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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: 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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 675
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu i Sant Pau
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Germans Trias i Pujol Hospital
    • Figueras, Barcelona, Spain, 17600
      • Hospital de Figueres
    • Granollers, Barcelona, Spain, 08400
      • Fundació Hospital-Asil de Granollers
    • Vic, Barcelona, Spain, 08500
      • Hospital de Vic
  • Tarragona
    • Reus, Tarragona, Spain, 43201
      • Hospital Universitari Sant Joan de Reus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

11

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Germans Trias i Pujol Hospital
• Collaborators: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Publications and helpful links

General Publications

• Molto J, Xinarianos G, Miranda C, Pushpakom S, Cedeno S, Clotet B, Owen A, Valle M. Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clin Pharmacokinet. 2013 Jul;52(7):543-53. doi: 10.1007/s40262-013-0057-6.

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): December 1, 2009

Study Registration Dates

• First Submitted: March 27, 2006
• First Submitted That Met QC Criteria: March 27, 2006
• First Posted (ESTIMATE): March 28, 2006

Study Record Updates

• Last Update Posted (ACTUAL): December 4, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: HIV; treatment experienced; protease inhibitors; non-nucleoside analog reverse transcriptase inhibitors; pharmacokinetic models
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Ritonavir; Lopinavir; Indinavir; Tipranavir; Nelfinavir; Darunavir; Atazanavir Sulfate; Efavirenz; Fosamprenavir; Amprenavir; Saquinavir
• Other Study ID Numbers: PK-TRANSVERSAL; 2004-001516-32