Paper # 621 
Bidirectional Pharmacokinetic Interaction between Posaconazole and Fosamprenavir
R Brüggemann1, M van Luin1, M van den Dungen1, A Colbers1, B Schouwenberg1, R le Blanc2, C Pharo3, and David Burger*1
1Radboud Univ Nijmegen Med Ctr, The Netherlands; 2GlaxoSmithKline BV, Zeist, The Netherlands; and 3GlaxoSmithKline Pharma Europe, Brentford, UK
Background: Posaconazole (POS), fosamprenavir (FPV),
and ritonavir (RTV) are all CYP3A4 inhibitors. FPV is also a CYP3A4 substrate,
whereas POS is metabolized by UDP-glucuronosyltransferase (UGT). RTV is
an inducer of UGT. Therefore, combining FPV/RTV with POS may lead to
potentially sub-therapeutic POS exposure, while exposure to FPV may be
increased with an increased risk of FPV toxicity. To manage the interaction
between FPV/RTV and POS, we hypothesized that RTV can be replaced by POS as an
alternative booster of the pharmacokinetics (PK) of FPV with minimal negative
effect on POS PK.
Methods: This was an open-label, randomized,
3-period, cross-over, single-center trial in 24 healthy volunteers. All
subjects received the following 3 treatments, separated by a washout period of
17 days: POS 400 mg BID for 10 days; FPV/RTV 700/100 mg BID for 10 days and POS
400 mg BID with FPV 700 mg BID for 10 days. Subjects were randomized to the 6
different treatment sequences. All drugs were taken with a standardized breakfast.
Blood was collected on day 10 of each treatment period for up to 12 hours after
dosing for PK analysis. Plasma concentrations of POS and FPV were determined
using validated HPLC methods. PK parameters were calculated using WinNonlin
5.2. Geometric mean ratios (GMR) and 90% confidence intervals (CI) of POS AUC
and Cmax in the test period (POS + FPV) vs in the reference period
(POS alone) were calculated and the same was done for FPV (FPV + POS vs
FPV/RTV). The absence of an interaction corresponds to the 90% CI of the GMR
falling completely within 0.80 to 1.25.
Results: There were 20 subjects that completed the
trial, 12 males and 8 females. Three subjects were excluded due to grade II /
III rash (one on FPV/RTV and 2 on FPV + POS). One subject withdrew consent. No
serious adverse events were reported. GMR (+90%CI) of POS AUC and Cmax
when taken with FPV vs POS alone were 0.77 (0.68 to 0.87) and 0.79 (0.71 to 0.89),
respectively, indicating that FPV has a negative effect on POS PK. The GMR of
FPV AUC and Cmax when taken as FPV + POS vs FPV/RTV was 0.35 (0.32
to 0.39) and 0.64 (0.55 to 0.76) respectively, indicating that POS does not
boost FPV PK, as effectively as RTV does.
Conclusions: POS should not be used concomitantly
with unboosted FPV. Further research is needed to determine if FPV/RTV can be
combined with an adjusted dose of POS without resulting in suboptimal POS
exposure and toxicity of FPV.
|
