763 
Pharmacokinetic Interaction of the Next Generation NNRTI UK-453,061 with Other Antiretrovirals and Assessment of Safety and Tolerability in Healthy Male Subjects
G Langdon1, J Davis1, G Layton1, H Choo2, M N Ndongo3, A Milton4, and Manoli Vourvahis*4
1Pfizer Global R&D, Sandwich, UK; 2Pfizer Res Clin, Singapore Gen Hosp; 3Pfizer Res Clin, Erasme, Brussels, Belgium; and 4Pfizer Global R&D, New London, CT, US
Background: UK-453,061
is a next-generation NNRTI showing potent antiviral activity against both
wild-type and clinically-relevant drug-resistant viruses. Three separate studies
in healthy male subjects investigated the effect of tenofovir/emtricitabine (Truvada®),
lopinavir/ritonavir (Kaletra™) and atazanavir (ATZ) on the pharmacokinetics of
UK-453,061 and a fourth evaluated the safety and tolerability of UK-453,061.
Methods: Each
drug interaction study enrolled 14 volunteers, treated for at least 10 days in
an open, randomized, placebo-controlled crossover study. Blood samples were
collected during the 24 hours following the last dose. A 28-day randomized,
double-blind, placebo-controlled parallel group study assessed safety and
tolerability of UK-453,061 (500 mg BID or 750 mg QD) compared to efavirenz
(600mg QD) or placebo in 66 subjects. Laboratory tests were carried out
throughout the study and the effect on the 6-b-hydroxycortisol/cortisol
ratio was examined.
Results:
|
Effect of
co-administered drug on steady-state UK-453,061 PK
|
Co-administered
drug
|
Dose
|
Ratio of
geometric means and 90% CI (%)
(UK-453,061+drug/UK-453,061+placebo)
|
|
AUC24
|
Cmax
|
|
Kaletra
n=12
|
400/100mg
BID
(Days 1-14)
|
56.6
(50.0-63.9)
|
63.0
(53.9-73.6)
|
|
ATZ
n=11
|
400mg QD
(Days 1-11)
|
103.1
(95.0-111.9)
|
103.0
(92.7-114.5)
|
|
ATZ + RTV
n=13
|
300/100mg
QD
(Days 1-11)
|
81.2
(74.6-88.4)
|
89.4
(80.6-99.1)
|
|
Truvada
n=12
|
300/200mg
QD
(Days 1-10)
|
88.0
(76.6-101.1)
|
90.1
(73.5-110.5)
|
|
Effect of
UK-453,061 on steady-state tenofovir PK
|
|
|
Ratio of
geometric means and 90% CI (%) (Truvada + UK-453,061/Truvada + placebo)
|
|
UK-453,061
n=12
|
1000mg QD
(Days 1-10)
|
129.8
(123.8-136.1)
|
119.2
(107.0-132.8)
|
Combinations were generally well tolerated
with mild to moderate adverse events characteristic of those previously
reported with each agent. The most frequent adverse events with UK-453,061
monotherapy were headache, diarrhea, dizziness and
nausea; no serious or severe treatment-emergent adverse events or permanent
discontinuations were reported for UK-453,061 monotherapy nor did any
laboratory abnormalities lead to withdrawal. The 6-b-hydroxycortisol/cortisol
ratios were raised.
Conclusions: UK-453,061 was well tolerated with no unexpected serious or severe
adverse events. Co-administration with ATZ or Truvada did not lead to any
clinically relevant interaction, although UK-453,061 increased tenofovir exposure.
The presence of Kaletra halved UK-453,061 exposure, consistent with the
induction of UK-453,061 metabolic pathways by lopinavir and ritonavir.
|
