Clinical trial NCT00995241: Pilot Study to Compare the Pharmacokinetics Parameters in Plasma and Intracellular of Raltegravir Administered Once a Day in Adult Patients Infected With HIV
Official title: Pilot Study to Compare the Pharmacokinetics Parameters in Plasma and Intracellular of Raltegravir Administered Once a Day in Adult Patients Infected With HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: Raltegravir
intracellular concentration
plasmatic concentration
HIV
Treatment experienced
Lead sponsor: Germans Trias i Pujol Hospital
Sponsor class: OTHER
Collaborators: name: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
First posted: 2009-10-15
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare plasma and intracellular pharmacokinetic parameters of raltegravir 800 mg administered once daily in HIV infected patients.

Detailed description: HIV integrase is the enzyme responsible for transferring the DNA encoded by HIV to host chromosomes, a necessary step for the replication of retroviruses. Raltegravir (RAL) is the first integrase inhibitor approved for HIV treatment of patients infected by this virus. RAL has demonstrated a marked antiretroviral activity against HIV strains resistant to other antiretroviral drug families and high virological efficacy in patients pre-treated so as naïve to antiretroviral treatment. In addition, its safety profile is very favourable.

Unlike what happens with other antiretrovirals such as protease inhibitors, there is not a relationship between the virological response to antiretroviral treatment with RAL and the trough concentration of drug in plasma. Similarly, in vitro studies have shown that, after infection of cultured cells, the rate of viral replication measured by p24 antigen production was continuing inhibited even when RAL was washed from the culture medium from the 8 hours after infection, suggesting the possibility of a post-antibiotic effect of the drug. Either way, as in the case of transcriptase inhibitor nucleoside analogues, this lack of correlation between pharmacokinetics and pharmacodynamics of RAL may only be the result of intracellular accumulation of drug in blood lymphocytes peripheral, which in turn could be explained either by setting the RAL to the pre-integration complex or through the saturation of certain cellular transporters responsible for pumping the RAL from the inside out-cell (efflux transporters). Anyway, the result would be a greater RAL intracellular half-life than plasmatic, which would translate into a clinically persistent antiretroviral effect compared with its concentration in plasma.

Based on the above is possible to suggest that the average life of RAL was longer in the peripheral blood lymphocytes than in plasma, and that this intracellular increased half-life could explain the absence of relationship between trough RAL concentration and its virological efficacy, post-antibiotic effect of RAL found in some studies in vitro which, on the other hand, could be relevant to the possible once-daily administration of raltegravir.

Eligibility criteria: Inclusion Criteria:

1. Age \> 18 years.
2. HIV documented infection.
3. Stable antiretroviral treatment for at least 4 weeks.
4. HIV viral load in plasma \<50 copies / mL for at least 12 weeks
5. Voluntary written informed consent.

Exclusion Criteria:

1. AIDS-defining illness in the previous 4 weeks
2. Suspicion of inadequate adherence to antiretroviral therapy
3. In the case of women, pregnant or breastfeeding, or non-use of contraceptives
4. History or suspicion of failure to cooperate adequately
5. Concomitant therapy in the two weeks prior to inclusion in the study with atazanavir, tenofovir, NNRTI, rifampicin, inhibitors of proton pump or other drugs with known interactions with raltegravir.

Primary outcomes:
measure: Plasmatic and intracellular concentration of raltegravir
timeFrame: 10 days
Secondary outcomes:
measure: Clearance, CL/F
timeFrame: 10 days
measure: Volume of distribution, V/F
timeFrame: 10 days
measure: Elimination half-life, t1/2
timeFrame: 10 days
measure: Area under the plasma concentration-time curve during the dosing interval AUC0-24
timeFrame: 10 days
measure: Maximum concentration
timeFrame: 10 days
measure: Time to maximum concentration, Tmax
timeFrame: 10 days
measure: Minimum concentration
timeFrame: 10 days
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
Study officials:
affiliation: Germans Trias i Pujol Hospital
name: Jose Molto, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Marta Valle, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: