Clinical trial NCT00622206: Pharmacokinetics of Low Dose Ritonavir
Official title: Pharmacokinetics of Low Dose Ritonavir in Thai Patients on a Saquinavir 1500 mg Based HAART Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: Pharmacokinetics
ritonavir
saquinavir
safety and toxicity
treatment experienced
Lead sponsor: The HIV Netherlands Australia Thailand Research Collaboration
Sponsor class: OTHER
First posted: 2008-02-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Compare the Pharmacokinetics of ritonavir and saquinavir(using either Saquinavir /Ritonavir 1500/100 mg or 1500/50 mg) Evaluate short term tolerability, safety and toxicity Evaluate if there is any relation between RTV concentration levels and boosting effect

Detailed description: This study will focus on the combination of Saquinavir (SQV) and RTV. Firstly, this is because SQV is widely used in Thailand and has shown to be an adequate first and second line antiretroviral agent. Secondly, reduced dose of SQV (1600 mg OD) has proven to generate adequate efficacy and good pharmacokinetic parameters in the Thai population\[5, 6\]. Now 500 mg tablets of SQV are becoming more and more available, therefore a 1500 mg OD dose will be of more interest for our study. A TDM comparison study between SQV 1600 OD mg and SQV1500 mg OD has been done (Ananworanich et al, unpublished data) and did not show any difference in terms of drug concentrations . The efficacy of this regimen has shown to be adequate as described in the STACCATO cohort\[7\]. So we consider it safe to use the SQV 1500 mg OD in our study.

It is not clear what RTV concentrations are necessary to obtain good levels for SQV. In the study of Autar et al \[5\] no relation between RTV levels and boosting effect was described. Besides that it might well be that even the boosting levels of RTV contribute to the toxicity of the antiretroviral treatment.For instance, a study performed in healthy volunteers on RTV 100 mg BID monotherapy, showed a significant increase in total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides and a marked reduction of high-density lipoprotein (HDL)\[8\]. This last finding was confirmed in the study of Boyd et al (submitted) in Thai HIV-infected patients.

Preliminary data from HIVNAT 019 \[9\] suggests that lower boosting dosage still give adequate levels of the other PIs. In this open label 4 arm study one arm contains Lopinavir/Ritonavir 266/66 mg bid together with SQV 600 mg bid. Despite the dose reduction in all PIs, adequate PK levels were obtained. Two arms (23 patients) in this study used normal dose of RTV (100 mg bid) in combination with Lopinavir and Saquinavir. Five of them had maximal concentrations (Cmax) above the therapeutic level RTV (\>2.1 mg/l). This finding is supported by clinical experience.

Therefore, looking into lower doses of RTV in the Thai population is of great interest A liquid formulation for RTV 50 mg will be used, as a capsule is not available yet. The liquid formulation has the same bioequivalence as the capsule and was used extensively during the time of manufactory problems of the Norvir capsule. Because of the bad taste of this formulation PK samples will be collected after one week, thereafter patients can return to their old regimen. A dose reduction of RTV can be of great importance for the Thai population as it prevents unnecessary toxicity and costs. If this PK study turns out to be adequate, an efficacy study can be performed and the boosting of other commonly used PI's, like IDV and Lopinavir, can be studied.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Documented positive test for HIV-1 infection
* HIV RNA viral load 50 \< copies for at least 3 months
* Written informed consent
* On a Saquinavir 1500 mg based HAART regimen for at least 3 months

Exclusion Criteria:

* Pregnant or lactating
* Use of concomitant medication that may interfere with the pharmacokinetics of saquinavir/ritonavir
* Inability to understand the nature and extent of the study and the procedures required
* ALT/ AST more than 5x upper limit
* Relevant history or current condition, illness that might interfere with drug absorption, distribution, metabolism or excretion.

Primary outcomes:
measure: To compare the Pharmacokinetics od ritonavir and saquinavir in Thai HIV-1 infected subjects using either Saquinavir /Ritonavir 1500/100 mg or 1500/50 mg
timeFrame: 6 months and 1 week
Secondary outcomes:
measure: Evaluate short term tolerability, safety and toxicity of this treatment strategy Evaluate if there is any relation between RTV concentration levels and boosting effect
timeFrame: 6 months and 1 week
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: HIV-NAT
Study officials:
affiliation: The HIV Netherlands Australia Thailand Research Collaboration
name: Kiat Ruxrungtham, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Avihingsanon A, van der Lugt J, Kerr SJ, Gorowara M, Chanmano S, Ohata P, Lange J, Cooper DA, Phanuphak P, Burger DM, Ruxrungtham K. A low dose of ritonavir-boosted atazanavir provides adequate pharmacokinetic parameters in HIV-1-infected Thai adults. Clin Pharmacol Ther. 2009 Apr;85(4):402-8. doi: 10.1038/clpt.2008.244. Epub 2008 Dec 31.