Blood levels of MK-1439, a next-generation HIV non-nucleoside reverse
transcriptase inhibitor (NNRTI) in phase 2b trials, rose significantly when
combined with ritonavir, but tenofovir had little effect, researchers reported
at the 53rd Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC) last week in Denver.
Matt Anderson from Merck presented findings from a study looking at
interactions between MK-1439 and two widely used antiretrovirals, ritonavir
(Norvir) and tenofovir disoproxil
fumarate (Viread, also in the Truvada, Atripla, Eviplera and Stribild co-formulations).
In studies to date, MK-1439 has shown good antiviral potency, safety and
tolerability. MK-1439 works well against NNRTI-resistant viruses with the K103N,
Y181C and G190A mutations. At this year's Conference on Retroviruses and Opportunistic Infections (CROI 2013), Anderson
reported that MK-1439 demonstrated robust activity and good tolerability as monotherapy
in a small phase 1b trial and had minimal central nervous system (CNS) toxicity –
a common concern with efavirenz.
MK-1439 is primarily metabolised by oxidation via the CYP3A4 enzyme in
the liver, which may lead to interactions with other drugs processed by the
same pathway. Early pharmacokinetic studies suggested MK-1439 did not inhibit or significantly
induce drug-metabolising CYP enzymes, and it did not meaningfully alter
researchers wanted to know if other antiretroviral drugs that act as CYP3A4 inhibitors or inducers would have clinically significant effects on
MK-1439. CYP3A4 inhibitors slow drug processing, which can lead to higher concentrations
and intensified side-effects. This is the principle behind "boosting"
other antiretrovirals with the potent CYP3A4 inhibitors ritonavir or cobicistat.
CYP3A4 inducers, in contrast, speed up processing and can lead to low drug
levels that do not adequately control viral replication.
Ritonavir is both a strong inhibitor
and an inducer of CYP3A4. Tenofovir has more "idiosyncratic interaction
potential" that does not follow a consistent pattern, the researchers
noted as background.
Merck investigators performed two
open-label, fixed-sequence studies – one for ritonavir, one for tenofovir –
each enrolling eight healthy HIV-negative volunteers. All were men and ages
ranged from 21 to 50 years.
In the ritonavir study, during the
first period participants received a single 50mg dose of MK-1439. During the
second period, after a seven-day washout, they received 100mg twice-daily
ritonavir for 20 days, with a second single 50mg dose of MK-1439 taken with the
morning ritonavir dose on day 14.
In the tenofovir study, during the
first period volunteers received a single 100mg dose of MK-1439. During the
second period, again after a seven-day washout, they received 300mg once-daily
tenofovir for 18 days, with a second single 100mg dose of MK-1439 taken with
tenofovir on day 14.
Blood samples were collected before
and after dosing during each period. Researchers measured pharmacokinetic
parameters including overall plasma concentration (area under the curve, or
AUC), 24-hour minimum or trough concentration (C24hr), maximum concentration
(Cmax), time to reach maximum concentration (Tmax) and
half-life, or time needed to eliminate half the drug. They also evaluated
adverse events, vital signs, electrocardiograms (ECGs) and laboratory safety values.
All participants in the ritonavir study
and all but one in the tenofovir study completed the trials. That individual
stopped due to diverticulitis, which was considered not related to the study
No serious adverse events or CNS
side-effects were seen in either study. Most participants reported mild to
moderate adverse events of limited duration (eight in the ritonavir study, four
in the tenofovir study), a majority of which were deemed possibly drug-related.
No significant effects on vital signs, ECGs or laboratory
safety measurements were observed.
Co-administration with ritonavir
approximately tripled overall AUC and trough concentrations of MK-1439,
although the maximum concentration only rose by about 30% (geometric mean
ratios 3.54, 2.91 and 1.31, respectively). Time to reach Cmax
increased from 3.5 to 5.0 hours, whilst the apparent half-life more than
doubled, from 13.9 to 34.9 hours.
These findings "[suggest] that ritonavir
has a limited effect on MK-1439 bioavailability and absorption, but a
significant effect on MK-1439 elimination, due to inhibition of CYP3A4,"
the researchers concluded.
Co-administration with tenofovir, in
contrast, had little effect on MK-1439 levels. AUC and C24hr
concentrations of MK-1439 remained about the same, with a small decrease in Cmax
(geometric mean ratios 0.97, 0.95 and 0.82, respectively). Tmax
(2.5 vs 3.0 hours) and apparent half-life (14.4 vs 15.8 hours) were also
"Co-administration with MK-1439 has no
clinically meaningful effect on the pharmacokinetics of MK-1439," according
to the researchers.
Responding to audience questions, Anderson indicated that the clinical
dose of MK-1439 has not yet been decided. He added that it is not yet clear whether
dose adjustment will be required when using MK-1439 with ritonavir or cobicistat.
"We need to know the clinical bounds of meaningful change – not just pharmacokinetics – which will come from clinical trials," he said.