Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer.
of apalutamide when added to castration include fatigue, nausea, abdominal pain, diarrhea, hypertension, rash, falls, , and an hypothyroidism.
Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.
Medical uses
Apalutamide is
indicated for the treatment of people with metastatic castration-sensitive prostate cancer and the treatment of people with non-metastatic castration-resistant prostate cancer.
Apalutamide
Contraindications
of apalutamide include
pregnancy and a history of or susceptibility to
.
Side effects
Apalutamide has been found to be
tolerability in
,
with the most common
reported when added to surgical or medical castration including fatigue,
nausea,
abdominal pain, and
diarrhea.
Other side effects have included
rash, falls and
, and
hypothyroidism, as well as
(in 0.2%), among others.
Apalutamide is an expected
teratogen and has a theoretical risk of
in male infants if taken by women during
pregnancy.
It may
male infertility.
When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce additional, estrogenic side effects like breast tenderness,
gynecomastia, and feminization in general by increasing
estradiol levels.
Similarly to the related second-generation NSAA
enzalutamide but unlike first-generation NSAAs like
flutamide and
bicalutamide, elevated liver enzymes and
hepatotoxicity have not been reported with apalutamide.
of rare interstitial lung disease with apalutamide exist similarly to with first-generation NSAAs however.
Overdose
There is no known
antidote for
overdose of apalutamide.
General supportive measures should be undertaken until clinical
toxicity, if any, diminishes or resolves.
Interactions
Apalutamide has a high potential for
.
In terms of effects of apalutamide on other drugs, the exposure of substrates of CYP3A4, CYP2C19, CYP2C9, UDP-glucuronosyltransferase,
P-glycoprotein, ABCG2, or OATP1B1 may be reduced to varying extents.
In terms of effects of other drugs on apalutamide, strong CYP2C8 or CYP3A4 inhibitors may increase levels of apalutamide or its major active metabolite N-desmethylapalutamide, while mild to moderate CYP2C8 or CYP3A4 inhibitors are not expected to affect their exposure.
Pharmacology
Pharmacodynamics
Antiandrogenic activity
Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an
antiandrogen.
It is similar both structurally and
pharmacology to the second-generation NSAA
enzalutamide,
but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution.
The latter difference may reduce its comparative risk of
and other central side effects.
Apalutamide has 5- to 10-fold greater affinity for the AR than
bicalutamide, a first-generation NSAA.
The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide.
Other activities
Apalutamide shows potent
enzyme inducer potential of cytochrome P450
similarly to enzalutamide.
It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase.
In addition, apalutamide is an inducer of
P-glycoprotein, ABCG2, and OATP1B1.
Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide ( = 3.0 and 2.7 μM, respectively),
Apalutamide has been found to significantly and concentration-dependently increase QT interval.
Pharmacokinetics
The mean absolute oral
bioavailability of apalutamide is 100%.
Mean peak levels of apalutamide occur 2 hours following administration, with a range of 1 to 5 hours.
Food delays the median time to peak levels of apalutamide by approximately 2 hours, with no significant changes in the peak levels themselves or in area-under-curve levels.
Steady-state levels of apalutamide are achieved following 4 weeks of administration, with an approximate 5-fold accumulation.
Peak concentrations for 160 mg/day apalutamide at steady-state are 6.0 μg/mL (12.5 μmol/L),
relative to peak levels of 16.6 μg/mL (35.7 μmol/L) for 160 mg/day
enzalutamide and mean (
R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/day
bicalutamide.
The mean volume of distribution of apalutamide at steady-state is approximately 276 L.
The plasma protein binding of apalutamide is 96%, while that of its major
metabolite N-desmethylapalutamide is 95%, both irrespective of concentration.
Apalutamide is metabolism in the liver by CYP2C8 and CYP3A4.
Chemistry
Apalutamide is a structural analogue of
enzalutamide and RD-162.
It is a
pyridine variant of RD-162. Enzalutamide and RD-162 were derived from the nonsteroidal androgen RU-59063, which itself was derived from the first-generation NSAA
nilutamide and by extension from
flutamide.
History
Apalutamide was originated by the University of California system and was developed primarily by Janssen Research & Development, a division of Johnson & Johnson.
It was first described in the literature in a United States patent application that was published in November 2007 and in another that was submitted in July 2010.
[ ][ ] A March 2012 publication described the discovery and development of apalutamide.
A phase I
clinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.
Information on phase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016.
Positive results for phase III trials were first described in 2017, and Janssen submitted a New Drug Application for apalutamide to the United States Food and Drug Administration on 11 October 2017.
Apalutamide was approved by the Food and Drug Administration in the United States, under the brand name Erleada, for the treatment of non-metastatic castration-resistant prostate cancer in February 2018.
It was subsequently approved in Canada, the European Union, and Australia.
Society and culture
Generic names
Apalutamide is the
generic term of the medication and is its international nonproprietary name.
It is also known by its developmental code names ARN-509 and JNJ-56021927.
Brand names
Apalutamide is marketed under the brand names Erleada and Erlyand.
Availability
Apalutamide is available in the United States, Canada, the European Union, and Australia.
Further reading
