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SHARE THIS ABSTRACT WITH A COLLEAGUE ABT-378/r is a novel HIV protease inhibitor (PI), with a mean inhibitory quotient (IQtrough = Trough Concentration/EC50) exceeding by 75-fold the protein binding-corrected EC50 for wild-type HIV when given at a dose of 400/100 mg (3 capsules) BID. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI). PK interaction is possible because NVP is a CYP3A inducer and ABT-378/r is a CYP3A substrate. Previously we observed no apparent interaction between 400/100 ABT-378/r and NVP after co-dosing for 21 days in a parallel arm study in healthy adult subjects; only 5 subjects completed the study due to adverse events (mostly rash). In a subsequent phase I/II study in 70 single PI-experienced, NNRTI-naïve adult subjects receiving ABT-378/r (400/100 or 400/200) and NVP combination, high antiviral activity was observed (66.7 and 76.5% <400 copies/mL, respectively, p=0.433, 24-week intent-to-treat). PK data obtained in a subset of patients were insufficient to assess a potential drug interaction, but demonstrated that high IQ values were achieved in this patient population. The objective was to assess the interaction in 100 HIV+ children (6 months to 12 yrs) who received either ABT-378/r 230/57.5 or 300/75 mg/m2 BID, with (treatment experienced) or without (treatment naïve) NVP. A liquid formulation of ABT-378/r was used. All four regimens were well tolerated and no discontinuation was due to intolerance. The 24-week intent-to-treat response rates were similar for the two dose groups (73.5% and 72.5%, p=0.999). A steady-state 12-h PK was obtained in 26 (14 with NVP) and 27 (12 with NVP) children receiving 230/57.5 and 300/75, respectively. Pre-dose concentrations were obtained in almost all children (N=94). No effect of age was observed. However, co-administration with NVP resulted in reduced ABT-378 concentrations for both doses, and the effect was similar for the two doses. The point estimates (90% CI) for Cmin and AUC were 0.45 (0.25, 0.82) and 0.78 (0.56, 1.09), respectively, for the 300/75 mg/m2 dose. Similar effects were observed for ritonavir. The dose of 300/75 mg/m2 BID yields ABT-378 concentrations similar to (with NVP) or slightly higher than (without NVP) concentrations in adults receiving 400/100 mg BID. A similar NVP effect may be present in adults receiving ABT-378/r and may warrant dose increase of ABT-378/r (to 4 capsules BID) in patients with substantially reduced ABT-378 susceptibility.
Assessment of the Pharmacokinetic Interaction Between Lopinavir/Ritonavir
(ABT-378/r)
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