Pharmacokinetics of Lopinavir/Ritonavir at Three Different Doses. (ENCORE3)

Pharmacokinetics of Plasma Lopinavir/Ritonavir Over a 12 Hour Dosing Interval Following Administration of 400/100, 200/150, and 200/50 mg Twice Daily to HIV-negative Healthy Volunteers

The purpose of this study is to assess the pharmacokinetics of plasma lopinavir/ritonavir over a 12-hour dosing interval, following administration to male and female HIV-negative healthy volunteers of:

1. Lopinavir/ritonavir 400/100 mg twice daily
2. Lopinavir/ritonavir 200/150 mg twice daily
3. Lopinavir/ritonavir 200/50 mg twice daily

Study Overview

• Status: Completed
• Conditions: Acquired Immunodeficiency Syndrome
• Intervention / Treatment: Drug: lopinavir/ritonavir

Detailed Description

Data during the development of lopinavir/ritonavir showed that lower drug doses had similar efficacy to the standard dose of 400/100mg twice daily. Lower drug doses are also associated with limited toxicity and cost.

The purpose of this study is to assess the pharmacokinetics of plasma lopinavir/ritonavir following administration to male and female HIV-negative volunteers of 400/100mg, 200/150mg and 200/50mg lopinavir/ritonavir twice daily. Each dosing phase will last for 7 days and each phase will be separated by a 7-day wash-out period. Pharmacokinetic evaluations will be made over a 12-hour interval at the end of each dosing phase.

Healthy subjects as determined by their medical history and physical examinations will be eligible to participate in the study. HIV-positive subjects will not be recruited as there is a risk that HIV-resistant mutations will be selected by an experimentally reduced dose of lopinavir/ritonavir. There is no reason to presume that there is any meaningful difference in the metabolic processing of lopinavir/ritonavir between HIV-infected and HIV-uninfected people.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9TH
    • St Stephen's Centre, Chelsea and Westminster Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must meet all of the following inclusion criteria within 28 days prior to the baseline visit:

  1. The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements
  2. Male or non-pregnant, non-lactating females
  3. Between 18 to 65 years, inclusive
  4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.
  5. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month after the study

Exclusion Criteria:

1. Any significant acute or chronic medical illness
2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations
3. Positive blood screen for hepatitis B core and/or C antibodies and/or hepatitis B surface antigen
4. Positive blood screen for HIV-1 and/or 2 antibodies
5. Current or recent (within 3 months) gastrointestinal disease
6. Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study
7. Exposure to any investigational drug or placebo within 3 months of first dose of study drug
8. Consumption of grapefruit, or Seville oranges or any grapefruit or Seville orange containing product within one week of first dose of study drug and for the duration of the study
9. Use of any other drugs, including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.
10. Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 30 days after the end of the treatment period
11. Previous allergy to any of the constituents of the pharmaceuticals administered in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LPV/r 400/100 mg; Lopinavir/ritonavir 400/100 mg twice daily (2 heat-stable 200/50 mg tablets twice daily (BID))	Drug: lopinavir/ritonavir; Each participant received three sequential doses of lopinavir/ritonavir: 400/100 mg twice daily (2 heat-stable 200/50 mg tablets BID), 200/150 mg twice daily (1 heat-stable 200/50 mg tablet BID plus 1 ritonavir 100 mg capsule BID), and 200/50 mg twice daily (1 heat-stable 200/50 mg tablet BID). Each dosing phase lasted for 7 days and each phase was separated by a 7-day wash-out period.; Other Names: Ritonavir; Meltrex
Experimental: LPV/r 200/150 mg; Lopinavir/ritonavir 200/150 mg twice daily (1 heat-stable 200/50 mg tablet BID plus 1 ritonavir 100 mg capsule BID)	Drug: lopinavir/ritonavir; Each participant received three sequential doses of lopinavir/ritonavir: 400/100 mg twice daily (2 heat-stable 200/50 mg tablets BID), 200/150 mg twice daily (1 heat-stable 200/50 mg tablet BID plus 1 ritonavir 100 mg capsule BID), and 200/50 mg twice daily (1 heat-stable 200/50 mg tablet BID). Each dosing phase lasted for 7 days and each phase was separated by a 7-day wash-out period.; Other Names: Ritonavir; Meltrex
Experimental: LPV/r 200/50 mg; Lopinavir/ritonavir 200/50 mg twice daily (1 heat-stable 200/50 mg tablet BID)	Drug: lopinavir/ritonavir; Each participant received three sequential doses of lopinavir/ritonavir: 400/100 mg twice daily (2 heat-stable 200/50 mg tablets BID), 200/150 mg twice daily (1 heat-stable 200/50 mg tablet BID plus 1 ritonavir 100 mg capsule BID), and 200/50 mg twice daily (1 heat-stable 200/50 mg tablet BID). Each dosing phase lasted for 7 days and each phase was separated by a 7-day wash-out period.; Other Names: Ritonavir; Meltrex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Lopinavir/Ritonavir Concentrations as Measured by the Area Under the Curve (AUC 0-12h).	Pharmacokinetics of plasma lopinavir/ritonavir over a 12-hour dosing interval following administration of lopinavir/ritonavir 400/100mg, 200/150mg and 200/50mg twice daily.	at the end of each 7-day dosing phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Number of reported adverse events, severity of adverse events and relationship to study drug was assessed by questions, physical examination and laboratory parameters. Adverse event data was used to assess the safety and tolerability of low lopinavir/ritonavir doses.	Up to 11 weeks from screening to final study visit

Collaborators and Investigators

• Sponsor: Kirby Institute
• Investigators: Principal Investigator: Marta Boffito, MD PhD, Chelsea and Westminster Hospital

Publications and helpful links

General Publications

• Jackson A, Hill A, Puls R, Else L, Amin J, Back D, Lin E, Khoo S, Emery S, Morley R, Gazzard B, Boffito M. Pharmacokinetics of plasma lopinavir/ritonavir following the administration of 400/100 mg, 200/150 mg and 200/50 mg twice daily in HIV-negative volunteers. J Antimicrob Chemother. 2011 Mar;66(3):635-40. doi: 10.1093/jac/dkq468. Epub 2010 Dec 17.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: September 25, 2009
• First Submitted That Met QC Criteria: September 25, 2009
• First Posted (Estimate): September 28, 2009

Study Record Updates

• Last Update Posted (Estimate): March 29, 2011
• Last Update Submitted That Met QC Criteria: March 2, 2011
• Last Verified: March 1, 2011

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; HAART; ART; Lopinavir/ritonavir; Lower dose selection
• 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; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; 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: NCHECR-ENCORE3