Pharmacokinetic modelling of darunavir/ritonavir dose reduction (800/100 mg to 400/100mg once daily) containing regimen in virologically suppressed HIV-infected patients as maintenance treatment: ANRS-165 DARULIGHT sub-study
Background: Several strategies aiming
at simplifying maintenance antiretroviral therapy without jeopardizing efficacy
are being explored to improve long term tolerability, adherence and reduce costs.
This sub-study was
conducted in the setting of the ANRS-165 Darulight trial to evaluate DRV and
RTV plasma pharmacokinetic parameters in patients switching from DRV/RTV (800/100mgQD)
containing regimen to DRV/RTV (400/100mg QD).
Methods: Patients enrolled in this
multicenter, open-label, phase II single arm trial with plasma HIV-RNA (pVL)< 50c/mL
for ≥12 months while receiving stable DRV/RTV (800/100mg QD)+2 NRTIs were offered
to participate in this pharmacokinetic sub-study. Intensive 24h pharmacokinetic
blood sampling was performed at D0 (before the switch) and 12 weeks after
switching to DRV/RTV (400/100 mg QD) (W12). Total and unbound (DRV) and total
(RTV) plasma concentrations were determined by UPLC-MS/MS. Steady-state pharmacokinetic
parameters (AUC, Cmin, Cmax, t1/2) were determined by a non-compartmental
analysis. Paired Geometric Mean Ratio (GMR; IC90%) (W12/D0) was calculated
(Wilcoxon test). Apparent Clearance (Cl/F) and distribution volume (Vd/F) and
effect of RTV AUC were assessed by a non-linear mixed effects modelling
approach, using Monolix software.
Results: Fifteen men were
included and 12 full pharmacokinetic pairs (W12/D0) were available. Median age
was 42 years (IQR, 41-47). Pharmacokinetic parameters are presented in Table. DRV
and RTV half-lives remained unchanged. DRV and RTV Cl/F and Vd/F were
determined using one-compartment model with first order absorption and linear
elimination. DRV Cl/F and Vd/F were 28.4L/h (RSE (relative standard error) 22%)
and 199L (RSE16%). RTV Cl/F and Vd/F were 21.3L/h (RSE7%) and 171L (RSE9%). RTV
AUC did not appear to be of significant effect on Cl/F.
Conclusions: In HIV-infected
patients receiving maintenance therapy with DRV/RTV (800/100mg QD)+2 NRTIs, a
reduction of DRV/RTV to 400/100mg QD was associated with non-significant
decreases of total DRV AUC and total/unbound DRV Cmin and a small decrease of unbound
DRV AUC. Unexpectedly, RTV exposure slightly increased with the reduced DRV
dosing regimen.
M.P. Lê1,2, J.-M. Molina3, V. Madelain2, F. Raffi4, M.-L. Chaix5, S. Gallien6, E.M.B. El Abbassi7, C. Katlama8, P. Delobel9, Y. Yazdanpanah10, J. Saillard11, G. Peytavin1,2, ANRS 165 DARULIGHT Study Group
1AP-HP, Hopital Bichat-Claude Bernard, Laboratoire de Pharmaco-Toxicologie, Paris, France, 2IAME, UMR 1137 INSERM Université Paris Diderot, Paris, France, 3AP-HP, Hôpital Saint Louis, Service de Maladies Infectieuses et Tropicales, - INSERM U941- Université Denis Diderot Paris VII, Paris, France, 4CHU Hotel Dieu, Service de Maladies Infectieuses et Tropicales, Nantes, France, 5AP-HP, Hôpital Saint Louis, Laboratoire de Virologie, Paris, France, 6AP-HP, Hopital Henri Mondor, Service d'immunologie clinique & maladies infectieuses, Créteil, France, 7AP-HP, Hôpital Saint Louis, SBIM-URC, Paris, France, 8AP-HP, Hôpital Pitié-Salpêtrière, Service de Maladies Infectieuses et Tropicales, Paris, France, 9Hopital Purpan, Service de Maladies Infectieuses et Tropicales, Toulouse, France, 10AP-HP, Hopital Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, Paris, France, 11France Recherche Nord & Sud Sida-hiv Hépatites (ANRS), Paris, France