Single Doses of the SERM Lasofoxifene Increases Testosterone Levels for over 28 Days in Healthy Men
https://endo.confex.com/endo/2014endo/webprogram/Paper13945.html
Lasofoxifene (laso) is a next-generation selective estrogen receptor modulator (SERM) that at a daily dose of 0.5 mg has been shown to reduce the risk of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke in postmenopausal women, but with an increased risk of venous thromboembolic events(1).
The effects of laso in males are unknown.
Certain SERMs have been shown to stimulate endogenous testosterone (T) production in men via perturbation of the gonadal axis(2).
Here we report the potent and prolonged effect of a single dose of laso to increase circulating T levels in young healthy men.
The study was an investigator-blind, randomized, placebo-controlled, parallel group, single ascending dose study of laso or placebo in 36 healthy male volunteers age 18-41, consisting of 5 fasted dose groups (1, 3, 10, 30 and 100 mg) and 1 fed dose group (100 mg) where each group has 4 subjects receiving laso and 2 receiving placebo. Pharmacokinetic parameters, luteinizing hormone (LH), and total T in plasma samples were measured out to 28 days postdose.
Following oral administration of single doses of laso, Cmax and AUC(0-∞) increased in a dose proportional fashion with overall mean T1/2 of 116 ± 44 hours (group mean Tmax of 6.0-9.5 hours). At the 100 mg dose, food appeared to have little effect on the absorption of laso and only delayed Tmax 2.5 hours to the parallel group.
Changes in LH were detected with the higher doses of laso (10, 30, and 100 mg) with a transient and relative small early decrease in LH (19-39% drop from baseline) within 24 hours, followed by a large rebound increase of 200-500% from baseline during days 3-7. LH levels remained elevated relative to baseline to day 28, the last data point collected, except for the 10 mg group in which LH levels gradually returned to the placebo level. The pooled placebo group also had a 25 ± 28% drop in LH at 12 hours.
T levels followed the pattern of change in LH.
At 12 hours, T levels were reduced relative to baseline by -31 ± 8% (placebo), -60 ± 0% (30 mg), -48 ± 20% (100 mg), and -48 ± 15% (100 mg fed).
At day 7, T levels were increased +22 ± 23% (placebo), +36 ± 0% (30 mg), +82 ± 20% (100 mg), and +90 ± 50% (100 mg fed).
T changes appeared to be more sensitive than LH whereas the 1 mg group had 46 ± 34% increase from baseline at day 3 versus 5 ± 14% for placebo.
The changes in T were long lasting and at day 28 the increases were 15 ± 28% (placebo), 24 ± 81% (1 mg), 57 ± 38% (3 mg), 28 ± 18% (10 mg), 81 ± 49% (30 mg), 109 ± 42% (100 mg), and 92 ± 38% (100 mg fed).
Group mean T levels appeared to plateau at 30-40 nmol/L 7-14 days postdose regardless of laso dose or LH level. For example, at day 21 T levels were 25.5 (3 mg), 35.2 (10 mg), 32.7 (30 mg), 39.3 (100 mg), and 33.2 (100 mg fed) nmol/L.
The pharmacodynamic effects of laso on the gonadal axis are quite different from other SERMs and warrant further study for potential clinical benefits of laso treatment in men.
(1) Cummings et al., N Engl J Med. 2010 Feb 25; 362(8):686-96.
(2) Grefhorst et al., J Clin Endocrinol Metab. 2010 Dec;95(12):5443-8.
Disclosure: KM: Employee, Ligand Pharmaceuticals Incorporated. RAM: Employee, Pfizer, Inc.. EGV: Employee, Ligand Pharmaceuticals Incorporated. LZ: Employee, Ligand Pharmaceuticals Incorporated. Nothing to Disclose: GCW
https://endo.confex.com/endo/2014endo/webprogram/Paper13945.html
Lasofoxifene (laso) is a next-generation selective estrogen receptor modulator (SERM) that at a daily dose of 0.5 mg has been shown to reduce the risk of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke in postmenopausal women, but with an increased risk of venous thromboembolic events(1).
The effects of laso in males are unknown.
Certain SERMs have been shown to stimulate endogenous testosterone (T) production in men via perturbation of the gonadal axis(2).
Here we report the potent and prolonged effect of a single dose of laso to increase circulating T levels in young healthy men.
The study was an investigator-blind, randomized, placebo-controlled, parallel group, single ascending dose study of laso or placebo in 36 healthy male volunteers age 18-41, consisting of 5 fasted dose groups (1, 3, 10, 30 and 100 mg) and 1 fed dose group (100 mg) where each group has 4 subjects receiving laso and 2 receiving placebo. Pharmacokinetic parameters, luteinizing hormone (LH), and total T in plasma samples were measured out to 28 days postdose.
Following oral administration of single doses of laso, Cmax and AUC(0-∞) increased in a dose proportional fashion with overall mean T1/2 of 116 ± 44 hours (group mean Tmax of 6.0-9.5 hours). At the 100 mg dose, food appeared to have little effect on the absorption of laso and only delayed Tmax 2.5 hours to the parallel group.
Changes in LH were detected with the higher doses of laso (10, 30, and 100 mg) with a transient and relative small early decrease in LH (19-39% drop from baseline) within 24 hours, followed by a large rebound increase of 200-500% from baseline during days 3-7. LH levels remained elevated relative to baseline to day 28, the last data point collected, except for the 10 mg group in which LH levels gradually returned to the placebo level. The pooled placebo group also had a 25 ± 28% drop in LH at 12 hours.
T levels followed the pattern of change in LH.
At 12 hours, T levels were reduced relative to baseline by -31 ± 8% (placebo), -60 ± 0% (30 mg), -48 ± 20% (100 mg), and -48 ± 15% (100 mg fed).
At day 7, T levels were increased +22 ± 23% (placebo), +36 ± 0% (30 mg), +82 ± 20% (100 mg), and +90 ± 50% (100 mg fed).
T changes appeared to be more sensitive than LH whereas the 1 mg group had 46 ± 34% increase from baseline at day 3 versus 5 ± 14% for placebo.
The changes in T were long lasting and at day 28 the increases were 15 ± 28% (placebo), 24 ± 81% (1 mg), 57 ± 38% (3 mg), 28 ± 18% (10 mg), 81 ± 49% (30 mg), 109 ± 42% (100 mg), and 92 ± 38% (100 mg fed).
Group mean T levels appeared to plateau at 30-40 nmol/L 7-14 days postdose regardless of laso dose or LH level. For example, at day 21 T levels were 25.5 (3 mg), 35.2 (10 mg), 32.7 (30 mg), 39.3 (100 mg), and 33.2 (100 mg fed) nmol/L.
The pharmacodynamic effects of laso on the gonadal axis are quite different from other SERMs and warrant further study for potential clinical benefits of laso treatment in men.
(1) Cummings et al., N Engl J Med. 2010 Feb 25; 362(8):686-96.
(2) Grefhorst et al., J Clin Endocrinol Metab. 2010 Dec;95(12):5443-8.
Disclosure: KM: Employee, Ligand Pharmaceuticals Incorporated. RAM: Employee, Pfizer, Inc.. EGV: Employee, Ligand Pharmaceuticals Incorporated. LZ: Employee, Ligand Pharmaceuticals Incorporated. Nothing to Disclose: GCW
