Study to Determine the Pharmacokinetic Behavior of Antiretroviral Drugs in Patients Infected by HIV

Study Overview
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Brief Summary
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The purpose of this study is to characterise the pharmacokinetic profiles of non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), and the influence of the individual characteristics on the pharmacokinetic parameters in the Spanish population of HIV-infected subjects.

Detailed Description
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The antiretrovirals were administered conventionally according to fixed dosage systems, or depending on the weight of the individual in the case of certain agents. However, the plasma levels of antiretrovirals following the administration of a fixed dose present a marked interindividual variability. Moreover, a significant proportion of the patients on treatment with PIs presented plasma levels regarded as suboptimal in previous studies. Moreover, for the correct modification of the dosage of a drug, populational data on its pharmacokinetic behaviour during the dosing interval is required. Only by integrating this information with the specific characteristics of each individual is it possible, using mathematical models, to estimate the effect that a modification of the dosage of the drug would have on its plasma concentration. However, populational data on the pharmacokinetic behaviour of antiretroviral agents are still very limited at this moment, and have not always been obtained in populations similar to the one to which they are to be applied. Thus, knowing the pharmacokinetic behaviour of the antiretroviral agents in our population and the influence of certain individual characteristics on this behaviour may be of great interest, since only in this way will we be able to tailor the dosage of antiretrovirals reliably in our patients.

Official Title
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Cross-sectional Study for the Characterisation of the Pharmacokinetic Parameters of Protease Inhibitors and Non-nucleoside Analog Reverse Transcriptase Inhibitors in the Spanish Population of HIV-infected Subjects

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Nevirapine
* Drug: Efavirenz
* Drug: Indinavir/ritonavir
* Drug: Nelfinavir
* Drug: Saquinavir/ritonavir
* Drug: Lopinavir/ritonavir
* Drug: Atazanavir
* Drug: Atazanavir/ritonavir
* Drug: Fos-amprenavir/ritonavir
* Drug: Tipranavir/ ritonavir
* Drug: Darunavir/ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age higher than 18 years. Documented HIV infection (at least one positive Western-blot) Stable antiretroviral treatment with PI or NNRTI, no changes over the last 4 weeks. Women may not be of fertile age (defined as at least one year from menopause or undergoing any surgical sterilisation technique), or negative pregnancy test. Exclusion Criteria: Subjects on treatment with more than one PI or with combinations of PI and NNRTI (the use of ritonavir in doses below 400 mg BID will not be regarded as a second PI). Treatment with other drugs with known significant pharmacological interactions with the investigational drug over the previous two weeks. Unsuitable adherence to treatment (one or more doses omitted in the last week, or two or more doses omitted in the last two weeks). Presence of clinical findings or a background of gastrointestinal disease or digestive surgery that may interfere in the pharmacokinetics of the medication. Active consumption of alcohol (>50 grams/day) or illegal drugs (except cannabis). In the case of women, pregnancy or breastfeeding. Record or suspicion of inability to cooperate properly

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NVP<br>Nevirapine | Drug: Nevirapine<br>* tablets 200 mg, 400 mg/day<br>* Other names: Viramune;|
| Experimental: EFV<br>Efavirenz | Drug: Efavirenz<br>* tablets 600 mg, 600 mg/day<br>* Other names: Sustiva;|
| Experimental: INV<br>Indinavir/ritonavir | Drug: Indinavir/ritonavir<br>* Indinavir: capsules 400 mg, 1600 mg/day Ritonavir: capsules 100 mg, 200 mg/day<br>* Other names: Crixivan/norvir;|
| Experimental: NFV<br>Nelfinavir | Drug: Nelfinavir<br>* tablets 250 mg, 2500 mg/day<br>* Other names: Viracept;|
| Experimental: SQV<br>Saquinavir/ritonavir | Drug: Saquinavir/ritonavir<br>* Saquinavir: tablets 500 mg, 2000 mg/day Ritonavir: tablets 100 mg, 200 mg/day<br>* Other names: Invirase/Norvir;|
| Experimental: LPV<br>Lopinavir/ritonavir | Drug: Lopinavir/ritonavir<br>* tablets lopinavir 200 mg + ritonavir 50 mg, 800/200 mg/day<br>* Other names: Kaletra;|
| Experimental: ATV<br>Atazanavir | Drug: Atazanavir<br>* capsules 200 mg, 400 mg/day<br>* Other names: Reyataz;|
| Experimental: ATV/rtv<br>Atazanavir/ritonavir | Drug: Atazanavir/ritonavir<br>* Atazanavir: capsules 150 mg, 300 mg/day Ritonavir: capsules 100 mg, 200 mg/day<br>* Other names: Reyataz/Norvir;|
| Experimental: Fos-APV<br>Fos-amprenavir/ritonavir | Drug: Fos-amprenavir/ritonavir<br>* Fos-amprenavir: capsules 700 mg, 1400 mg/day Ritonavir: capsules 100 mg, 200 mg/day<br>* Other names: Telzir/norvir;|
| Experimental: TPV<br>Tipranavir/ritonavir | Drug: Tipranavir/ ritonavir<br>* Tipranavir: tablets 250 mg, 1000 mg/day Ritonavir: capsules 100 mg, 400 mg/day<br>* Other names: Aptivus/Norvir;|
| Experimental: DRV<br>Darunavir/ritonavir | Drug: Darunavir/ritonavir<br>* Darunavir: tablets 300 mg, 1200 mg/day Ritonavir: capsules 100 mg, 200 mg/day<br>* Other names: Prezista/norvir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the plasma concentration of the PI/NNRTI drugs (Ka absorption constant, CI: plasma clearance, Vd: volume of distribution). |  | In the 12 hour (h) pharmacokinetic curve | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demographic: race, gender, age |  | In the 12 h pharmacokinetic curve | 
| Clinical: weight, height, liver/renal impairment, HIV infection stage, tobacco/alcohol consumption |  | In the 12 h pharmacokinetic curve | 
| Adverse events |  | In the 12 h pharmacokinetic curve | 
| Laboratory: creatinine, albumin, Quick Index, bilirubin, GOT, GPT, GGT, FA, CD4 lymphocyte count, HIV viral load, HBsAg and anti-HCV, alpha acid glycoprotein |  | In the 12 h pharmacokinetic curve | 
| Antiretroviral and concomitant treatment, adherence (number of doses omitted in the last two weeks) |  | In the 12 h pharmacokinetic curve | 
| Pharmacokinetics: maximum concentration (Cmax), time to maximum concentration (Tmax), plasma concentration at the end of the posology interval (Ctrough), half-life (T1/2), area under the curve (ABC) |  | In the 12 h pharmacokinetic curve | 
| Genetic study of polymorphism of CYP3A4 and P-glycoprotein |  | In the 12 h pharmacokinetic curve | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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protease inhibitors, non-nucleoside analog reverse transcriptase inhibitors, pharmacokinetic models, treatment experienced, HIV