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Genetic Predictors of Variability in the Drug-drug Interaction Between Darunavir/Ritonavir and Pravastatin

This study has been completed.
Sponsor:
Collaborator:
Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT00630734
First received: February 28, 2008
Last updated: May 20, 2014
Last verified: May 2014
Results First Received: September 12, 2011  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: HIV Infections
Hyperlipidemia
Interventions: Drug: Pravastatin
Drug: Darunavir
Drug: Ritonavir
Other: Washout

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Healthy volunteers were recruited from the Denver metro area between March 2008 and September 2009.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were genetically screened for solute carrier organic anion transporter family, member 1B1 (SLCO1B1) diplotypes as follows: Group 1, *1A/*1A (reference diplotype); Group 2, *1A/*1B or *1B/*1B diplotypes; and Group 3, subjects with at least one copy of the *5, *15, or *17 haplotype.

Reporting Groups
  Description
SLCO1B1 Group 1 SLCO1B1 *1A/*1A diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18
SLCO1B1 Group 2 SLCO1B1 *1A/*1B or *1B/*1B diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18.
SLCO1B1 Group 3 Carriers of at least one SLCO1B1 *5, *15, or *17 haplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18

Participant Flow:   Overall Study
    SLCO1B1 Group 1     SLCO1B1 Group 2     SLCO1B1 Group 3  
STARTED     11     13     8  
COMPLETED     9     12     7  
NOT COMPLETED     2     1     1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
SLCO1B1 Group 1 SLCO1B1 *1A/*1A diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18
SLCO1B1 Group 2 SLCO1B1 *1A/*1B or *1B/*1B diplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18
SLCO1B1 Group 3 Carriers of at least one SLCO1B1 *5, *15, or *17 haplotype; Pravastatin 40 mg by mouth daily on days 1-4, washout on days 5-11, darunavir/ritonavir 600/100 mg by mouth twice daily on days 12-18, with pravastatin 40 mg added back on days 15-18
Total Total of all reporting groups

Baseline Measures
    SLCO1B1 Group 1     SLCO1B1 Group 2     SLCO1B1 Group 3     Total  
Number of Participants  
[units: participants]
  9     12     7     28  
Age  
[units: participants]
       
<=18 years     0     0     0     0  
Between 18 and 65 years     9     12     7     28  
>=65 years     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  36  ± 11     37  ± 12     39  ± 11     36  ± 11  
Gender  
[units: participants]
       
Female     2     9     4     15  
Male     7     3     3     13  
Region of Enrollment  
[units: participants]
       
United States     9     12     7     28  



  Outcome Measures
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1.  Primary:   Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

2.  Primary:   Relative Change in Pravastatin Maximum Plasma Concentration (Cmax)   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

3.  Secondary:   Pravastatin Alone: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

4.  Secondary:   Pravastatin Alone: Pravastatin Maximum Plasma Concentration (Cmax)   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

5.  Secondary:   Pravastatin + Darunavir/Ritonavir: Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

6.  Secondary:   Pravastatin + Darunavir/Ritonavir: Pravastatin Maximum Plasma Concentration (Cmax)   [ Time Frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose ]

7.  Other Pre-specified:   Darunavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval   [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]

8.  Other Pre-specified:   Darunavir Maximum Plasma Concentration (Cmax)   [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]

9.  Other Pre-specified:   Ritonavir Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval   [ Time Frame: 0, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]

10.  Other Pre-specified:   Ritonavir Maximum Plasma Concentration (Cmax)   [ Time Frame: 0,1, 2, 3, 4, 5, 6, 8, 12 hours post-dose ]


  Serious Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
Pravastatin Alone Pravastatin 40 mg by mouth daily on days 1-4; Includes 32 participants who received at least one dose of pravastatin 40 mg during days 1-4.
Darunavir/Ritonavir Alone Darunavir/Ritonavir 600/100 mg by mouth twice daily on days 12-14; Includes 31 participants who received at least one dose of darunavir/ritonavir during days 12-14.
Pravastatin + Darunavir/Ritonavir Darunavir/ritonavir 600/100 mg by mouth twice daily and pravastatin 40 mg by mouth once daily on days 15-18. Includes 28 participants who received at least one dose of darunavir/ritonavir and pravastatin during days 15-18.

Serious Adverse Events
    Pravastatin Alone     Darunavir/Ritonavir Alone     Pravastatin + Darunavir/Ritonavir  
Total, serious adverse events        
# participants affected / at risk     0/32 (0.00%)     0/31 (0.00%)     1/28 (3.57%)  
General disorders        
Angioedema † [2]      
# participants affected / at risk     0/32 (0.00%)     0/31 (0.00%)     1/28 (3.57%)  
# events     0     0     1  
Events were collected by systematic assessment
[2] 1 patient experienced grade 2 angioedema (as described by DAIDS criteria). This was not technically SAE, but did require pharmacologic intervention to prevent a more serious reaction.




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The study included only heterozygous carriers of the SLCO1B1 *15 and *17 haplotypes. Pravastatin urine concentrations were not measured; therefore the impact of darunavir/ritonavir on pravastatin renal clearance was not assessed in this population.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Christina Aquilante, Pharm.D.
Organization: University of Colorado Denver
phone: 303-724-6126
e-mail: christina.aquilante@ucdenver.edu


No publications provided


Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT00630734     History of Changes
Other Study ID Numbers: 07-0272, TMC114HIV4003
Study First Received: February 28, 2008
Results First Received: September 12, 2011
Last Updated: May 20, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board