| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the * Center for Research in Reproduction and
Contraception, Divisions of General Internal Medicine and Endocrinology,
Metabolism, and Nutrition, Department of Medicine, University of Washington
Medical School, Seattle, Washington; and
GlaxoSmithKline Research and Development,
Research Triangle Park, North Carolina.
| Correspondence to: Stephanie T. Page, University of Washington, Box 356138, 1959 NE Pacific St, Seattle, WA 98195 (e-mail: page{at}u.washington.edu). |
| Received for publication June 6, 2007; accepted for publication December 11, 2007. |
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionReferences |
|---|
-reductase inhibitor dutasteride (D) to oral T in oil dramatically
improves concentrations of serum T. In this study we evaluate the absorption
of oral T+D, comparing nanomilled T (NmT+D) vs T dissolved in oil (Capmul;
CpT+D), as nanomilling might offer a simpler, more practical means of oral T
administration, given the limited solubility of T in oil. Twelve healthy men
were administered leuprolide on Day –14 to suppress endogenous T
biosynthesis and were pretreated with D to block 5-reductase. Once
hypogonadal, subjects were sequentially administered 200- and 400-mg doses of
CpT+D and NmT+D in the fasted and fed states. Serum T and dihydrotestosterone
(DHT) were measured: before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24
hours after each dose. Two weeks after leuprolide administration, T levels
were below the normal range. A 400-mg dose of either formulation of oral T+D
increased mean serum T above the lower limit of the normal range for
8–10 hours. Food had a minimal effect on the pharmacokinetic parameters
of the NmT+D formulation but decreased the maximum observed concentration
after dosing (Cmax) for CpT+D. Serum DHT remained below the normal
range throughout the study period with both formulations. No significant
changes in liver function tests or other adverse events were observed. A
400-mg dose of either oral T+D formulation normalized serum T for 8–10
hours and suppressed DHT. NmT allows for tablet formulation, and its
pharmacokinetics were not affected by food, demonstrating the feasibility of
oral nanomilled T as a promising and practical twice-daily therapy for the
treatment of male hypogonadism.
Key words: Androgen, 5-reductase
The only orally available testosterone replacement products currently approved for use in the United States are alkylated T derivatives, such as methyltestosterone, which can cause cholestatic jaundice, drug-induced hepatocellular injury, and peliosis hepatitis, and have been associated with the development of liver adenomas (Westaby et al, 1977). Oral testosterone undecanoate is available in many countries and is not associated with the liver injury seen with methyltestosterone. However, the bioavailability of testosterone undecanoate is significantly dependent upon the simultaneous ingestion of a fatty meal (Bagchus et al, 2003) and it must be dosed at least 2 times a day. A safe, oral formulation of T with reliable bioavailability might be preferable for some men compared with currently available options.
Oral administration of crystalline T does not greatly increase serum T
levels due to extensive hepatic first-pass metabolism and low bioavailability
(Foss, 1939;
Johnsen et al, 1974;
Nieschlag et al, 1975;
Daggett et al, 1978). However,
we recently demonstrated that the addition of a 5-reductase inhibitor
to orally administered T in an oil emulsion profoundly improved the absorption
of T compared with oral T alone (Amory and
Bremner, 2005; Amory et al,
2006). In these studies, serum T levels within the normal range
were achieved for 10 hours in normal men with reversible, medically induced
hypogonadism when a single dose of T was administered orally in oil together
with a 5-reductase inhibitor. Unfortunately, the solubility of T in oil
is partially temperature dependent, making it difficult to encapsulate the
dose in an acceptable volume at room temperature without precipitation.
Nanomilling, a process of formulating compounds into nanometer-sized particles
using high-sheer media milling, has been shown to improve the bioavailability
of some lipophilic compounds
(Merisko-Liversidge et al,
2003).
We hypothesiszed that oral nanomilled T (NmT) would be as orally bioavailable as T in oil. Therefore, we conducted a pharmacokinetic study comparing dutasteride (D) coadministered with oral T in oil (Capmul; CpT) vs D coadministered with encaspulated NmT. We administered CpT+D or NmT+D in both fasting and fed states to healthy men whose endogenous T production had been temporarily suppressed by the gonadotropin-releasing hormone (GnRH) agonist, leuprolide. Serum T and dihydrotestosterone (DHT) concentrations were assessed over a 24-hour period after each oral dose.
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
Study Design
The study design is outlined in Figure
1. Fourteen days prior to dosing (Day –14), subjects
received an injection of the GnRH agonist leuprolide (7.5 mg intramuscularly),
which suppresses T production in men by 95%, reaching hypogonadal levels by 2
weeks after injection (Mazzei et al, 1990;
Perez-Marreno et al, 2002). At
this same visit, subjects received a single 24.5-mg loading dose of D to
rapidly attain steady-state concentrations (approximately 40 ng/mL)
necessitated by the long half-life and large volume of distribution of D.
Subjects then self-administered 0.5 mg D daily for the duration of the study
(25 days, Day –14 through Day 11). On study days 1, 2, 3, 8, 9, and 10,
subjects had blood drawn before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and
24 hours after administration of oral T+D for measurement of serum T and DHT
(CpT on days 1–3 and NmT on days 8–10;
Figure 1). On days 1, 2, 8, and
9, the oral T was dosed while fasting, whereas on days 3 and 10, the T was
administered with a 750-kcal meal, including at least 250 kcal (
30 g) of
fat. Serum liver enzymes, creatinine, and blood counts were obtained at each
clinic visit and daily during oral T dosing. Based upon pharmacokinetic data
from prior studies of oral T administered in oil
(Amory and Bremner, 2005;
Amory et al, 2006), a sample
size of 12 subjects was estimated to have an 84% power to detect a difference
greater than 40% in the serum testosterone area under the curve
(AUC0–24) between CpT and NmT at the 400-mg dose at an
of .05.
Measurements
Serum total T and DHT were measured by a validated gas chromatography/mass
spectroscopy assay (Taylor Technologies, Princeton, NJ). Interassay
coefficients of variation for low, mid, and high levels of T and DHT were
5.4%, 4.5%, and 1.2%, and 6.3%, 6.3%, and 3.3%, respectively. Intraassay
coefficients of variation for low, mid, and high levels of T and DHT were
3.7%, 4.1%, and 0.8%, and 1.4%, 3.4%, and 5.1%, respectively. Lower limits of
detection for T and DHT were 50.0 pg/mL and 10.0 pg/mL, respectively.
Statistics
AUC0–24, maximum observed concentration after dosing
(Cmax), and time to maximum observed concentration
(Tmax) were calculated for each subject after subtraction of
baseline T or DHT concentration for each day (WinNonlin 4.1; Pharsight,
Mountain View, Calif). Following loge transformation,
AUC0–24 and Cmax of testosterone and DHT were
analyzed separately by a mixed-effect model fitting day as a fixed effect and
subject as a random effect. No adjustments for multiple comparisons were made.
For all comparisons, a P < .05 was considered significant. Version
8.2 of the SAS system (SAS Institute Inc, Cary, NC) was used to analyze the
data.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
Serum Testosterone
In all subjects, serum T levels were suppressed well below the normal range
by day 1, 2 weeks after Lupron adminstration (383 ± 161 ng/dL at
baseline vs 170 ± 18 ng/dL on Day 0; P < .001), and on the
morning of each study day (ie, 24 hours after the previous T dose; data not
shown).
In the fasting state, the combination of D and either 200 or 400 mg of CpT or NmT rapidly raised serum T above the lower limit of normal for approximately 4 hours (200 mg) and approximately 8 hours (400 mg; Figure 2). In the fasting state, the AUC0–24 after CpT or NmT administration was similar after correction for baseline T levels (Table 2). Dosing of oral CpT+D with food significantly decreased the Cmax for serum T compared with fasting adminstration. However, food did not affect the Cmax or AUC0–24 of the NmT formulations. When the oral T was administered with food, AUC0–24 and Cmax were not significantly different between CpT+D and NmT+D. For both formulations, dose-dependent increases in exposure were observed in the fasting state (Table 2).
|
|
Serum DHT Levels
Serum DHT levels were suppressed to well below the normal range by day 1 of
the study, following the loading of D
(Table 1;
Figure 3). In the fasting
state, the combination of D with either 200 or 400 mg of CpT or NmT raised
serum DHT slightly above the predose value by 1 hour; however, DHT levels
remained well below the normal range throughout the treatment period
(Table 3). Food intake did not
affect the DHT levels for either oral T formulation compared with the fasting
doses.
|
|
Safety and Tolerability
There were no clinically significant or serious adverse events during the
study. Three subjects complained of mild hot flashes and decreased libido
after completion of the last dose of oral T due to low T levels attributable
to leuprolide administration. These subjects received a 200-mg injection of T
enanthate with symptom resolution. There were no significant changes in serum
liver or kidney function tests or vital signs during the study (data not
shown).
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
-reductase inhibitor to oral T profoundly increases the absorption of
oral T administered in oil (Amory and
Bremner, 2005; Amory et al,
2006), presumably by inhibiting 5-reductase in the
gastrointestinal tract, although the precise mechanism is not known. However,
T in oil has significant solubility constraints, requiring larger volume
administration and/or heating to avoid precipitation within a capsule. Here we
expand our previous observations and demonstrate that the administration of
encapsulated NmT when combined with dutasteride increases serum T to above the
lower limit of the normal range for 8–10 hours in healthy volunteers
with reversible, medically induced hypogonadism. Oral CpT+D and NmT+D resulted
in a similar AUC0–24 and Cmax at both doses.
However, in contrast to NmT+D, the pharmacokinetics of the 400-mg dose of
CpT+D were significantly affected by food. Indeed, the higher Cmax
associated with CpT+D given while fasting resulted in peak T levels
significantly above the upper limit of the normal range
(Figure 2). The
supraphysiologic serum T levels were approximately 40%–45% lower with
NmT+D than with the CpT+D formulation when taken fasting. Although the data
are presented after adjustment for baseline T levels at each point, more
extensive, larger studies will be necessary to further characterize the
possible effects of concomitant food administration with each formulation.
The time the mean T levels were in the normal range with either formulation
at the 400-mg dose suggests that a twice-daily dosing frequency would provide
adequate testosterone exposure for men with testosterone deficiency. Given the
similarities in the pharmacokinetics of the CpT and NmT formulations and the
greater simplicity of dosing T in the smaller volume made possible with
nanomilling, the nanomilled preparation appears to be the most practical for
further development. There were no apparent toxicities or side effects
associated with either form of oral T delivery in this short study. It is
possible, however, that changes in lipids, erythrocytosis, or body composition
might be observed in a longer trial of these testosterone formulations, since
such changes have been associated with other forms of androgen delivery
(Srinivas-Shankar and Wu, 2006). Moreover, it is possible the twice-daily
administration could exacerbate such effects, given the potential for swings
in testosterone levels throughout the day with such a dosing schedule. These
evaluations will be the subject of future, longer-term studies. As expected
with the 5-reductase inhibition by D, serum DHT levels were suppressed
well below the normal range throughout the study.
In addition to providing an alternative route of administration for T
therapy, it is possible that the combination of oral T+D could have advantages
over T treatment alone. Previous work suggests that the combination of T plus
a 5-reductase inhibitor provides the anabolic benefits of T therapy
without stimulating prostate growth in older men
(Amory et al, 2004;
Page et al, 2005). In
addition, recent results suggest that 5-reductase inhibitors may reduce
the risk of prostate cancer, presumably by lowering DHT concentrations
(Thompson et al, 2003). In
theory, the ability to selectively increase serum T without increasing serum,
and perhaps tissue, DHT could minimize the risk of some androgen-dependent
diseases, such as benign prostatic hypertrophy and androgenic alopecia, a
hypothesis only addressable with long-term studies.
In the current study, we have demonstrated that oral testosterone, either nanomilled or in Capmul, when combined with dutasteride results in normalization of serum T levels in healthy men with medically induced, reversible hypogonadism. This work demonstrates the feasibility of an effective, twice-daily oral testosterone dosing regimen for the treatment of male hypogonadism. The combination of oral testosterone plus dutasteride is an exciting prospect for future investigations. Longer-term studies to determine the safety and efficacy of this approach to androgen replacement therapy are warranted.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
Amory JK, Matsumoto AM. The therapeutic potential of testosterone patches. Expert Opin Investig Drugs. 1998; 7: 1977 –1985.[CrossRef][Medline]
Amory JK, Page ST, Bremner WJ. Oral testosterone in oil:
pharmacokinetic effects of 5alpha reduction by finasteride or dutasteride and
food intake in men. J Androl. 2006; 27: 72
–78.
Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM,
Bremner WJ, Tenover JL. Exogenous testosterone or testosterone with
finasteride increases bone mineral density in older men with low serum
testosterone. J Clin Endocrinol Metab. 2004; 89: 503
–510.
Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C,
Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in
middle-aged and older men: estimates from the Massachusetts Male Aging Study.
J Clin Endocrinol Metab. 2004; 89: 5920
–5926.
Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS. Important effect of food on the bioavailability of oral testosterone undecanoate. Pharmacotherapy. 2003; 23: 319 –325.[CrossRef][Medline]
Behre HM, Kliesch S, Leifke R, Link RM, Nieschlag E. Long-term
effect of testosterone therapy on bone mineral density in hypogonadal men.
J Clin Endocrinol Metab. 1997; 82: 2386
–2390.
Brachet C, Vermeulen J, Heinrichs C. Children's virilization and the use of a testosterone gel by their fathers. Eur J Pediatr. 2005;164: 646 –647.[CrossRef][Medline]
Daggett PR, Wheeler MJ, Nabarro JD. Oral testosterone, a reappraisal. Horm Res. 1978; 9: 121 –129.[Medline]
Foss GL. Clinical administration of androgens. Lancet. 1939;1: 502 –504.
Fossa SD, Opjordsmoen S, Haug E. Androgen replacement and quality of life in patients treated for bilateral testicular cancer. Eur J Cancer. 1999;35: 1220 –1225.[CrossRef][Medline]
Johnsen SG, Bennett EP, Jensen VG. Therapeutic effectiveness of oral testosterone. Lancet. 1974; 2: 1473 –1475.[Medline]
Mazzei T, Mini E, Rizzo M, Periti P. Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients. J Int Med Res. 1999; 18(suppl 1): 42 –56.
Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18: 113 –120.[CrossRef][Medline]
Nieschlag E, Mauss J, Coert A, Kicovic P. Plasma androgen levels in
men after oral administration of testosterone or testosterone undecanoate.
Acta Endocrinol (Copenh). 1975; 79: 366
–374.
Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ,
Tenover JL. Exogenous testosterone (T) alone or with finasteride increases
physical performance, grip strength, and lean body mass in older men with low
serum T. J Clin Endocrinol Metab. 2005; 90: 1502
–1510.
Perez-Marreno R, Chu FM, Gleason D, Loizides E, Wachs B, Tyler RC. A six-month, open-label study assessing a new formulation of leuprolide 7.5 mg for suppression of testosterone in patients with prostate cancer. Clin Ther. 2002; 24: 1902 –1914.[CrossRef][Medline]
Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A,
Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL.
Effects of testosterone replacement in hypogonadal men. J Clin
Endocrinol Metab. 2000;85: 2670
–2677.
Srinivas-Shankar U, Wu FC. Drug insight: testosterone preparations. Nat Clin Pract Urol. 3: 653 –665.
Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto
AM, Snyder PJ, Weber T, Longstreth J, Berman N. Long-term pharmacokinetics of
transdermal testosterone gel in hypogonadal men. J Clin Endocrinol
Metab. 2000;85: 4500
–4510.
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG,
Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek
CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development
of prostate cancer. N Engl J Med. 2003; 349: 215
–224.
Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM. Liver damage from long-term methyltestosterone. Lancet. 1977; 2: 262 –263.[Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
