Optimization of Darunavir Therapy and Dosage Recommendations

Optimization of Darunavir Therapy Through Population Pharmacokinetic Modeling, Simulations and Dosage Guidelines

This study will assess and characterize the variability observed in the response to darunavir therapy, an antiretroviral medication used against the Human Immunodeficiency Virus (HIV). More specifically, it aims to quantify variations in the drug's blood concentrations and determine the sources of such variability, both genetic and non-genetic. In light of this information, current dosage guidelines will then be reviewed.

Data will be used to create a population pharmacokinetic model. Inter- and intra-individual pharmacokinetic variability will be quantified and linked to patient-specific covariates, both genetic and non-genetic in nature. Pharmacokinetic-pharmacodynamic relationships will be established, linking drug exposure to efficacy (as measured by CD4 cell count and viral load reduction) and toxicity (as measured by frequency and degree of adverse events). Simulations will be conducted for specific patient profiles and current dosage guidelines reviewed. Pharmacokinetic design : combined sparse/intensive sampling Sparse sampling : One blood sample collected in each individual at a random post-intake time (during a routine visit to the hospital), up to three times over the course of the study period (months 1-18). Intensive sampling : Eight blood samples collected over six hours in a subset of twelve individuals (during an additional observation period, months 19-22).

The investigated drugs are Prezista (darunavir 600 mg twice-daily or 800 mg once-daily) and Rezolsta (darunavir 800 mg/cobicistat 150 mg once-daily)

Assessment of darunavir whole-body clearance and inter-compartmental clearance through population pharmacokinetic methods

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Assessment of darunavir area under the concentration-time curve through population pharmacokinetic methods

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Assessment of the pharmacokinetic booster (either ritonavir or cobicistat, depending on the subject) AUC through population pharmacokinetic methods

Up to 18 months (blood sampling for PK once at each visit, three visits per patient over the study period)

Inclusion Criteria: Capable of giving informed consent HIV-positive Routinely followed at the Cliniques universitaires Saint-Luc Treated with darunavir Inclusion Criteria (intensive sampling): - Perfect adherence to treatment (as assessed by anamnesis and based on available PK data for each patient) Exclusion Criteria: - N/A

Stillemans G, Belkhir L, Vandercam B, Vincent A, Haufroid V, Elens L. Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations. Clin Pharmacokinet. 2021 Feb;60(2):177-189. doi: 10.1007/s40262-020-00920-z.