Pharmacokinetics (PK) Study of Once Daily Darunavir/Ritonavir and Twice and Once Daily Raltegravir in HIV-infected Subjects

HIV Infections Clinical Trial

Official title: Plasma and Intracellular Pharmacokinetics of Once Daily Darunavir/Ritonavir and Twice and Once Daily Raltegravir in HIV-infected Subjects

Status Completed

Clinical Trial Summary

The study aims to help us understand if the HIV drugs darunavir (taken with ritonavir) and raltegravir will affect each other when they are given at the same time.

The purpose of the study is to assess the pharmacokinetics (how a drug is absorbed, distributed and eliminated from your body) of darunavir and ritonavir when these are taken with and without raltegravir.

The duration of the study will be up to 50 days plus a screening visit which will take place up to 4 weeks prior to the start of the study, and a follow up visit which takes place 1-2 weeks after the last dose of study medication.

Subjects will continue to take 2 of their usual drugs (those called nucleoside reverse transcriptase inhibitors -NRTI) throughout the study.

For the first 21 days subjects will take their usual NRTI plus raltegravir 400mg twice daily. After this, subjects will also receive either:

Group 1) Darunavir/ritonavir 800mg/100mg once daily AND raltegravir 400mg twice daily or Group 2) Darunavir/ritonavir 800mg/100mg once daily AND raltegravir 800mg once daily

Subjects will take this regimen for 14 days. Subjects will be randomly allocated to either Group 1 or 2. You will have an equal (50/50) chance of being allocated to Group 1 or 2.

Clinical Trial Description

The integrase inhibitor raltegravir has shown to a potent new agent for the treatment of HIV infection.

When raltegravir and darunavir/ritonavir have been combined in the Benchmark studies, they provided an excellent virological response in highly experienced patients.

Darunavir once daily use is increasing due to patients' preference for once daily regimens.

Raltegravir has not shown any pharmacokinetic/pharmacodynamic relationship and doses of 100 to 400 mg twice daily have shown similar virological responses. This may be due to intracellular drug accumulation.

However, data on the use of darunavir/r plus raltegravir once daily and on raltegravir intracellular concentrations are not available.

Whether raltegravir is efficacious when administered once daily is unknown. However, concentrations higher the IC95 of 33nM have been associated to a favourable virological response.

Therefore, we would like to investigate the plasma and intracellular pharmacokinetics of darunavir/ritonavir and raltegravir when co-administered once daily in order to provide further data to support the use of these agents once daily, patients' preferred dosing schedule.

Pharmacogenetics holds promise in HIV treatment because of the complexity and potential toxicity of multi antiretroviral drug therapies that are prescribed for long periods. Thus far, few candidate genes have been examined for a limited number of allelic variants, but a number of confirmed associations have already emerged.

From a public health perspective, as antiretroviral medications become increasingly available to racially and ethnically diverse populations worldwide, understanding the genetic structures of each population may allow us to anticipate the impact of adverse responses, even in groups that were not represented in drug registration trials.

The existing literature on pharmacogenetic determinants of antiretroviral drug exposure, drug toxicity, as well as genetic markers associated with the rate of disease progression underline the recent advances which occurred in the past few years.

However, it is expected that larger-scale comprehensive genome approaches will profoundly change the landscape of knowledge in the future. Additional studies are needed to assess the implications for long-term responses to antiretroviral agents.

For this reason we plan to collect a single blood sample from each participant in our intensive pharmacokinetic studies, such as this one, in order to be able to investigate the association between genetic polymorphisms in drug disposition genes (such as those encoding for cytochrome P450 isoenzymes or transmembrane transporters) and drug exposure. A candidate gene approach will be utilised to examine loci of interest. This procedure will provide potentially important information on genetic influences on plasma drug concentrations and give insight into how to improve the management of HIV-infected patients by individualising therapy. These studies will not be powered for genetic associations but will enable us to build a data base of genotype-phenotype. Prospective genetic studies would need to be planned based on these preliminary data. ;

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

• NCT number: NCT01047995
• Study type: Interventional
• Source: St Stephens Aids Trust
• Status: Completed
• Phase: Phase 1
• Start date: June 2009
• Completion date: December 2009