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Journal of Gerontology: MEDICAL SCIENCES
Cite journal as: J Gerontol A Biol Sci Med Sci. 2013 January;68(1):87–95
doi:10.1093/gerona/gls078
© The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.
All rights reserved. For permissions, please e-mail: [email protected].
Advance Access publication March 28, 2012
Journal of Gerontology: MEDICAL SCIENCES © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America.
Cite journal as: J Gerontol A Biol Sci Med Sci All rights reserved. For permissions, please e-mail: [email protected].
doi:10.1093/gerona/gls078
1
AS men and women grow old, they lose muscle mass,
muscle strength , and leg power ( 1 , 2 , 3 , 4 , 5 , 6 ), mostly
due to the preferential loss of type II muscle fi bers ( 5 ).
Sarcopenia, the age-associated loss of muscle mass and
strength, increases the risk of falls, fractures, physical disability,
and poor quality of life ( 1 , 3 , 6 , 7 ). Similarly, the
course of many illnesses, such as chronic obstructive lung
disease, end - stage renal disease, and some types of cancer,
is punctuated by the loss of muscle mass and physical function,
which contributes to mobility limitation and disability
( 7 , 8 ). Thus, there is an unmet need for anabolic therapies
that improve physical function and reduce the burden of
disability in persons experiencing functional limitations
due to aging or illness. Among the various candidate function -
promoting anabolic therapies that are in development,
androgens are the farthest along in development.
Testosterone administration increases muscle mass and
strength ( 9 , 10 , 11 , 12 , 13 , 14 , 15 ), but concerns regarding its
potential adverse effects on the prostate have restrained
enthusiasm for its use as an anabolic therapy and have
motivated efforts to develop selective androgen receptor
modulators (SARMs), a new class of androgen receptor
The Safety, Pharmacokinetics, and Effects of
LGD-4033, a Novel Nonsteroidal Oral, Selective
Androgen Receptor Modulator, in Healthy Young Men
Shehzad Basaria , 1 Lauren Collins , 1 , * E. Lichar Dillon , 2 , * Katie Orwoll , 1 Thomas W. Storer , 1
Renee Miciek , 1 Jagadish Ulloor , 1 Anqi Zhang , 1 Richard Eder , 1 Heather Zientek , 3 Gilad Gordon , 3
Syed Kazmi , 3 Melinda Sheffi eld-Moore , 2 , * and Shalender Bhasin 1
1 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Massachusetts .
2 Department of Medicine, University of Texas Medical Branch, Galveston .
3 Ligand Pharmaceuticals , San Diego, California .
* These authors contributed equally and are joint second authors.
Address correspondence to Shalender Bhasin, MD, Section of Endocrinology, Boston University School of Medicine, Boston, MA 02118.
Email: [email protected]
Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of
selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a
novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affi nity and selectivity.
Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered
daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.
Methods. In this placebo-controlled study, 76 healthy men (21 – 50 years) were randomized to placebo or 0.1, 0.3, or
1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specifi c antigen, electrocardiogram,
hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.
Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was
similar between active and placebo groups. Hemoglobin, prostate-specifi c antigen, aspartate aminotransferase, alanine
aminotransferase, or QT intervals did not change signifi cantly at any dose. LGD-4033 had a long elimination half-life and
dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent
suppression of total testosterone, sex hormone – binding globulin, high density lipoprotein cholesterol, and triglyceride
levels. Follicle-stimulating hormone and free testosterone showed signifi cant suppression at 1.0-mg dose only. Lean body
mass increased dose dependently, but fat mass did not change signifi cantly. Hormone levels and lipids returned to baseline
after treatment discontinuation.
Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profi le, and increased lean body mass even during
this short period without change in prostate-specifi c antigen. Longer randomized trials should evaluate its effi cacy
in improving physical function and health outcomes in select populations.
Key Words: Selective androgen receptor modulators — SARMs — Sarcopenia — Function promoting anabolic therapies —
Cachexia .
Received December 8 , 2011 ; Accepted February 2 , 2012
Decision Editor: Luigi Ferrucci, MD, PhD
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288 BASARIA ET AL.
ligands that are tissue selective ( 8 , 16 , 17 , 18 , 19 ). The last
decade has witnessed substantial pharmaceutical efforts to
develop nonsteroidal SARMs to treat muscle wasting and
functional limitations associated with acute and chronic illness
and aging ( 8 , 16 , 17 , 18 , 19 ). LGD-4033 is a novel nonsteroidal,
oral SARM that binds to androgen receptor with
high affi nity (Ki of ~ 1 nM) and selectivity. In animal models,
LGD-4033 has demonstrated anabolic activity in the muscle,
anti-resorptive and anabolic activity in bone, and robust
selectivity for muscle versus prostate.
Here we report the results of a randomized, double-blind,
placebo-controlled, ascending-dose study, which evaluated
the safety, tolerability, and pharmacokinetics (PK) of LGD-
4033 in healthy men. We also evaluated the effects of graded
doses of LGD-4033 on lean body mass (LBM), muscle
strength , and physical function. LGD-4033 doses of 0.1,
0.3, and 1.0 mg were selected for multiple dosing over 21
days because a previous phase I single ascending-dose study
had established the safety of up to 22 mg LGD-4033. We also
tested the hypothesis that the LGD-4033 increases muscle
mass by stimulating fractional synthetic rate (FSR) of mixed -
muscle proteins, measured using continuous steady state
infusion of labeled phenylalanine in men randomized to either
placebo or 0.3-mg daily dose of LGD-4033. This dose was
selected for FSR study because preclinical data suggested
that this dose was the most likely to increase LBM.
Study Design
This was a double-blind, placebo-controlled, multiple
once-daily dose escalation study of LGD-4033 in healthy
men, approved by Boston University ’ s Institutional Review
Board. All subjects provided written, informed consent.
Subjects
Nonsmoking, healthy men, 21 – 50 years, with body mass
index between 18 and 32 kg/m 2 , who were capable of
providing informed consent, were eligible. We excluded
subjects who had an active disease, prostate-specifi c antigen
>3 ng/mL, aspartate aminotransferase or ALT >1.5 times the
upper limit of normal, hematocrit <37% or >48%, creatinine
>2.0 mg/dL, and (HDL) cholesterol <40 mg/dL ; had used
anabolic steroids, recombinant human growth hormone,
dehydroepiandrosterone , and androstenedione during the
past year ; or were using any recreational drug.
Study Intervention
Three dose levels — 0.1, 0.3 , and 1.0 mg — were evaluated
against placebo. Each dose of LGD-4033 or placebo
was administered daily orally with 8 ounces of water
after an overnight fast. A total of 20 doses were administered
over 21 days; no dose was given on day 2 to allow
PK sampling for 48 hours after the fi rst dose. The 21-day
treatment period was followed by a 5-week observation
period.
Randomization
The subjects were randomized to the active drug or
placebo group based on protocol-defi ned randomization
schema: six active and two placebo in 0.1-mg cohort; 10 – 12
active and 10 – 12 placebo in 0.3-mg and 1.0-mg cohorts.
A protocol amendment after the completion of 1.0-mg
cohort added 12 active and six placebo subjects in the
0.1-mg cohort. Randomization lists, generated by the
biostatistician, were sent directly to Investigational Drug
Service.
The subjects were initially assigned to either placebo or
0.1 mg LGD-4033 daily. At the completion of each dose
level, the safety data were reviewed by a Safety Panel and
separately by a Data and Safety Monitoring Board, which
determined whether the dose could be escalated to a higher
level, based on prespecifi ed safety criteria. Dose escalation
proceeded only if an acceptable safety profi le with no clinically
signifi cant and/or unexpected toxicity was observed at
the lower dose.
Blinding
The study was a double-blind trial with concealed randomization.
The subjects and study personnel were unaware
of the intervention. Only the biostatistician and Investigational
Drug Service were aware of the subject ’ s group
allocation. The Investigational Drug Service maintained the
randomization code and dispensed the study medication
based on the randomization list.
Outcomes
The primary aim was to assess the safety and tolerability
of escalating doses of LGD-4033 following repeated oncedaily
oral administration for 21 days. Secondary aims included
the determination of the PK and pharmacodynamics of
LGD-4033 and its effects on mixed - muscle FSR. Additionally,
we investigated the effects of 21 days of treatment with
LGD-4033 on LBM measured by dual - energy x-ray absorptiometry,
maximal voluntary strength measured by one repetition
maximum method, and physical function, assessed
by the stair-climbing power, recognizing that a 21-day duration
may not be suffi ciently long to fully elucidate the
anabolic effects of the SARM on LBM, muscle strength,
and physical function.
Schedule of Events
LGD-4033 concentrations were measured using a validated
liquid chromatographic – tandem mass spectrometry
method in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 8,
10, 12, 24, 28, 32, and 48 hours after the fi rst dose. Oncedaily
dosing recommenced on day 3 for 20 days , and on day
21, venous blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10,
12, 24, 28, 32, 48, 72, 96, 120 , and 168 hours after day 21
dosing.
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 89
3
Luteinizing hormone, follicle-stimulating hormone,
adrenocorticotropic hormone, cortisol, total and free testosterone,
sex hormone – binding globulin levels, and plasma
lipids were measured periodically throughout the 21-day
intervention period and 7 and 35 days after drug cessation.
LBM and fat mass were measured at baseline and on days
20 and 28. Leg press strength and stair-climbing power and
speed were assessed at baseline and between days 23 and 25.
M ethods
Body composition was assessed using dual-energy x-ray
absorptiometry (Hologic 4500) scanner, calibrated using a
soft tissue phantom before each scan. To measure the leg
press strength ( 15 , 20 , 21 ), subjects underwent whole-body
warm up, followed by one set of 5 – 10 repetitions using
40 % – 60% of the estimated maximum. Following appropriate
rest periods between attempts, subjects lifted progressively
heavier weights until the subject could not complete the lift.
The last successfully completed lift was recorded as the one
repetition maximum .
The 12-step stair-climb test required subjects to ascend a
staircase with step rise of 17 cm as fast as possible with time
recorded by activation of switchmats on the 8th and 12th
stair ( 15 , 20 , 21 ). The test – retest reliability is 0.85 and coeffi
cients of variation 2%. After familiarization, two trials
were given with the best time taken as the stair-climb score.
Power was calculated from the time elapsed, body weight,
and vertical distance.
Fractional Protein Synthesis Rates
On days 1 and 20, at 7 am , an 18-gauge catheter was
inserted into the forearm vein of each arm, one for blood
sampling and one for tracer infusion. Baseline blood samples
were drawn for analysis of amino acid enrichments from
one arm, heated with a heating pad. At 8 am , a primed
(2.0 μ mol / kg) constant infusion (0.06 μ mol / kg / min utes ) of
l -[ring- 13 C 6 ] phenylalanine was started and maintained for
6 hours. Venous blood was obtained at 0, 60, 120, 150, 165,
180, 195, 210, 240, 300, 330, 345, and 360 min utes during
the infusion. Two muscle biopsies (100 – 300 mg) were taken
at 180 and 360 min utes from vastus lateralis, ~ 10 to 15 cm
above the knee, using a 5-mm Bergstrom biopsy needle, and
snap frozen in liquid nitrogen for storage in a − 80 ° C freezer
until analysis.
Phenylalanine enrichments in arterialized venous blood
was determined after deproteinization with sulfosalicylic acid,
extraction with cation exchange chromatography (Dowex AG
50W-8X, 100 – 200 mesh H+ form; BioRad Laboratories,
Richmond, CA), derivatization using tert -butyldimethylsilyl,
followed by gas chromatography – mass spectrometry in
electron impact mode (GC HP 5890, MSD HP 5989, Hewlett
Packard, Palo Alto, CA ; 22 ).
Muscle samples were weighed and the proteins precipitated
with 800 μ l of 10% sulfosalicylic acid. Intracellular
phenylalanine enrichment was determined by extraction
with cation exchange chromatography (Dowex AG 50W-8X,
200 – 400 mesh H+ form; BioRad Laboratories, Inc.), tert -
butyldimethylsilyl derivatization, and gas chromatography –
mass spectrometry in electron impact mode ( 22 ). The
remaining pellet containing bound mixed-muscle proteins
was repeatedly washed, dried at 50°C overnight , and hydrolyzed
in 3 mL of 6 N HCL at 110 ° C for 24 hours. Amino
acids in the hydrolysate were extracted and derivatized and
analyzed by monitoring the ions 238 and 240 ( 22 ).
Mixed - muscle FSR was calculated by measuring the
incorporation of l -[ring- 13 C 6 ]-phenylalanine into protein
using the precursor – product model:
= − × × P2 P1 M FSR [(E E ) /(E t)]60 100,
where E P1 and E P2 are enrichments of bound l -[ring- 13 C 6 ]-
phenylalanine in the fi rst and second muscle biopsies, t is the
time between biopsies, and E M is the mean l -[ring- 13 C 6 ]-
phenylalanine enrichment in muscle intracellular pool ( 22 ).
Hormone Assays
Total testosterone was measured using liquid chromatography
– tandem mass spectrometry ( 23 ) , and free testosterone
was calculated using a published law-of-mass-action
equation ( 24). Serum luteinizing hormone, follicle-stimulating
hormone , and sex hormone – binding globulin were measured
using two site - directed immunofl uorometric assays
( 9 , 21 ).
Statistical Analyses
Safety parameters were listed and summarized by study
intervention, dose, and time point. Adverse events were
tabulated by System Organ Class and Preferred Term based
on MedDRA dictionary version 12.
Plasma drug concentration – time data were analyzed using
noncompartmental methods. PK parameters were summarized
by dose group , and selected PK parameters were
analyzed using comparative statistics. Dose proportionality
of PK parameters was assessed by linear regression.
Pharmacodynamic assessments were summarized for each
dose and time point. Changes from baseline in hormone levels,
lipids, and FSR were analyzed using repeated measures
analyses of variance, with a dose factor and time-in-treatment
factor and baseline value as covariate. A similar approach
was used to analyze change from baseline in LBM, one repetition
maximum strength , and stair-climbing power.
For dual-energy x-ray absorptiometry , muscle strength,
and stair-climbing power, a trend analysis of change from
baseline was applied using a mixed-model analysis of repeated
measures and adjusted for baseline value. Two postbaseline
measures up to day 28 were utilized in repeated
measure model. This analysis was performed on evaluable
subjects who had baseline measures and at least one
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490 BASARIA ET AL.
post-baseline measure. Placebo subjects from the three cohorts
were pooled for analysis. This resulted in sample sizes
of 30 men for dual-energy x-ray absorptiometry analysis
and 29 men for muscle strength analysis in the placebo
group, 17 in the 0.1-mg, 10 in the 0.3-mg, and 11 in the 1.0-mg
dose groups.
R esults
Flow of Subjects
A total of 389 subjects were screened in person, 131 were
eligible , and 76 were randomized (CONSORT diagram,
Supplementary Appendix Figure 1 ). Eight subjects were
either lost to follow-up or discontinued and 68 subjects
completed the trial.
Subjects
The participants were young (mean age 37 years), lean
( body mass index 25.8 kg/m 2 ) , and had normal testosterone,
luteinizing hormone , and follicle-stimulating hormone
levels ( Table 1 ). The groups were similar in their baseline
characteristics.
Compliance
The compliance, assessed by drug logs and by counting
the unused tablets, was 100%, among men who were included
in the effi cacy analysis.
Safety Data
LGD-4033 was safe and well tolerated at all doses. The
frequency of adverse events was similar between the placebo
and any dose group. Headache, pain related to muscle
biopsy, and dry mouth were the most common events and
did not show dose relationship ( Supplementary Appendix
Table 1 ). More upper respiratory tract infections were
observed in LGD-4033 1.0 - mg group , but these events were
not considered drug related. No drug-related severe or serious
adverse events occurred. One cellulitis (in placebo group)
and one gastroenteritis (0.3 mg group) were severe but were
not considered study drug related. There was no study discontinuation
due to adverse events. There were no clinically
signifi cant changes in liver enzymes, hematocrit, prostatespecifi
c antigen , or electrocardiogram at any dose.
Pharmacokinetics
LGD-4033 displayed a prolonged elimination half-life
(24 – 36 hours) and linear PK ( Figure 1 ). There was a dose -
proportional increase in LGD-4033 concentrations on
days 1 and 21. Serum LGD-4033 concentrations were nearly
threefold higher on day 21 than on day 1, refl ecting accumulation
upon multiple dosing. The mean areas under the
drug concentration curve on day 21 were 19, 85 , and 238 ng
24 hour/mL, respectively, in men receiving 0.1, 0.3, and 1.0 mg
LGD-4033 daily.
Hormone Levels
There was a dose-dependent suppression of total testosterone
and sex hormone – binding globulin levels from
baseline to day 21 ( Figure 2 ). Free testosterone suppression
was noted at the 1.0-mg dose only. The suppression of
total testosterone was greater than that of free testosterone.
Serum luteinizing hormone levels did not show any
meaningful changes from baseline, whereas the folliclestimulating
hormone levels were suppressed only in the
1.0-mg dose group ( Figure 2D and E ). Upon discontinuation
of LGD-4033, the hormone levels returned to baseline
by day 56.
Table 1. Baseline Characteristics of the Subjects
Placebo/LGD Dose Group Placebo
LGD-4033 Doses
0.1 mg 0.3 mg 1 mg All Subjects
N 33 18 11 14 76
Age (years) 36.0 (9.4) 37.0 (10.4) 35.6 (8.4) 40.9 (8.7) 37.1 (9.4)
Body weight (kg) 81.5 (13.6) 78.2 (13.9) 80.5 (13.5) 84.6 (10.2) 81.2 (13.0)
Height (cm) 176.8 (6.4) 178.0 (9.6) 175.3 (7.3) 176.8 (6.9) 176.9 (7.4)
Body mass index (kg/m 2 ) 25.9 (3.4) 24.6 (3.0) 26.2 (3.5) 27.0 (2.7) 25.8 (3.3)
TESTO (ng/dL) 549 (136) 564 (153) 543 (111) 551 (144) 552 (136)
FT (ng/dL) 11.39 (3.11) 11.4 (3.1) 11.4 (3.4) 11.36 (3.3) 11.2 (3.1)
Sex hormone – binding globulin (nmol/L) 34.1 (11.7) 37.5 (21.6) 34.0 (8.6) 36.4 (11.1) 35.3 (14.1)
Luteinizing hormone (U/L) 3.9 (1.9) 3.6 (1.5) 3.0 (0.7) 3.7 (1.1) 3.7 (1.5)
Follicle-stimulating hormone (U/L) 4.0 (3.4) 3.1 (2.1) 4.1 (2.0) 4.1 (2.2) 3.8 (2.7)
prostate-specifi c antigen (ng/mL) 0.8 (0.5) 1.3 (1.6) 0.7 (0.2) 0.8 (0.5) 0.9 (0.9)
Lean body mass (kg) 60.6 (9.1) 58.9 (7.6) 60.6 (8.7) 63.9 (4.7) 60.7 (8.1)
Fat mass (kg) 16.4 (7.5) 13.3 (7.5) 15.7 (5.5) 17.2 (6.5) 15.7 (7.0)
Leg press strength (N) 1440.6 (381.0) 1364.8 (298.8) 1535.0 (287.1) 1476.1 (247.6) 1441.3 (326.8)
Stair-climbing power (W) 659.3 (123.1) 614.2 (125.3) 678.7 (98.4) 665.9 (136.8) 651.8 (122.2)
Notes : The subjects assigned to the placebo group in each of the three cohorts were pooled for the purpose of analyses. Data are mean ± ( SD ). The number of
subjects in each group is shown in row 2. FT= free testosterone; TESTO = testosterone.
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 91
5
Plasma Lipids
Total and low density lipoprotein (LDL) cholesterol did
not change signifi cantly from baseline at any dose ( Table 2 ).
HDL cholesterol decreased from baseline at doses ≥ 0.3 mg;
HDL cholesterol returned to baseline after treatment discontinuation
( Table 2 ). Triglyceride levels decreased from
baseline across all doses.
Body Composition
LBM increased dose dependently ( p for trend = .04 ;
Figure 3A ). The increase in LBM averaged 1.21 kg at the
1.0 - mg dose ( p = .047 vs placebo). The increase in LBM
was correlated with the dose. Fat mass ( Figure 3B ) did not
change signifi cantly. The increase in appendicular skeletal
muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -
cantly differently from that in the placebo group (change
from baseline − 0.2, 0.04, 0.47 , and 0.37 kg for the placebo,
0.1, 0.3, and 1.0-mg groups, p for trend = .078).
L4033-2: Day 1 PK
0.1
1
10
100
0 10 20 30 40 50
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0 30 60 90 120 150 180
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
Muscle Performance and Physical Function
The increase in strength averaged 68.3 N at the 1.0-mg
dose, but this change was not signifi cantly different from
that in the placebo group ( Figure 3C ). Stair - climbing speed
and power revealed a trend toward dose-related improvement,
but these changes did not achieve statistical signifi cance.
Fractional Mixed - Muscle Protein Synthesis Rates
Plasma phenylalanine concentrations did not change signifi
cantly from 180 to 360 min utes indicating achievement
of a steady state. Baseline FSR averaged ~ 6% / h , consistent
with published literature. The change in FSR from baseline,
measured in the fasted state, did not differ signifi cantly
between 0.3-mg dose and the placebo groups (0.033 ± 0.016
vs 0.031 ± 0.011, p = .99; Supplementary Appendix Table 2 ).
D iscussion
LGD-4033 was safe and well tolerated over the range of
doses that were evaluated over a 3-week period. Even during
this short treatment period, there was clear evidence of
the compound ’ s androgenic activity, as refl ected in the
increase in LBM, and signifi cant suppression of testosterone,
sex hormone – binding globulin , and HDL cholesterol levels.
In spite of demonstrable androgenic activity, serum prostatespecifi
c antigen did not change signifi cantly. The study also
revealed other attractive PK attributes of the drug — including
a prolonged circulating half-life, dose - proportional systemic
exposure, and robust relationships between the dose and
outcomes. The gains in LBM were similar to those reported
with another SARM ( 17 ), although the treatment duration
in the latter trial was substantially longer (12 weeks).
The study had many features of a good trial design; subject
allocation by randomization, concealed randomization,
blinding, and independent appraisal of safety data by a Data
and Safety Monitoring Board . By virtue of being an ascendingdose
study, the study also had some inherent constraints.
The doses of study medication were administered sequentially
in ascending order rather than in random order. The
sample size, although substantially larger than in most
phase I ascending - dose studies, was not based on considerations
of effect sizes, as the study ’ s primary aim was to
establish safety and tolerability rather than effi cacy. Similarly,
the 3 -week study duration was not designed to demonstrate
maximal effects on skeletal muscle mass and muscle strength
which were not the primary outcomes of the trial. In light of
these inherent constraints, it is particularly remarkable that
signifi cant dose-dependent gains in LBM were evident in
this short duration, indicating this SARM ’ s substantial
androgenic – anabolic activity on the skeletal muscle.
Several attractive PK features of this SARM are noteworthy.
Its prolonged elimination half - life renders it amenable
to once daily or even a less frequent dosing regimen.
Daily administration of the drug was associated with doseproportional
increase in systemic exposure resulting in
Figure 1. Pharmacokinetics of LGD-4033 in Healthy Men. Legend.LGD-4033
concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6,
8, 10, 12, 24, 28, 32, and 48 hours after the fi rst dose (upper panel). Once-daily
dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5,
1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168 hours after day 21
dosing (lower panel).
L4033-2: Day 1 PK
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- mg (n=6)
Cohort 2- (n=11)
3- 1 mg (n=14)
L4033-2: Day 21 PK
Time (h)
Plasma Conc. (ng/mL)
Cohort 1- mg (n=5)
2- 0.3 mg (n=10)
3- 1 mg (n=11)
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692 BASARIA ET AL.
A B
C D
E F
Figure 2. (A) The effects of LGD-4033 selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone
levels are shown. The data are mean ± standard error of the mean ( SEM ) , n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in
the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( B ) Change in the free testosterone levels from baseline. Change from
baseline in serum free testosterone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and
14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( C ) Change in sex hormone – binding globulin levels from baseline.
Change from baseline in serum sex hormone – binding globulin levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose,
11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( D ) Change in luteinizing hormone
(U/L) levels from baseline. Change from baseline in serum luteinizing hormone levels is shown. The data are mean ± SEM, n = 33 in the placebo group, 18 in the
0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period. ( E ) Change in follicle -
stimulating hormone (U/L) levels from baseline. Change from baseline in serum follicle-stimulating hormone levels is shown. The data are mean ± SEM, n = 33
in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment
period. ( F ) Change in prostate - specifi c antigen (ng/mL) levels from baseline. Change from baseline in prostate-specifi c antigen levels is shown. The data are mean ±
SEM, n = 33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the
21-day treatment period.
A B
C D
E F
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 93
7
predictable accumulation upon multiple dosing. There was
a robust relationship between the dose and the plasma concentrations.
The mean area-under-the-curves (AUC) in men
receiving the 0.3 - and 1.0 - mg dose were above the drug
AUC estimated to be effi cacious in monkeys, and all three
doses produced AUCs that exceeded the AUC estimated to
be effi cacious in orchidectomized rats.
In a manner typical of all oral androgens ( 25 , 26 , 27 ), the
oral administration of LGD-4033 was associated with signifi
cant suppression of HDL cholesterol at the 1.0-mg dose.
Triglyceride levels also decreased, but LDL cholesterol did
not change. Neither the mechanism nor the clinical signifi -
cance of the HDL suppression with orally administered
androgens is well understood ( 25 ). HDL cholesterol has
been negatively associated with the risk of coronary artery
disease in epidemiological studies ( 25 , 28 ); however, pharmacologically
induced changes in HDL cholesterol have
not been necessarily associated with changes in cardiovascular
risk. In animal models, the degree of anti-atherogenic
effect of HDL cholesterol is determined more by the mechanism
of HDL modifi cation than by the changes in HDL
levels ( 28 , 29 ). Thus, the increases in HDL cholesterol due
to overproduction of apoA1, but not due to inhibition of
HDL catabolism, have been found to be atheroprotective
( 28,29,30,31,32). The HDL lowering effect of oral androgens
has been attributed to the upregulation of scavenger receptor
B1 and the hepatic lipase, both of which are involved in HDL
catabolism ( 32 , 33 ). Neither the hyperexpression of scavenger
receptor B1 nor that of hepatic lipase has been associated
with acceleration of atherogenesis, even though increased
Table 2. The Effects of LGD-4033 Selective Androgen Receptor
Modulator on Plasma Lipids
Treatment Group *
Mean ( SD )
Baseline
Mean ( SE ) Change From
Baseline
Day 21 Day 56
Total cholesterol (mg/dL)
Placebo 163.4 (28.1) − 1.6 (2.9) 5.2 (4.2)
0.1 mg 163.3 (33.5) − 10.8 (3.6) 0.4 (5.5)
0.3 mg 168.6 (16.6) − 18.0 (4.8) 6.4 (5.0)
1 mg 175.1 (33.5) − 14.3 (8.1) 0.3 (4.4)
HDL cholesterol (mg/dL)
Placebo 52.5 (11.8) − 1.7 (1.2) 0.4 (1.8)
0.1 mg 56.1 (17.3) − 1.0 (2.6) 3.5 (2.3)
0.3 mg 50.3 (8.0) − 10.4 (1.4) 0.6 (1.7)
1 mg 49.2 (11.7) − 19.4 (2.1) − 1.1 (3.2)
LDL cholesterol (mg/dL)
Placebo 92.4 (26.2) 0.9 (2.6) 4.4 (3.7)
0.1 mg 91.0 (29.6) − 5.5 (3.3) − 4.5 (4.9)
0.3 mg 101.5 (15.9) − 2.8 (4.5) 1.7 (3.7)
1 mg 106.8 (31.6) 7.1 (7.1) 4.42 (4.0)
Triglycerides (mg/dL)
Placebo 92.6 (36.8) − 4.3 (4.7) 1.9 (7.5)
0.1 mg 80.0 (31.0 ) − 21.4 (8.1) 7.2 (9.1)
0.3 mg 84.4 (26.1) − 24.0 (4.3) 20.8 (8.0)
1 mg 95.4 (39.1) − 10.1 (6.7) − 15.6 (8.0)
Notes : * Number of subjects with at least one post - baseline test: placebo =
30, 0.1 mg = 17, 0.3 mg = 10 , and 1 mg = 14. LDL = Low density lipoprotein.
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-0.5
0.0
0.5
1.0
1.5
2.0
*
* p =0.047 vs. Placebo
A
Total Body
PBO 0.1 mg 0.3 mg 1 mg
-1.0
-0.5
0.0
0.5
B 1.0
C
PBO 0.1 mg 0.3 mg 1 mg
-50
0
50
100
150
Change from Baseline (Newton) Change from Baseline (kg) Change from Baseline (kg)
Figure 3. (A) Mean ( SE ) lean mass (kg) change from baseline up to day 28.
Change from baseline in lean body mass is shown. The data are mean ± standard
error of the mean , n = 30 in the placebo group pooled from the three cohorts,
17 in the 0.1 - mg dose, 10 in the 0.3 - mg group, and 11 in the 1.0 - mg group. BL =
baseline. * p < .05 vs placebo. PBO = placebo; p for trend = .04. ( B ) Mean ( SE )
fat mass (kg) change from baseline up to day 28. Change from baseline in fat
mass is shown. The data are mean ± standard error of the mean , n = 30 in the
placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo. p for trend = .261.
( C ) Change in leg press strength (Newton) from baseline. Change from baseline
in fat mass is shown. The data are mean ± standard error of the mean , n = 30 in
the placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo; p for trend = .203.
expression of each is associated with reduced HDL cholesterol
( 28,29,30,31). Thus, clinical signifi cance of the HDL decrease
associated with oral androgens remains unclear. Long - term
studies are needed to clarify the effects of long-term SARM
administration on cardiovascular risk. In the interim, the
initial trials are likely to be conducted for acute or subacute
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894 BASARIA ET AL.
indications, such as cancer cachexia and functional limitations
associated with acute illness or hip fracture, where
the short-term changes in HDL cholesterol may not be
clinically important.
Exogenous androgens would be expected to lower
endogenous testosterone levels. However, LGD-4033 has
been shown to increase bone mineral density, periosteal
bone formation, and femur bending strength in preclinical
models. Other SARMs have also been shown to maintain
measures of sexual function in the orchiectomized rodent
model ( 18 ).
The mechanisms by which androgens increase muscle
mass remain incompletely understood. Testosterone administration
induces hypertrophy of both type I and type II
muscle fi bers ( 34 ). Muscle fi ber hypertrophy can result
from either increased muscle protein synthesis or decreased
muscle protein degradation. Our studies did not reveal a signifi
cant difference in fractional muscle protein synthesis
between the placebo and the active drug groups at the 0.3-mg
dose. These studies were conducted in the fasted state when
the fractional muscle protein synthesis is low; however, testosterone
trials that have reported an increase in FSR have
also been conducted in the fasted state as have trials that
failed to show improvements in FSR ( 35 ). Previous human
and animal studies have shown inhibition of muscle proteolysis
and muscle protein degradation pathways during
testosterone administration, as potential mechanisms for
increased muscle mass ( 36 , 37 ). Testosterone also increases
the number of satellite cells ( 38 ) by promoting the proliferation
of satellite cells and the differentiation of muscle progenitor
cells ( 39 , 40 ). Those mechanisms were not investigated
in this study.
The past decade has witnessed the emergence of a number
of nonsteroidal SARMs from several pharmaceutical
companies. Currently, SARMs are being developed as a
new class of function - promoting anabolic therapies to treat
the loss of muscle mass and function associated with aging
and illness, cancer cachexia, osteoporosis, and other conditions
associated with muscle loss. This 3-week phase I study,
by demonstrating the safety and tolerability of LGD-4033
and signifi cant gains in muscle mass and strength, paves
the way for longer term effi cacy trials in one or more
populations of older individuals for which SARMs may
be indicated. Short-term indications for grievous conditions,
such as cancer cachexia or functional limitations
following an acute illness or hip fracture, might provide
a more attractive risk:benefi t profi le for initial trials of
SARMs than long-term indications such as aging-associated
sarcopenia.
F unding
This trial was supported by Ligand Pharmaceuticals.
S upplementary M aterial
Supplementary material can be found at: http://biomedgerontology.
oxfordjournals.org/
Acknowledgment
The authors thank the Data and Safety Monitoring Board: Glenn
Cunningham, MD, and Ronal S. Swerdloff, MD.
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Estou praticando musculação numa média de 1 vez a cada 15 dias, não estou sedentário pratico lutas quase todo dia

Segunda feira dia 30/04/2018 retornarei a rotina de treinos para hipertrofia

Duas semanas depois, dia 14/05/2018 irei iniciar o sarms

Qualquer duvida ou sugestão sobre o ciclo estou a disposição

 

PROTOCOLO

Será utilizado 5mg por dia durante 15 dias, dependendo dos resultados dos 15 dias iniciais optarei pelos seguintes protocolos

 

1-4 5mg lgd-4033/dia

4-6 10mg lgd-4033/dia

 

ou

 

1-2 5mg lgd-4033/dia

2-5 10mg lgd-4033/dia

 

TPC

Utilizarei tribulus junto ao ciclo como tentativa de menor inibição do eixo

E tamoxifeno 20mg, durante a ultima semana do ciclo e uma semana após

 

MEDIDAS

Altura aproximada 172cm

Peso 74kg

BF aproximado 14%

[VBOL 580]

Por que escolheu essa TPC logo de cara ?

[Ph007 3]

Em 28/04/2018 em 21:51, ShreddedBrah disse:

Por que escolheu essa TPC logo de cara ?

O Estudo que eu tenho acesso mostrou uma queda significativa no FSH em 21 dias em uma dose de 1mg

Levando isso pra 40 dias em uma dose de 5 a 10 vezes maiores, tenho medo da morte do meu pau, prefiro prevenir do que remediar, até pq só ha vantagens, tanto em saude quanto em manter os ganhos

 

Atualizando 28/05/2018

 

Voltei a treinar 30/04/2018

Inicio do uso 14/05/2018 (5mg/dia)

 

De quando comecei treinar até aqui foram +3kg, atuais 77kg, sem aumento do bf e bastante aumento de força, estou gostando dos resultados

Supinando com 80kg pra 6 reps, que é um recorde pessoal

Estou suplementando Whey, Tribulus, Creatina e Vitamina D

hoje (28/05/2018) começo a dose de 10mg/dia e sigo assim até acabar o pote

[gabrielfreiberger 68]

Boa mano, acompanhando.

 

Alguma diferença no eixo?

[Ph007 3]

Em 28/05/2018 em 16:57, gabrielfreiberger disse:

Boa mano, acompanhando.

 

Alguma diferença no eixo?

 

ATUALIZANDO 07/06/2018

    Ontem e hoje senti um pouco de desanimo e libido um pouco baixa, eu diria que esta começando a inibir o eixo, daqui poucos dias vou começar com o tamoxifeno 20mg/dia com o objetivo de aumentar o LH e FSH, ja vou comprar amanhã

    Sexta feira atualizo os resultados

[Ph007 3]

editado

Editado Junho 12, 2018 às 01:58 por Ph007

[Ph007 3]

Em 28/05/2018 em 16:57, gabrielfreiberger disse:

Boa mano, acompanhando.

 

Alguma diferença no eixo?

A "queda no eixo" que tinha sentido estava mais ligado a cansaço e falta de sono

Descansei bem ontem hoje to 100% disposto, então eixo deve estar ok, se continuar assim nem vou mandar tamox, se der farei exames no final

[Landof 7]

Se der pra fazer, tenho curiosidade, não deixe de postar.

Acompanhando!

 

[TheMuscleMan 19]

Eae amigo, como foram os resultados até o presente momento? Se der relata pra nós.. valeu!

[Wellington951 4]

pode relatar o resto aqui??