582
Pharmacokinetics of Vicriviroc are not Affected in Combination with Five Different Protease Inhibitors Boosted by Ritonavir
Angela Sansone*, A Keung, E Tetteh, H Weisbrot, M Martinho, S Lang, R Keller, and M Kraan
Schering-Plough Res Inst, Kenilworth, NJ, US
Background: Combination antiretroviral therapy is standard of care
for HIV/AIDS. Many agents are metabolized by cytochrome P450 enzymes and/or are
affected by the p-glycoprotein transporter protein (pGp). In this study, the potential interaction of
several ritonavir (RTV) boosted protease inhibitors (PI) on vicriviroc (VVC), a
novel CCR5 receptor antagonist, were evaluated.
Methods: An open-label, fixed sequence, sequential period,
multiple-drug interaction study was conducted in 8 exonerative volunteers for
each PI. VVC pharmacokinetics (PK) were
evaluated in combination with 5 PIs boosted with RTV. PIs studied were: atazanavir (ATV) [300mgQD],
indinavir (IDV) [800mgBID], fosamprenavir (FOS) [700mgBID], nelfinavir (NFV)
[1250mgBID], and saquinavir (SQV) [1000mgBID as Fortovase®]. RTV dosing was 100mg QD or BID, as
recommended for each PI. VVC+RTV were
given for 14 days prior to addition of each PI; triple combinations were administered
for 14 additional days (7 days for ATV) and f/up with boosted PIs without VVC thereafter
for 7 days. Plasma concentrations of VVC were collected over a 24-hr period on days
14, 21, and 28 (except ATV). Safety was monitored by clinical and standard lab
evaluations and periodic ECGs. PK
parameters calculated included Cmax, Cmin, Tmax, AUC(0-24hr), and CL/F; analyses
used standard methodology.
Results: 8 subjects completed all drug cohorts, except NFV in which
3 subjects discontinued. Two withdrew for non-treatment related causes and one
for rash. PK parameters showed no significant
effect of any boosted PI on VVC concentrations measured in a RTV-containing
regimen.
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VVC Parameter - mean
(%CV)
|
|
Treatment (Study Day)
|
Cmax(ng/mL)
|
AUC(0-24 hr) (ng•hr/mL)
|
|
VVC+RTV(14)
|
189(25)
|
3500(29)
|
|
VVC+RTV+ATV(21)
|
206(23)
|
3880(27)
|
|
VVC+RTV(14)
|
199(22)
|
3310(26)
|
|
VVC+RTV+IDV(28)
|
189(32)
|
3540(42)
|
|
VVC+RTV(14)
|
165(22)
|
2930(25)
|
|
VVC+RTV+FOS(28)
|
165(24)
|
2850(20)
|
|
VVC+RTV(14)
|
137(19)
|
2120(33)
|
|
VVC+RTV+NFV(28)
|
122(26)
|
2000(26)
|
|
VVC+RTV(14)
|
198(27)
|
3570(26)
|
|
VVC+RTV+SQV(28)
|
223(26)
|
4000(30)
|
There were no serious AEs. The
most frequent AEs were GI disorders and headache.
Conclusions: There were no
significant changes in VVC plasma concentrations when combined with RTV-boosted
PIs. Regardless of whether a PI affected other CYP450 enzymes or pGp, no
additional effect on VVC exposure was seen over that observed with RTV alone. All
3-agent combinations were well tolerated. Neither modification to VVC dosing,
nor therapeutic drug monitoring is needed when VVC is added to a RTV-boosted PI
regimen.
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