769 
Pharmacokinetic/Pharmacodynamic Analyses of Once-daily Darunavir in the ARTEMIS Study
Vanitha Sekar*1, C Vanden Abeele2, B Van Baelen2, P Vis3, L Lavreys2, M De Pauw2, S Dincq2, T Vangeneugden2, S Spinosa-Guzman2, and R Hoetelmans2
1Tibotec Inc, Yardley, PA, US; 2Tibotec, Inc, Mechelen, Belgium; and 3Exprimo NV, Mechelen, Belgium
Background: In the phase
III ARTEMIS trial, treatment-naive HIV-1-infected adult patients were
randomized to receive darunavir/ritonavir (DRV/r) 800/100 once daily (n =
343) or lopinavir (LPV)/r 800/200 mg total daily dose (n = 346), plus
all received a fixed daily-dose of tenofovir (TDF)/emtricitabine (FTC). At week
48, 84% of DRV/r and 78% of LPV/r patients achieved viral load <50
copies/mL. The current analysis explored the relationship between DRV
pharmacokinetics and efficacy and safety following treatment with DRV/r 800/100
mg once daily in ARTEMIS.
Methods: Sparse blood
sampling was performed for 335 patients randomized to the DRV/r arm to
determine steady-state area under the curve (AUC24h) and predicted
trough concentration (C0h) for DRV using a population
pharmacokinetic model. Relationships between DRV pharmacokinetics and efficacy
at week 48 were assessed using analysis of co-variance models. Efficacy
measurements tested in the model included change in viral load from baseline
and proportion of patients achieving viral load <50 copies/mL. The
relationships between DRV pharmacokinetics and safety, and the occurrence of
adverse events of interest were investigated using descriptive methods.
Results: Plasma DRV C0h
exceeded the in-vitro protein-binding corrected EC50 target
concentration of 55 ng/mL for wild type virus in all 335 patients evaluated
(range 368 to 7242 ng/mL). No relationships were observed between DRV pharmacokinetic
and efficacy response parameters. Changes in viral load from baseline at week
48 by DRV AUC24h quartile ranges of ≤75,598; 75,599 to 87,854;
87,855 to 103,840, and >103,840 ng·h/mL were –3.11, –3.17, –3.07, and –3.11
log10 copies/mL, respectively. For these DRV AUC24h quartile
ranges, the proportion of patients reaching viral load <50 copies/mL was
94%, 95%, 90%, and 93% (observed data), respectively. No apparent relationships
were observed between DRV pharmacokinetic parameters and occurrence of rash,
nervous system and psychiatric disorders, or cardiac, gastrointestinal, liver,
lipid, and glucose-related adverse events.
Conclusions: No relevant
relationships between DRV pharmacokinetics and efficacy or safety at week 48
were observed at a DRV/r dose of 800/100 mg once daily in ARV-naïve
HIV-1-infected adult patients.
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