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Objectives: Before producing this form, we would like to simulate on existing data, the twice daily recommended doses and propose an adapted number of tablets for the once-daily administration.
Study design: A meta-analysis of DRV/r pharmacokinetics on existing data in children will be made. Simulations of doses multiple of 120/20 mg will be performed on the different weight bands for once and twice daily administration.
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Two models, one for darunavir and one for ritonavir will be constructed in parallel. Ritonavir exposure, trough concentration will be estimated for each sample. These parameters and the ritonavir concentration at the time of sampling will be added on darunavir model to explain the booster effect. Different pharmacokinetics model will be used, representing competitive and non-competitive models.
Simulations will then be performed with doses multiple of 120/20 mg once daily and twice daily in the 10-20 mg weight bands. Darunavir trough concentrations and exposure will be estimated for each patient and compared with the values for adults. The trough concentrations will also be compared with 10 times the protein binding-adjusted EC50 - the concentration at which 50% of wild type virus is effectively treated with the drug - i.e. 0.55 mg/L. If needed other doses for darunavir and for ritonavir will be tested.
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[1] Brochot A, Kakuda TN, Van De Casteele T, Opsomer M, Tomaka FL, Vermeulen A, Vis P. Model-Based Once-Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV-1-Infected Patients Aged ?3 to

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2020-4423

Research Proposal

Project Title: Darunavir/r modelling to simulate the adequacy of a 120/20 mg form for different weight bands and administration schemes.

Scientific Abstract: Background: The development of a new FDC DRV/r 120/20 mg has been added on WHO priority list. The UNIVERSAL study will verify that the administration of the WHO recommended with this new formulation provides adequate concentrations.
Objectives: Before producing this form, we would like to simulate on existing data, the twice daily recommended doses and propose an adapted number of tablets for the once-daily administration.
Study design: A meta-analysis of DRV/r pharmacokinetics on existing data in children will be made. Simulations of doses multiple of 120/20 mg will be performed on the different weight bands for once and twice daily administration.
Participants: Data from ARIEL, DELPHI and DIONE, Chapas-4, SMILE and therapeutic drug monitoring data will be asked.
The main outcome measures are darunavir pharmacokinetic primary parameters (clearances, volumes) and secondary parameters (residual concentrations, exposure) . The objectives of the meta-analysis are to describe darunavir pharmacokinetics, especially in children from 10 to 20 kg, describe interactions between darunavir and ritonavir pharmacokinetics and explain intersubject variability with age, bodyweight, alpha-1 glycoprotein. Simulations will be performed to check that the 2 and 3 tablets BID in the 10-13.9 and 14-19.9 kg produced comparable exposure to adults and acceptable residual concentrations and to propose a once-daily administration with the 120/20 mg tablets once daily.
Statistical Analysis: A non-linear mixed effect modeling method will be used for analysis and simulations.

Brief Project Background and Statement of Project Significance: Published pharmacokinetics data for the 3-6 years old children are very sparse. Data comes from the ARIEL study, including 24 treatment-experienced children weighting 10 to

Specific Aims of the Project: The aims of the study are to:
- Describe darunavir pharmacokinetics, especially in children from 10 to 20 kg.
- Describe interactions between darunavir and ritonavir pharmacokinetics
- Explain intersubject variability with age, bodyweight, alpha-1 glycoprotein and refine the effect of maturation of darunavir pharmacokinetics
- Simulate if the 2 and 3 tablets BID in the 10-13.9 and 14-19.9 kg produced comparable exposure to adults and acceptable residual concentrations.
- Propose a once-daily administration with the 120/20 mg tablets once daily.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: Preliminary research to be used as part of a grant proposal Participant-level data meta-analysis Meta-analysis using data from the YODA Project and other data sources

Software Used: R

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Existing data will be collected from different sources in order to construct the most robust model. Data from :
- ARIEL, DELPHI and DIONE study : Intensive PK were performed in ARIEL (children from 3 to 6 years old, 24 in bid, 10 in qd), DELPHI (41 children from 6 to 17 years old, with BID regimen) and children from DIONE (12 children from 12 to 17 years old with QD regimen).
- Chapas-4 study : Intensive 24h PK study was performed in 32 children; 8 children per weight bands: 14 to 19.9 kg, 20-24.9 kg, 25-34.9 kg and 35 kg.
- SMILE : In 150 children from 12 to 17 years old (6-12?), samples were collected at W4, W12 and W24.
- Therapeutic drug monitoring data from different hospitals, as Cochin Hospital in Paris will be added.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Darunavir and ritonavir concentrations are main outcome measure. They will be used as continuous variables.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Time after drug administration calculated from date/time of administration and date/time of sampling will be used (continuous variable).

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: The other variables needed for the analyses are:
- Dose, dose interval, galenic form
- date of treatment initiation (i.e. is the patient at steady state)
- age, bodyweight
- alpha-1 glycoprotein if present
- cotreatments

Statistical Analysis Plan: The data will be analyzed using a population approach. This method allows the inclusion of patients with few measurements per patient and authorizes the collection of samples at variable times compared to the intake, provided that there are a sufficient number of patients (n ? 30). The analysis is done simultaneously on all the data for a molecule. Compartmental models are used to describe the evolution of concentrations over time using constants representing the absorption, distribution and elimination of the drug.
The first step of this non-linear mixed effect modeling consists in finding the best curve describing all the concentrations as a function of time using the maximum likelihood method. This curve is called population prediction, it describes the curve of an "average patient" using median absorption, distribution and elimination constants.
The second step is for each concentration of each patient to explain the difference between the concentration observed and the concentration predicted by the model. Using Bayesian estimates, a concentration curve over time will be plotted for each patient, based on individual's absorption, distribution and elimination constants. An observed concentration will therefore correspond to a concentration predicted individually and a concentration predicted by the population model; the differences between these concentrations being the residual error and the interindividual variability.
The third step is to explain this interindividual variability by clinically relevant factors (demographic, genetic, co-medication). For example, if there is a significant sex effect, one population curve will represent male pharmacokinetics and another one will represent female pharmacokinetics. Thus, taking into account the significant covariates, a population curve could represent the average pharmacokinetics a 4 years old boy of 12 kg bodyweight.
Two models, one for darunavir and one for ritonavir will be constructed in parallel. Ritonavir exposure, trough concentration will be estimated for each sample. These parameters and the ritonavir concentration at the time of sampling will be added on darunavir model to explain the booster effect. Different pharmacokinetics model will be used, representing competitive and non-competitive models.
Simulations will then be performed with doses multiple of 120/20 mg once daily and twice daily in the 10-20 mg weight bands. Darunavir trough concentrations and exposure will be estimated for each patient and compared with the values for adults. The trough concentrations will also be compared with 10 times the protein binding-adjusted EC50 - the concentration at which 50% of wild type virus is effectively treated with the drug - i.e. 0.55 mg/L. If needed other doses for darunavir and for ritonavir will be tested.
Considering the potential availability of the data, first the model already published by Brochot et al. will be applied on the ARIEL, DIONE and DELPHI data to simulate exposure and trough concentrations produced for different numbers tablets of the 120/20 mg darunavir/r, according to weight bands. When the other data will be available, all the data will be reanalyzed together according to the analysis plan and simulations will be performed.

Narrative Summary: The WHO-led Paediatric Antiretroviral Drug Optimization (PADO) group recently reviewed medium-term priorities to give more effective child-friendly HIV drugs. A potent ritonavir-boosted protease inhibitor-fixed-dose combination of darunavir (DRV/r) at a paediatric dose of 20 mg ritonavir plus 120 mg darunavir was high on this priority list. The UNIVERSAL study will verify that the administration of the WHO recommended weight band dosing, using the newly developed FDC of DRV/r 120/20 mg tablets provides adequate concentrations. Before this trial, we would like to simulate on existing data these twice daily recommended doses and propose a once-daily administration with 120/20 mg tablets.

Project Timeline: - project start date: as soon as data are available
- analysis completion date: The model already published will be applied on the ARIEL, DIONE and DELPHI data to simulate exposure and trough concentrations produced for different numbers tablets of the 120/20 mg darunavir/r (2 months). When the other data will be available (mid of 2021), all the data will be reanalyzed together and simulations will be made (end of 2021)
- Date manuscript drafted and first submitted for publication: data used to test in the UNIVERSAL study. If interesting, a meta-analysis of all the data can be part of a manuscript.
- Date access for a 12 month period, with the possibility of an extension : end of 2021

Dissemination Plan: The simulations will be used to define best dosage for a 120/20 mg tablets which thus be tested in the UNIVERSAL study. A meta-analysis of darunavir/r data in children and the derived simulations could have an interest to be published. If so, it will be first submit to the YODA project before to a peer-reviewed journal as Antimicrobial Agents and Chemotherapy.

Bibliography:

[1] Brochot A, Kakuda TN, Van De Casteele T, Opsomer M, Tomaka FL, Vermeulen A, Vis P. Model-Based Once-Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV-1-Infected Patients Aged ?3 to