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

• Vd: volume of distribution
• The primary endpoint is the plasma concentration of the PI/NNRTI drugs. Assuming a mono-compartmental pharmacokinetic model with first-order kinetics, the following pharmacokinetic parameters will be estimated for each study group:
• Ka: absorption constant
• Cl: plasma clearance

• Demographic: race, gender, age [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: No ]
• Clinical: weight, height, liver/renal impairment, HIV infection stage, tobacco/alcohol consumption [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: No ]
• Adverse events [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: Yes ]
• Laboratory: creatinine, albumin, Quick Index, bilirubin, GOT, GPT, GGT, FA, CD4 lymphocyte count, HIV viral load, HBsAg and anti-HCV, alpha acid glycoprotein [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: Yes ]
• Antiretroviral and concomitant treatment, adherence (number of doses omitted in the last two weeks) [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: No ]
• 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) [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: No ]
• Genetic study of polymorphism of CYP3A4 and P-glycoprotein [ Time Frame: In the 12 h pharmacokinetic curve ] [ Designated as safety issue: No ]

• Demographic: race, gender, age.
• Clinical: weight, height, liver/renal impairment, HIV infection stage, tobacco/alcohol consumption.
• Adverse events
• Laboratory: creatinine, albumin, Quick Index, bilirubin, GOT, GPT, GGT, FA, CD4 lymphocyte count, HIV viral load, HBsAg and anti-HCV.
• Antiretroviral and concomitant treatment, adherence (number of doses omitted in the last two weeks).
• 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).

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.

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.

• Drug: Nevirapine
  tablets 200 mg, 400 mg/day
  Other Name: Viramune
• Drug: Efavirenz
  tablets 600 mg, 600 mg/day
  Other Name: Sustiva
• Drug: Indinavir/ritonavir

  Indinavir: capsules 400 mg, 1600 mg/day

  Ritonavir: capsules 100 mg, 200 mg/day

  Other Name: Crixivan/norvir
• Drug: Nelfinavir
  tablets 250 mg, 2500 mg/day
  Other Name: Viracept
• Drug: Saquinavir/ritonavir

  Saquinavir: tablets 500 mg, 2000 mg/day

  Ritonavir: tablets 100 mg, 200 mg/day

  Other Name: Invirase/Norvir
• Drug: Lopinavir/ritonavir
  tablets lopinavir 200 mg + ritonavir 50 mg, 800/200 mg/day
  Other Name: Kaletra
• Drug: Atazanavir
  capsules 200 mg, 400 mg/day
  Other Name: Reyataz
• Drug: Atazanavir/ritonavir

  Atazanavir: capsules 150 mg, 300 mg/day

  Ritonavir: capsules 100 mg, 200 mg/day

  Other Name: Reyataz/Norvir
• Drug: Fos-amprenavir/ritonavir

  Fos-amprenavir: capsules 700 mg, 1400 mg/day

  Ritonavir: capsules 100 mg, 200 mg/day

  Other Name: Telzir/norvir
• Drug: Tipranavir/ ritonavir

  Tipranavir: tablets 250 mg, 1000 mg/day

  Ritonavir: capsules 100 mg, 400 mg/day

  Other Name: Aptivus/Norvir
• Drug: Darunavir/ritonavir

  Darunavir: tablets 300 mg, 1200 mg/day

  Ritonavir: capsules 100 mg, 200 mg/day

  Other Name: Prezista/norvir

• Experimental: NVP
  Nevirapine
  Intervention: Drug: Nevirapine
• Experimental: EFV
  Efavirenz
  Intervention: Drug: Efavirenz
• Experimental: INV
  Indinavir/ritonavir
  Intervention: Drug: Indinavir/ritonavir
• Experimental: NFV
  Nelfinavir
  Intervention: Drug: Nelfinavir
• Experimental: SQV
  Saquinavir/ritonavir
  Intervention: Drug: Saquinavir/ritonavir
• Experimental: LPV
  Lopinavir/ritonavir
  Intervention: Drug: Lopinavir/ritonavir
• Experimental: ATV
  Atazanavir
  Intervention: Drug: Atazanavir
• Experimental: ATV/rtv
  Atazanavir/ritonavir
  Intervention: Drug: Atazanavir/ritonavir
• Experimental: Fos-APV
  Fos-amprenavir/ritonavir
  Intervention: Drug: Fos-amprenavir/ritonavir
• Experimental: TPV
  Tipranavir/ritonavir
  Intervention: Drug: Tipranavir/ ritonavir
• Experimental: DRV
  Darunavir/ritonavir
  Intervention: Drug: Darunavir/ritonavir

Inclusion Criteria:

1. Age higher than 18 years.
2. Documented HIV infection (at least one positive Western-blot)
3. Stable antiretroviral treatment with PI or NNRTI, no changes over the last 4 weeks.
4. 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:

1. 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).
2. Treatment with other drugs with known significant pharmacological interactions with the investigational drug over the previous two weeks.
3. Unsuitable adherence to treatment (one or more doses omitted in the last week, or two or more doses omitted in the last two weeks).
4. Presence of clinical findings or a background of gastrointestinal disease or digestive surgery that may interfere in the pharmacokinetics of the medication.
5. Active consumption of alcohol (>50 grams/day) or illegal drugs (except cannabis).
6. In the case of women, pregnancy or breastfeeding.
7. Record or suspicion of inability to cooperate properly