Post on 23-Dec-2015
Projects I participated in
• CEP cell study • NES-2 study• Pharmacokinetics of modified release testosterone in
healthy men
Pharmacokinetics of modified slow release oral testosterone in
experimentally hypogonadal men.
PI: John Amory MD, MPH
Background
• Hypogonadism affects 6-10% of men depending on age– Sx: low libido, fatigue, ED, osteoporosis, depression and poor physical
performance (decreased muscle mass and strength)• Testosterone can be repleted for either primary or secondary
androgen deficiency – Current forms: alkylated testosterone, IM administration, testosterone
patch, testosterone gels, buccal tablet– Limitations of many of the current forms of testosterone
administration.• Investigation: Oral testosterone• Hypothesis: Administration of oral testosterone to healthy men
who are rendered experimentally hypogonadal three times daily will increase and keep testosterone levels within the normal range
Methods• Subjects:
– Healthy men age 18-55 – Exclusion: previous participation in drug study in the previous 6 months,
lab abnormalities, testicular disease or trauma, psychiatric disorders, illicit drugs, >3 alcoholic beverages daily.
– 14 subjects screened; 12 subjects recruited• 1 excluded for HTN• 1 excluded for PAD
• Acycline (300 mcg SQ x 1)• Oral testosterone 300 mg PO TID WM• Two 24 hour study periods
– Day 1-2 and day 9-10– Blood drawn at: 1, 2, 4, 6, 8,10, 12, 14, 16, and 24 hours after admission
to the GCRC• Testosterone• DHT• Estrogen• SHBG
Baseline CharacteristicsCharacteristic
Age (yr) 28.1 ± 11.5
Body weight (kg) 79.9 ± 7.5
BMI (kg/m2) 24.2 ± 1.5
FSH (IU/L) 3.2 ± 1.5
LH (IU/L) 5.4 ± 4.4
Testosterone (ng/ml) 5.1 ± 1.3
PSA (ng/mL) 0.91 ± 0.56
Serum Testosterone
0
200
400
600
800
1000
1200
0 4 8 12 16 20 24
Serum Testosterone
Day 1-2
Day 9-10
Tes
tost
ero
ne (
ng/d
L)
Time (hrs)
Serum Estradiol
0
5
10
15
0 4 8 12 16 20 24
Serum Estradiol Day 1-2
Day 9-10
Est
radi
ol (
pg/
mL)
Time (hrs)
Free Testosterone
0
5
10
15
20
25
30
35
0 4 8 12 16 20 24
Free Testosterone
Day 1-2
Day 9-10
Fre
e T
est
oste
rone
(ng
/dL)
Time (hrs)
Maximal Hormonal LevelsDay 1-2 Day 9-10
Testosterone* (p=0.03) 1000 119 ng/dL 945 260 ng/dL
DHT* (p=0.01) 257 36 ng/dL 163 32 ng/dL
Free Testosterone (p= 0.77) 26.9 12.6 ng/dL 30.2 35.8 ng/dL **
**Outlier in the group where Free T was an order of magnitude greater than all other subjects
Adverse Events
• 8 non serious events in 6 subjects– 1 subject had symptoms of hypogonadism after
the study period but before the follow up visit.– 1 subject had transient elevations of his AST, ALT
and alkaline phosphatase in the setting of 6+ EtOH drinks which normalized despite continued administration of oral testosterone
• No GI side effects or intolerance
Discussion summary points
• Normalization of testosterone occurred within 1 hour of administration of testosterone with the majority of men maintaining hormone levels within the normal range
• DHT was elevated above the normal range but appeared to decrease over time
• Though total testosterone decreased at steady state, free testosterone levels remained the same correlating with an approximately 25% decreased level of SHBG
Conclusion
• Administration of oral testosterone at 300 mg three times daily appears to correct experimentally induced hypogonadism in healthy young men and may be a viable technique for future repletion of testosterone in androgen deficient men
Limitations
• Oral dosing of this medication was three times daily
• Does not mimic physiologic circadian rhythm of endogenous testosterone
• Though serum total testosterone and free testosterone are largely within normal limits, supraphysiologic levels of DHT were achieved
• Number of subjects was very small and data have large interindividual variability
Future directions
• Effect of meals and hormone absorption • Monitoring hormone levels in larger
populations particularly in light of the significant variability
• Significance of supraphysiological levels of DHT and relationship to prostate health
Acknowledgements
• Great thanks to:– UW
• Bill Bremner• John Amory• Stephanie Page• Robert Bale• Iris Neilson• Mark Bentz• Kathy Winter• Kathryn Duncan• Dorothy McGuiness• Connie Pete
– GSK• Richard Clark• Hui Zhi• Mark Bush• Ralph Caricofe