Principal Investigator: R. Chris Rathbun, PharmD, BCPS

Please Note: Research is in data analysis, for information on publications, please refer to contact information below

Abstract:

With the advent of long-term nucleoside analogue-associated toxicity and increased antiretroviral resistance, combination therapy that includes dual protease inhibitors is increasingly being utilized by clinicians. Treatment with once-daily antiretroviral regimens is also a high priority to clinicians to improve patient adherence.  Atazanavir is a once-daily protease inhibitor with a favorable lipid profile.   Lopinavir/ritonavir and atazanavir may prove to be a potent and well-tolerated combination; however, little is known about the drug interaction potential with these agents.  Preliminary experience with this combination has been reported, but formal pharmacokinetic studies with adequate statistical power are needed. Thirty HIV-infected individuals will be enrolled in this open-label, parallel pharmacokinetic study to provide at least 24 evaluable subjects to assess the potential for pharmacokinetic interaction under controlled conditions over 12-20 days.  Subjects receiving either lopinavir/ritonavir or atazanavir/ritonavir as part of their antiretroviral therapy will be recruited from the Infectious Diseases Institute clinic and will have a pharmacokinetic study performed with and without coadministration of the other protease inhibitor to examine whether the pharmacokinetics of either agent are altered.  The clinical hypothesis to be tested is whether coadministration of lopinavir/ritonavir tablets (Kaletra™) and atazanavir (Reyataz™) alters the pharmacokinetic profile of lopinavir or atazanavir.  This will be determined by comparing the pharmacokinetic parameters (AUC0-12,24, Cmax, Cmin) for lopinavir, ritonavir, and atazanavir in HIV-infected subjects.  Results from this study will provide valuable empiric dosing information to clinicians when using this combination and can guide the development of subsequent studies to determine optimal dosage adjustment should they be deemed necessary.

Highly active antiretroviral therapy (HAART) has been demonstrated to decrease the morbidity and mortality associated with HIV infection.[1]  Despite success with HAART, antiretroviral toxicity and drug resistance remain as important obstacles to achieving durable virologic suppression in some patients.[2,3]  Antiretroviral treatment strategies include the use of multiple protease inhibitors; however, little is known about the implications of this practice on serum concentration of newer agents and the resultant impact on safety and effectiveness. 

The objective of this application is to determine the pharmacokinetics of lopinavir, ritonavir, and atazanavir when lopinavir/ritonavir and atazanavir are used in combination.  The clinical hypothesis to be tested by this proposal is whether co-administration of lopinavir/ritonavir (Kaletra™) and atazanavir (Reyataz™) alters the pharmacokinetic profile of lopinavir or atazanavir.  This will be determined by comparing the pharmacokinetic parameters (AUC0-12,24, Cmax, Cmin) for lopinavir, ritonavir, and atazanavir in HIV-seropositive individuals.  The working hypothesis is that no difference in pharmacokinetic parameters for lopinavir or atazanavir exists.  The rationale for this study is that combination protease inhibitor therapy serves as a valuable therapeutic option for patients with extensive antiretroviral drug resistance; therefore, dosing guidelines are needed to assist clinicians in appropriate use of these agents.  We hypothesize that pharmacokinetic changes may result when HIV protease inhibitors are co-administered.  Furthermore, the extent of pharmacokinetic changes may place patients at risk for either increased toxicity or treatment failure as a result of inadequate serum concentrations.  Knowledge of these collective findings is pivotal for appropriate selection and dosing of antiretroviral therapy.

We plan to test our hypothesis and accomplish the objective of this application by pursuing the following two specific aims: 

1.            Evaluate the pharmacokinetics of lopinavir, ritonavir, and atazanavir following co-administration of lopinavir/ritonavir and atazanavir. 

                The working hypothesis is that protease inhibitors utilizing the same metabolic pathway(s) for metabolism are prone to drug-drug interactions when used concomitantly, thereby altering their pharmacokinetic profile(s).

2.            Examine the ability of lopinavir/ritonavir and atazanavir to maintain serum concentrations above the protein binding-corrected 95% inhibitory concentration.

                Target concentrations to optimize the likelihood of viral suppression in antiretroviral treatment-naïve patients have been determined for atazanavir and lopinavir when administered separately.  It is postulated that pharmacokinetic interactions could theoretically result in concentrations below these limits, increasing the likelihood of incomplete viral suppression depending on the nature of the interaction. 

It is our expectation that concurrent administration of lopinavir/ritonavir and atazanavir will alter the pharmacokinetic profile(s) of the administered agent(s); thereby increasing the risk for either virological failure secondary to subtherapeutic serum concentrations or adverse events secondary to supratherapeutic concentrations.  In the event a pharmacokinetic interaction is not observed, this study will illustrate that the potential for treatment failure or toxicity is not increased by use of this combination.  The resultant outcome of this investigation will be the establishment of dosing recommendations for lopinavir/ritonavir and atazanavir that will serve to guide clinicians in the safe and effective use of this drug combination in clinical practice.

Contact Information:

R. Chris Rathbun, PharmD, BCPS (405) 271-6878  Ext 47254