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: November 19, 2012
Last verified: November 2012
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
  Show All Outcome Measures

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 ]
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Measure Type Primary
Measure Title Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
Measure Description AUC of pravastatin when administered with darunavir/ritonavir divided by AUC of pravastatin when administered alone. The AUC was measured over a 24-hour dosing interval.
Time Frame 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours post-dose  
Safety Issue No  

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.
The population analyzed included participants who completed the pravastatin alone phase and the pravastatin + darunavir/ritonavir phase of the study.

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

Measured Values
    SLCO1B1 Group 1     SLCO1B1 Group 2     SLCO1B1 Group 3  
Number of Participants Analyzed  
[units: participants]
  9     12     7  
Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval  
[units: ng*hr/ml]
Mean ( 95% Confidence Interval )
  1.09  
  ( 0.73 to 1.46 )  
  1.59  
  ( 0.83 to 2.36 )  
  1.75  
  ( 0.52 to 2.97 )  


Statistical Analysis 1 for Relative Change in Pravastatin Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval
Groups [1] All groups
Method [2] ANOVA
P Value [3] 0.43
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Relative change data were compared between SLCO1B1 diplotype groups using one-way ANOVA (with post-hoc Bonferroni tests).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Threshold of significance was P<0.05.



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


  Other Adverse Events


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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.


Limitations and Caveats
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.  


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: November 19, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board