Lopinavir/Ritonavir (Kaletra) PK in Children

Pharmacokinetics of Lopinavir Crushed Versus Whole Tablets in Pediatric Patients

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV/AIDS Treatment
• Intervention / Treatment: Drug: lopinavir/ritonavir (Kaletra®) tablets

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego - Skaggs School of Pharmacy and School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Whole Then Crushed Tablets; These subjects will take whole lopinavir tablets at Study Visit 1, and crushed tablets at Study Visit 2.	Drug: lopinavir/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).; Other Names: Kaletra®
Experimental: Crushed Then Whole Tablets; These subjects will take crushed tablets at Study Visit 1, and whole tablets at Study Visit 2.	Drug: lopinavir/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).; Other Names: Kaletra®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lopinavir Area Under the Curve (AUC)	Lopinavir Area Under the Plasma Concentration versus Time Curve (AUC)	pre-dose, 1,2,4,6,8, and 12 hours post-dose

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Collaborators: American Association of Colleges of Pharmacy
• Investigators: Principal Investigator: Brookie Best, PharmD, MAS, University of California, San Diego

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: December 15, 2008
• First Submitted That Met QC Criteria: December 16, 2008
• First Posted (Estimate): December 17, 2008

Study Record Updates

• Last Update Posted (Estimate): July 6, 2012
• Last Update Submitted That Met QC Criteria: June 2, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: pediatrics; antiretroviral treatment; treatment experienced; HIV/AIDS; ritonavir; lopinavir; resource-limited settings; Kaletra®; crushed tablets
• 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; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir
• Other Study ID Numbers: 10894