HIV/AIDS Treatment, HIV Infections
Conditions
Keywords
HIV/AIDS, pediatrics, resource-limited settings, lopinavir, ritonavir, Kaletra®, antiretroviral treatment, crushed tablets, treatment experienced
Brief summary
The objective of this study is to compare the pharmacokinetics of lopinavir tablets administered to pediatric patients as either whole or crushed tablets. The study is a randomized,open-label, crossover study of pediatric subjects already taking lopinavir/ritonavir tablets as part of their clinical care. THe investigators hypothesize that lopinavir exposure in pediatric patients will be lower after taking a dose of the tablet formulation, crushed and mixed with pudding or yogurt, as compared to the exposure after taking a dose with tablets swallowed whole.
Detailed description
By the end of 2005, approximately 2.3 million children worldwide were living with HIV/AIDS.1 At least 660,000 children worldwide have advanced HIV/AIDS and are in dire need of antiretroviral treatment. While many barriers exist to scaling up HIV/AIDS care and treatment globally, access to life-saving treatments for children is increasing. The protease inhibitor, lopinavir/ritonavir (Kaletra®), is recommended as a first-line agent by the World Health Organization and by the US Department of Health and Human Services for the treatment of pediatric patients in resource-limited settings and in the United States. The prescribing information states that these tablets may not be crushed, broken or chewed, and the manufacturer does not plan to examine the pharmacokinetics of crushed tablets at this time. The company found that the crushed tablets were poorly absorbed in a small pharmacokinetic study in several dogs. While this information has spread through investigators by word-of-mouth, this information has not been published in any forum by the company, and no guidance as to the extent of the decrease in absorption has been provided. However, patients and caregivers are dosing pediatric patients with crushed tablets to overcome some of the limitations of the oral solution. If crushed tablet administration yields significantly lower systemic exposure to lopinavir than whole tablets, then patients using this administration technique will be at higher risk for development of viral resistance and treatment failure. This administration technique must be studied so that providers have evidence to support recommendations about this dose administration strategy.
Interventions
DRUGlopinavir/ritonavir (Kaletra®) tablets
The subject will bring their own prescription of lopinavir/ritonavir. The patient will take a witnessed dose of lopinavir/ritonavir with an 6 ounce glass of cool water (if taken whole) or mixed in 4 ounces of Jell-O brand pudding (if crushed).
Sponsors
American Association of Colleges of Pharmacy
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Documented HIV infection * Taking lopinavir/ritonavir (Kaletra) tablets at standard pediatric doses for greater than two weeks * Concomitant medications and/or natural products, including potentially interacting products, have been stable for greater than two weeks and are not expected to change over the course of the study * Ability to understand study procedures and assent to participate * Parental or guardian consent * Aged 6 - 17 years
Exclusion criteria
* Acute serious medical illness or infection (in the judgment of the investigator)requiring treatment and/or hospitalization within 14 days prior to study entry * Pregnancy * Concomitant medications/natural products that have been started within past two weeks and/or that will be changed over the course of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lopinavir Area Under the Curve (AUC) | pre-dose, 1,2,4,6,8, and 12 hours post-dose | Lopinavir Area Under the Plasma Concentration versus Time Curve (AUC) |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between August 2008 to August 2009 from the Special Immunology Program at Children' National Medical Center in Washington DC.
Participants by arm
| Arm | Count |
|---|---|
| Whole Then Crushed Tablets These subjects will take whole lopinavir tablets at Study Visit 1, and crushed tablets at Study Visit 2. | 6 |
| Crushed Then Whole Tablets These subjects will take crushed tablets at Study Visit 1, and whole tablets at Study Visit 2. | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Crushed Then Whole Tablets | Whole Then Crushed Tablets | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 13 Years | 12 Years | 13 Years |
| Region of Enrollment United States | 7 participants | 6 participants | 13 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Lopinavir Area Under the Curve (AUC)
Lopinavir Area Under the Plasma Concentration versus Time Curve (AUC)
Time frame: pre-dose, 1,2,4,6,8, and 12 hours post-dose
Population: All subjects who completed the pharmacokinetic sampling visits with whole tablet administration were analyzed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Subjects Taking Whole Tablets | Lopinavir Area Under the Curve (AUC) | 144 mg*hr/L |
| All Subjects Taking Crushed Tablets | Lopinavir Area Under the Curve (AUC) | 92 mg*hr/L |
Comparison: Lopinavir AUC was compared between whole tablet and crushed tablet administration by using a ratio of crushed/whole AUC.p-value: <0.0590% CI: [0.45, 0.69]t-test, 2 sided