Download Rilpivirine: A second-generation nonnucleoside reverse

clinical review Rilpivirine
clinical review
Rilpivirine: A second-generation nonnucleoside
reverse transcriptase inhibitor
Christopher James, Lee Preininger, and Meryn Sweet
M
ore than 20 antiretrovirals are
approved by the Food and
Drug Administration (FDA)
for the treatment of human immunodeficiency virus (HIV) infection.
Antiretrovirals comprise five types
of drugs, including nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse
transcriptase inhibitors (NNRTIs),
protease inhibitors, integrase inhibitors, and entry inhibitors. Highly active antiretroviral therapy (HAART)
has decreased morbidity and mortality associated with HIV infection.
By suppressing the viral load to
undetectable HIV type 1 (HIV-1)
RNA levels and increasing CD4+ Tlymphocyte counts in HIV-infected
patients, treatment has resulted in
decreased opportunistic infections
and mortality.1 HAART consists of at
least 3 drugs that suppress HIV replication and includes 2 NRTIs plus an
NNRTI, a protease inhibitor, an integrase inhibitor, or an entry inhibitor. Four antiretroviral regimens are
currently recommended by the U.S.
Department of Health and Human
Services (DHHS) for HIV-1-infected
patients who have not previously received antiretroviral therapy.2
Purpose. The pharmacology, pharmacokinetics, drug interactions, clinical efficacy,
adverse effects, dosage and administration, and place in therapy of rilpivirine are
reviewed.
Summary. Rilpivirine is a human immunodeficiency virus type 1 (HIV-1)-specific
nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in
adult patients not previously treated with
antiretroviral therapy. Rilpivirine is primarily metabolized by the cytochrome P-450
(CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers
of this pathway. Coadministration with CYP
3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing
the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes
or drugs that increase gastric pH may lead
to decreased concentrations of rilpivirine,
thus promoting virological failure or
resistance to rilpivirine. Two Phase III, randomized, double-blind, double-dummy,
active-controlled trials compared rilpivirine
As more treatment options have
become available, HAART has become more efficacious, more potent,
more convenient, and better tolerated. However, virological failure is
Christopher James, Pharm.D., is Clinical Pharmacy Specialist; and
Lee Preininger, Pharm.D., is Clinical Pharmacy Specialist, HIV
Community Program, Christiana Care Health System, Wilmington,
DE. Meryn Sweet is a pharmacy student, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA.
Address correspondence to Dr. James at the HIV Community
Program, Christiana Care Health System, P.O. Box 1668, Wilmington,
DE 19899-1668 ([email protected]).
with efavirenz in HIV-infected adults not
previously treated with an antiretroviral.
The investigators concluded that rilpivirine,
when combined with two nucleoside or
nucleotide reverse transcriptase inhibitors,
was noninferior to efavirenz for reaching
the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL)
in adults with HIV infection not previously
treated with antiretroviral therapy. The
most commonly reported adverse effects
included depression, insomnia, headache,
and rash. Rilpivirine is administered as
a single 25-mg tablet given once daily
in combination with other antiretroviral
drugs in order to optimize efficacy and reduce resistance.
Conclusion. Rilpivirine is a viable NNRTI for
HIV-infected patients who have not previously received antiretroviral therapy.
Index terms: Antiretroviral agents; Blood
levels; Dosage; Drug administration; Drug
interactions; HIV infections; Mechanism
of action; Metabolism; Pharmacokinetics;
Rilpivirine; Toxicity
Am J Health-Syst Pharm. 2012; 69:857-61
still a concern, necessitating continued research for new antiretroviral
treatment options. In May 2011, FDA
approved rilpivirine (Edurant, Tibotec Therapeutics, Raritan, NJ), an
The authors have declared no potential conflicts of interest.
Copyright © 2012, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/12/0502-0857$06.00.
DOI 10.2146/ajhp110395
Am J Health-Syst Pharm—Vol 69 May 15, 2012
857
clinical review Rilpivirine
NNRTI, for use in combination with
other antiretrovirals for the treatment of HIV-1 infection in adults
not previously treated with antiretroviral therapy.3,4 This article reviews
the pharmacology, pharmacokinetics, efficacy, safety, and clinical use of
rilpivirine.
Chemistry and pharmacology
The chemical name for rilpivirine
hydrochloride is 4-[[4-[[4-[(E)-2cyanoethenyl]-2,6-dimethyl­phenyl]
amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride.4 It
has a molecular weight of 402.88 Da.
The genetic material of HIV is
positive-sense (5´ to 3´), singlestranded RNA; the virus must transcribe this RNA into double-stranded
proviral DNA.5 HIV transcription
is accomplished using reverse transcriptase, which is released with the
viral genomic RNA into cytoplasm of
the cell after the fusion and uncoating
of the viral envelope.6,7 Rilpivirine is
a diarylpyrimidine NNRTI that
works through noncompetitive inhibition of HIV-1 reverse transcriptase,
thereby stopping replication. It does
not inhibit the human cellular DNA
polymerases a, b, and g. Rilpivirine
demonstrates antiviral activity at a
median effective concentration value
of 0.73 nM (0.27 ng/mL).4
Pharmacokinetics
Rilpivirine exhibited linear pharmacokinetics after the administration of a single dose and multiple
doses, up to a dosage of 150 mg daily
in healthy volunteers.8,9 While the
absolute bioavailability is unknown,
the maximum rilpivirine plasma
concentration is achieved within four
to five hours after oral administration.4 Rilpivirine is most bioavailable
when taken with a normal meal, ideally containing 533 kcal. Rilpivirine’s
absorption decreases by 40% when
taken in a fasted state or when taken
with a high-fat, high-calorie meal
(928 kcal) compared with a normal
meal. In addition, rilpivirine ab858
sorption decreases by 50% when it
is taken with a protein-rich meal or
nutritional drink.4,10
Rilpivirine requires a low gastric pH for adequate absorption.
Concomitant administration with
acid-suppressive agents can significantly reduce its absorption and oral
bioavailability. Caution should be
used when administering rilpivirine
concomitantly with antacids and
histamine H2-receptor antagonists.
The area under the concentration–
time curve (AUC) for rilpivirine
was reduced by 76% when given 2
hours after famotidine administration, but no effect was found when
rilpivirine was administered 12 hours
after famotidine administration in
healthy volunteers.4,11 Coadministration with proton pump inhibitors is
contraindicated. Rilpivirine’s AUC
was reduced by 40% when administered with omeprazole 20 mg daily in
healthy volunteers.12
Rilpivirine is more than 99%
bound to plasma proteins in a
concentration-dependent manner.13
The exact volume of distribution
in humans has not been examined.
In vitro studies have indicated that
rilpivirine is primarily metabolized
by oxidative metabolism through the
cytochrome P-450 (CYP) 3A isoenzyme system.4
Eighty-five percent of an oral
dose of rilpivirine is excreted in the
feces, with 25% remaining as unchanged drug. Approximately 6%
of the dose is excreted in the urine,
with only trace amounts remaining
unchanged. Rilpivirine’s half-life is
approximately 50 hours.4
Dose exposure is higher in patients with mild-to-moderate hepatic
impairment (Child-Pugh classes A
and B); however, no dosage adjustment is required in this population.4
Rilpivirine has not been evaluated
in patients with severe hepatic impairment (Child-Pugh class C). No
dosage adjustment is required for
patients with mild-to-moderate renal
insufficiency.4 Caution and increased
Am J Health-Syst Pharm—Vol 69 May 15, 2012
monitoring are recommended when
using rilpivirine in patients with
severe renal insufficiency; however,
because it is highly bound to plasma
proteins, rilpivirine is not likely to be
significantly removed by hemodialysis or peritoneal dialysis. The safety
and effectiveness of rilpivirine in
pediatric patients have not been established.4 Rilpivirine is a pregnancy
category B drug. While data on rilpivirine in pregnant women are lacking, studies of pregnant or lactating
rats taking rilpivirine dosages of up
to 400 mg/kg daily—approximately
40 times higher than the exposure
in humans with the approved 25-mg
daily dose—revealed maternal toxicity but no effect on fertility and no
embryonic or fetal toxicity.4
Clinical efficacy
The product labeling for rilpi­
virine was based on the results of a
Phase IIb dose-finding study, as well
as two Phase III trials.
Phase IIb trial. A Phase IIb trial
of rilpivirine was conducted with
368 patients with HIV-1 infection
who had not previously been treated
with antiretroviral therapy. In this
trial, patients were randomized to
receive regimens of two NRTIs with
rilpivirine 25 mg daily, rilpivirine 75
mg daily, rilpivirine 150 mg daily, or
efavirenz 600 mg daily (randomization was done in a 1:1:1:1 fashion).14
Rilpivirine dosing was blinded,
while efavirenz was administered
open label as an active control. The
primary efficacy endpoint was the
proportion of patients with confirmed HIV-1 RNA levels of <50
copies/mL at 48 weeks, analyzed by
the time to loss of virological response (TLOVR) algorithm. TLOVR
is an intent-to-treat algorithm, so
premature treatment discontinuation, regardless of the reason, is considered treatment failure. Virological
response was achieved with all rilpivirine dosages, as well as with efavirenz,
at 48 weeks (78.9% for rilpivirine versus 80.9% for efavirenz) and was sus-
clinical review Rilpivirine
tained during the 96-week extension
period (73.1% for rilpivirine versus
70.8% for efavirenz). The median
CD4+ T-lymphocyte counts also
increased for the rilpivirine-treated
and efavirenz-treated groups by week
48 (108.0–123.0 cells/µL for the rilpivirine groups versus 120.5 cells/µL
for the efavirenz group) and continued to increase through the 96-week
extension period (138.0–149.0 cells/
µL for the rilpivirine groups versus 170.5 cells/µL for the efavirenz
group). No significant difference
was seen among treatment groups
with regard to virological response
or CD4+ T-cell count. Based on the
similar efficacy observed with the
three rilpivirine dosages, the 25-mg
daily dose was further developed and
studied in Phase III trials due to its
favorable risk:benefit profile.14
Phase III clinical trials. Two
Phase III, randomized, double-blind,
double-dummy, active-controlled
trials, ECHO and THRIVE, further
compared rilpivirine with efavirenz
in HIV-infected adults not previously treated with an antiretroviral.15,16 Both trials enrolled patients in
21 different countries, including the
United States, Canada, South Africa,
and countries in Europe, Asia, and
Latin America.
In the ECHO trial, patients were
randomized to receive rilpivirine
(n = 346) or efavirenz (n = 344).15
All patients received a background
regimen of tenofovir plus emtricitabine. In the THRIVE trial, patients were randomized to receive
either rilpi­virine or efavirenz, with
340 patients in each group.16 The
background regimen consisted of
two investigator-selected NRTIs:
tenofovir plus emtricitabine (60%),
zidovudine plus lamivudine (30%),
or abacavir plus lamivudine (10%).
Both trials were performed in adults
with HIV-1 RNA levels of ≥5000
copies/mL, no NNRTI-resistant mutations at baseline, and sensitivity to
NRTIs.15,16 Demographics and baseline characteristics were balanced
between the rilpivirine and efavirenz
groups. Randomization was stratified by screening HIV-1 RNA levels.
In THRIVE, randomization was further stratified by NRTI background
regimen.16
Pooled results of the trials showed
that at week 48, mean CD4+ Tlymphocyte counts had increased in
the rilpivirine- and efavirenz-treated
groups by 192 and 176 cells/ m L,
respectively.4 Both groups also demonstrated comparable virological
response rates (HIV-1 RNA levels of
<50 copies/mL). As in the Phase IIb
trial, the primary endpoint was assessed by the intent-to-treat TLOVR
algorithm. Rilpivirine was found to
be noninferior, with a virological response rate of 84.3%, compared with
82.3% for efavirenz (p < 0.0001).
However, patients who received rilpivirine with an HIV-1 RNA level of
>100,000 copies/mL had a somewhat
reduced response rate when compared with patients with a an HIV-1
RNA level of ≤100,000 copies/mL
(77% versus 90%). Patients in the
efavirenz-treated group maintained
a similar virological response rate
across the HIV-1 RNA viral load
strata (81% for HIV-1 RNA levels
of >100,000 copies/mL versus 84%
for HIV-1 RNA levels of ≤100,000
copies/mL).
Rilpivirine’s most common adverse effects were psychological in
nature, with rash being the second
most common adverse effect. However, the frequency of adverse effects was lower than that seen in the
efavirenz-treated group. The adverse
effects observed in the rilpivirinetreated group were associated with
fewer treatment discontinuations
compared with the efavirenz-treated
group.17
The mean serum creatinine concentration of patients receiving
rilpivirine increased slightly from
baseline (mean change, 0.09 mg/dL;
range, –0.20 to 0.62 mg/dL), but no
significant change from baseline was
observed in the efavirenz-treated
group. Despite this increase, the
glomerular filtration rate remained
in a healthy range for all patients,
and no grade 3 or 4 serum creatinine
concentration changes were noted.
Changes in the lipid profile were
noted in both treatment groups, but
abnormalities of grade 3 and 4 were
less common in patients receiving
rilpivirine than in those receiving
efavirenz.17
The investigators of both the
ECHO and THRIVE studies concluded that rilpivirine, when combined with two NRTIs, was noninferior to efavirenz for reaching the
endpoint of confirmed virological
response (HIV-1 RNA level of <50
copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy.17 The rilpivirinetreated groups had a high virological
response rate, a durable increase in
CD4+ T-lymphocyte counts, and
fewer adverse effects than observed
with efavirenz. However, virological failure, particularly in patients
with a baseline HIV-1 RNA level
of ≥100,000 copies/mL, was more
frequently observed with rilpivirine,
which led to more frequent antiretroviral resistance.17
Resistance and cross-resistance
The most common NRTI and
NNRTI mutations associated with virological failure in rilpivirine-treated
patients were M184I and E138K,
respectively.17 Other frequently observed mutations that cause decreased susceptibility to rilpivirine
include L100I, K101E, V106I/A,
V108I, E138G/Q/R, V179F/I,
Y181C/I, V189I, G190E, H221Y,
F227C, and M230I/L.4 Patients who
displayed phenotypic resistance were
also shown to have cross-resistance
to etravirine, efavirenz, and nevira­
pine, which affects future therapy.
Due to similarities in chemical structure, approximately 90%
of people who were resistant to
rilpi­v irine were also resistant to
etravirine. In addition, NRTI- and
Am J Health-Syst Pharm—Vol 69 May 15, 2012
859
clinical review Rilpivirine
resistance-associated substitutions
were more frequently associated with
rilpivirine virological failure than
with efavirenz virological failures in
the ECHO (70% versus 31%) and
THRIVE (64% versus 33%) trials.15,16
The most common NRTI mutation
observed was M184I/V, which is associated with resistance to lamivudine and emtricitabine. This mutation was seen in 26 of 28 patients in
the ECHO trial and 12 of 14 patients
with NRTI resistance in the THRIVE
trial.15,16
Safety
The ECHO and THRIVE trials
compared the safety of rilpivirine
and efavirenz. Pooled analysis of the
two trials revealed that an adverse
effect occurred in 90% of patients
receiving rilpivirine and 92% of
patients receiving efavirenz.17 Grade
2–4 adverse effects occurred in 16%
of rilpivirine-treated patients and
31% of efavirenz-treated patients
(p < 0.0001). Discontinuation rates
due to these adverse effects were
3% and 8% for the rilpivirine- and
efavirenz-treated groups, respectively.
The most common adverse events
reported in ECHO and THRIVE were
insomnia, headache, nausea, dizziness, rash, and abnormal dreams or
nightmares.15,16 However, a comparison to efavirenz in a pooled analysis
of the clinical trials demonstrated that
rash (3% versus 14%, p < 0.0001), adverse psychiatric events (15% versus
23%, p = 0.0002), and adverse neurologic events (17% versus 38%, p <
0.0001) were observed less frequently
with rilpivirine.17 Of the 1368 patients
involved in the trials, discontinuation
rates due to any adverse event from
rilpivirine and efavirenz were 3% and
8%, respectively.
When compared to efavirenz,
there were no significant differences
between the groups in regards to
change in the Q-Tc interval.17 Rilpivirine was associated with fewer grade
3 or 4 lipid abnormalities.17
Drug interactions
Rilpivirine is primarily metabolized by the CYP3A isoenzyme system. Therefore, providers should be
cautious when administering drugs
that are inhibitors or inducers of
this pathway. Coadministration with
CYP3A inhibitors may lead to increased concentrations of rilpivirine,
thereby increasing the risk of adverse effects. Coadministration with
inducers of CYP3A isoenzymes or
drugs that increase gastric pH may
lead to decreased concentrations of
rilpivirine, thus promoting virological failure or resistance to rilpivirine.4
Rilpivirine is contraindicated in patients taking carbamazepine, oxcarbazepine, phenobarbital, phenytoin,
rifamycins, proton pump inhibitors,
or St. John’s wort.4
Caution is also advised in patients
taking rilpivirine concomitantly
with antacids, histamine H2-receptor
antagonists, clarithromycin, erythromycin, azole antifungal agents, and
methadone.4,11,18 A complete listing of
drug interactions with rilpivirine is
Table 1.
Drug Pricing for Nonnucleoside Reverse Transcriptase Inhibitors
Drug Regimen
Rilpivirine 25 mg daily
Efavirenz 600 mg daily
Nevirapine IRa 200 mg twice dailyb
Etravirine 200 mg twice daily
Price Per Tablet
or Capsule ($)
25.20
756.00
22.10
663.00
10.24614.24
15.30
919.75
IR = immediate release.
Initial recommended adult dosage is 200 mg daily for first 14 days of therapy.
a
b
860
Average Wholesale
Price for 1-Mo
Supply19 ($)
Am J Health-Syst Pharm—Vol 69 May 15, 2012
included in the manufacturer’s prescribing information.4
Economic considerations
Compared with the monthly cost
of therapy with other NNRTIs, the
cost of rilpivirine is generally comparable and not expected to affect
prescribing decisions. Comparative
drug pricing, as the average wholesale price, for NNRTIs is listed in
Table 1.19
Future directions
The labeling for a single fixed-dose
combination tablet of rilpivirine
with tenofovir and emtricitabine
(Complera, Gilead Sciences, Foster
City, CA) was recently approved by
FDA.3,20 Recruitment has begun for
a trial comparing this combination
tablet with efavirenz plus emtri­
citabine or tenofovir.1,21
Rilpivirine was briefly studied in
patients who were not responding
to antiretroviral therapy during a
proof-of-principle trial.22 Rilpivirine
was studied in patients with at least
one NNRTI mutation, and significant reductions in viral load were
observed after seven days of therapy.
However, additional studies are
needed to investigate the efficacy of
rilpivirine in this patient population.
In addition, the results of a small
study by Crauwels and colleagues23
indicated that the effect of efavirenz
on the induction of rilpivirine metabolism may persist for longer than
three weeks after efavirenz has been
discontinued. This effect would limit
clinicians’ ability to switch patients
from an efavirenz-based regimen to
one including rilpivirine.
Place in therapy
Rilpivirine is a viable option in
the NNRTI antiretroviral drug class
for adults with HIV-1 infection not
previously treated with an antiretroviral. As with any new medication
therapy, the risks and benefits should
be considered before its use. Rilpivirine was recently deemed an al-
clinical review Rilpivirine
ternative NNRTI by the DHHS
treatment guidelines, with efavirenz
remaining the preferred NNRTI.1,24
Rilpivirine’s recent availability in a
combination tablet and less-frequent
adverse effects, especially psychological and neurologic adverse effects,
make it a welcome alternative to
efavirenz. However, providers should
be mindful of decreased response
rates in patients with baseline HIV1 RNA levels of >100,000 copies/
mL. Patients with virological failure
were more likely to exhibit crossresistance to etravirine, efavirenz,
and nevirapine, which may affect
future therapy options.
Conclusion
Rilpivirine is a viable NNRTI for
HIV-infected patients who have not
previously received antiretroviral
therapy.
7.
8.
9.
10.
11.
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