Acquired Immunodeficiency Syndrome
Conditions
Keywords
HIV, ART, HAART, Pharmacokinetics, Lopinavir/ritonavir, Lower dose selection
Brief summary
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
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.
Interventions
DRUGlopinavir/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.
Sponsors
Kirby Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Lopinavir/Ritonavir Concentrations as Measured by the Area Under the Curve (AUC 0-12h). | at the end of each 7-day dosing phase | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Up to 11 weeks from screening to final study visit | 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All participants were given three sequential doses of lopinavir/ritonavir: lopinavir/ritonavir 400/100mg twice daily (2 heat-stable 200/50mg tablets BID), lopinavir/ritonavir 200/150mg twice daily (1 heat-stable 200/50mg tablet BID plus 1 ritonavir 100mg capsule BID), lopinavir/ritonavir 200/50mg twice daily (1 heat-stable 200/50mg tablet BID). Each dosing phase lasted for 7 days and each phase was separated by a 7-day wash-out period. Pharmacokinetic evaluations were made over a 12-hour interval at the end of each dosing phase. | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age Continuous | 36 years STANDARD_DEVIATION 9.49 |
| Region of Enrollment United Kingdom | 22 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 22 |
| serious Total, serious adverse events | 0 / 22 |
Outcome results
Primary
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.
Time frame: at the end of each 7-day dosing phase
Population: 22 participants completed the three sequential dosing phases and pharmacokinetic evaluations as per protocol. The same 22 participants are in the analysis population for each lopinavir/ritonavir dose (arm).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LPV/r 400/100 mg | Plasma Lopinavir/Ritonavir Concentrations as Measured by the Area Under the Curve (AUC 0-12h). | 99599 ng.h/mL |
| LPV/r 200/150 mg | Plasma Lopinavir/Ritonavir Concentrations as Measured by the Area Under the Curve (AUC 0-12h). | 73603 ng.h/mL |
| LPV/r 200/50 mg | Plasma Lopinavir/Ritonavir Concentrations as Measured by the Area Under the Curve (AUC 0-12h). | 45146 ng.h/mL |
Comparison: Dosing regimens lopinavir/ritonavir 200/150mg BID (Phase 2) and lopinavir/ritonavir 200/50mg BID (Phase 3) will be considered equivalent to lopinavir/ritonavir 400/100mg BID (Phase 1) if the 90% confidence interval (CI) for the mean AUC0-12h ratio and maximum concentration (Cmax) ratio lie between 0.80 and 1.25.p-value: <0.05maximum likelihood regression
Secondary
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.
Time frame: Up to 11 weeks from screening to final study visit
Population: 22 participants completed the three sequential dosing phases and pharmacokinetic evaluations as per protocol. The same 22 participants are in the analysis population for each lopinavir/ritonavir dose (arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r 400/100 mg | Adverse Events | 27 number of adverse events |
| LPV/r 200/150 mg | Adverse Events | 2 number of adverse events |
| LPV/r 200/50 mg | Adverse Events | 4 number of adverse events |