphorylation
Drug Administration Schedule
Lamivudine
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Pharmacokinetics
Combivir
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: 2001-08-31
Enrollment: 20
Sex: ALL
Minimum age (years): 12
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to see if the full daily dose of Combivir (zidovudine \[ZDV\]/lamivudine \[3TC\]) taken once a day is as effective as the usual recommended twice-a-day dose.

Studies have shown that the antiviral activity of ZDV can continue in the body even after there does not appear to be any ZDV left in the blood. This occurs because the body breaks down the drug into substances that remain active against HIV. The body also breaks down 3TC, a drug that is combined with ZDV in the Combivir product, in a similar way. Since antiviral activity may continue after Combivir is removed from the body, it may not be necessary to take the drug as often as once thought. This study carefully measures levels of the active substances in order to find out whether the same amount of antiviral activity occurs with less-frequent dosing.

Detailed description: Initial dosing regimens of ZDV were based on the plasma half-life of the drug. However, recent studies of the intracellular metabolism of ZDV have demonstrated that the active anabolite, ZDV-TP, is present within the cell for an extended period of time relative to the drug in the plasma. This suggests that antiviral activity may be present for a sufficient time frame with less-frequent dosing of the drug. Careful comparison of the rate and extent of intracellular phosphorylated ZDV metabolites as a function of schedule will determine whether less-frequent dosing has a sound pharmacological basis. Also, the intracellular metabolism of 3TC is via different enzymes than that of ZDV and there are quantitative differences in the amount of triphosphate formed from both drugs. This study will provide information about intracellular metabolites when both ZDV and 3TC are concurrently administered.

This is a study of 2 schedules of Combivir therapy. At study entry or Part I, all patients take Combivir twice daily for the 7-day adherence assessment. Patients who have demonstrated 70 percent or greater adherence \[AS PER AMENDMENT 7/20/01: 70 percent compliance with the study regimen for Combivir. This corresponds to taking at least 10 of the prescribed 14 Combivir tablets during the 7 days prior to an adherence assessment, including all scheduled doses in the 24-hour period prior to that assessment.\], and have taken all scheduled Combivir doses in the previous 24 hours, have pharmacokinetic samples obtained and are randomized to Group A or Group B in Part II. Group A patients take 2 Combivir tablets once daily; Group B patients take 1 Combivir tablet twice daily. After patients have completed the targeted duration of Part II (7 days for Group A and 7-14 days for Group B), they are assessed for adherence. Patients who have demonstrated 70 percent or greater adherence, and have taken all scheduled Combivir doses in the previous 24 hours, have pharmacokinetic samples obtained and then change to the alternate dosing schedule. Group A patients take 1 Combivir tablet twice daily; Group B patients take 2 Combivir tablets once daily. After patients have completed the targeted duration of Part III (7-14 days for Group A and 7 days for Group B), they are assessed for adherence. All patients who meet the adherence criteria have pharmacokinetic samples obtained. After completion of Part III pharmacokinetic studies, patients have completed the study. (Note: Combivir will not be provided in this study.)

Eligibility criteria: Inclusion Criteria

Patients may be eligible for this study if they:

* Are 12 through 24 years of age.
* Are HIV-positive.
* Weigh more than 40 kg.
* Have a CD4 cell count above 250 cells/microL.
* Have taken at least 4 weeks of 3 or more anti-HIV medications, which must include ZDV and 3TC (as individual drugs or Combivir) and either a protease inhibitor or nonnucleoside reverse transcriptase inhibitor, and do not plan to change these medications during the study period.
* Have consent of a parent or guardian if under 18 years of age.
* Have a negative pregnancy test, if female and able to have children.
* Agree to use 2 effective methods of birth control (birth control pills plus a barrier method or 2 barrier methods) while taking study medication, if female and able to have children.

Exclusion Criteria

Patients will not be eligible for this study if they:

* Have an opportunistic (AIDS-related) infection that requires treatment at study entry.
* Are receiving anti-cancer medications for cancer.
* Are taking certain anti-HIV medications (nucleoside or nucleotide reverse transcriptase inhibitors, other than ZDV and 3TC), or hydroxyurea.
* Are pregnant or breast-feeding.
* Have diseases (other than HIV infection) or other conditions that, in the investigator's opinion, would interfere with the study.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: San Diego
country: United States
facility: Univ of California, San Diego
state: California
city: Jacksonville
country: United States
facility: Univ of Florida Health Science Ctr / Pediatrics
state: Florida
city: Atlanta
country: United States
facility: Emory Univ Hosp / Pediatrics
state: Georgia
city: Chicago
country: United States
facility: Mt Sinai Hosp Med Ctr / Dept of Pediatrics
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Chicago Children's Memorial Hosp
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ / Charity Hosp of New Orleans
state: Louisiana
city: Boston
country: United States
facility: Children's Hosp of Boston
state: Massachusetts
city: Jackson
country: United States
facility: Univ of Mississippi Med Ctr
state: Mississippi
city: Newark
country: United States
facility: Univ of Medicine & Dentistry of New Jersey / Univ Hosp
state: New Jersey
city: Paterson
country: United States
facility: St Joseph's Hosp & Med Center
state: New Jersey
city: New York
country: United States
facility: Metropolitan Hosp Ctr
state: New York
city: Stony Brook
country: United States
facility: State Univ of New York at Stony Brook
state: New York
city: Syracuse
country: United States
facility: SUNY Health Sciences Ctr at Syracuse / Pediatrics
state: New York
city: Philadelphia
country: United States
facility: Children's Hosp of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine
state: Pennsylvania
city: Memphis
country: United States
facility: Saint Jude Children's Research Hosp of Memphis
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hosp / Baylor Univ
state: Texas
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico / Univ Children's Hosp AIDS
Study officials:
name: Patricia Flynn
role: STUDY_CHAIR
References:
citation: Flynn PM, Rodman J, Lindsey JC, Robbins B, Capparelli E, Knapp KM, Rodriguez JF, McNamara J, Serchuck L, Heckman B, Martinez J; PACTG P1012 Team. Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother. 2007 Oct;51(10):3516-22. doi: 10.1128/AAC.01626-06. Epub 2007 Jul 30.