Pharmacokinetics of a single dose of Buccal testosterone

ELSEVIER

Pharmacoltinetics of a Single Dose of Buccal Testosterone Seokjoong

Kim,*+ Wallace Snipes,+ Gary D. Hodgen,”

The bioavailability, pharmacokinetics, and metabolism of a novel transbuccal delivery system of testosterone was investigated in five healthy eugonadal men. Total serum testosterone (T), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) concentrations were determined from blood samples obtained at 8:00 a.m. (zero hour), and 30 min and 1,2, 3,4, 6, 12 and 24 hours later on day 1, and again on day 2, after dosing. This single transbuccal administration of Buccal T induced a prompt rise in serum T and DHT concentrations The maximal concentration (C,,J of T was 19.56 7.64 ng/mL (mean + SD; 5.3-fold increase from the baseline) at 30 min (T,,.J after administration. The elimination halflife of Buccal T was about 1.75 h. Serum DHTpeaked at 1 h at a concentration of I.46 A 0.46 ng/mL (2.3-fold increase from the baseline). The drug was well tolerated. This study suggests that the Buccal T is a promising delivery system for natural T. CONTRACEPTION 1995;52:313-316 WORDS: buccal testosterone, pharmacokinetics, tosterone, dihydrotestosterone

KEY

tes-

Introduction he possibility of widespread use of androgens in normal men for contraception, the prevention of osteoporosis and possibly coronary artery disease, the maintenance of normal sexual function and/or well-being, especially in the healthy elderly, and large scale abuse by athletes have propelled androgen replacement out of the narrow confines of male hypogonadism. 1-5 Because of this recent appreciation of the much wider public health implications surrounding the clinical use of androgens, studies have been focused on the modification of testosterone (T) administration.

T

‘The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507; tzetachron, Inc 100 N. Scrence Park Road, State College, PA 16803; *Present address: Department of Obsetrics and Gynecology, Afou Untversity Medical School, 5. Wonchon-dong, Paldal-ku, Suwon, Korea 441-74 Name and address for correspondence, Freedolph Anderson, M.D , The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virgrnia Medical School, 601 Colley Avenue, Norfolk, VA 23507. Tel: 804-446-5266; Fax: 804-446-5905 Submitted for publication April 19. 1993 Revised July 31, 1995 Accepted for publication August 30. 1995

0 1995 Elsevier Science Inc. 655 Avenue of the Americas, New

York,

NY 10010

and Freedolph

Anderson*

None of the currently available modalities of T are considered ideal for long-term, convenient and/or reliable T replacement. Injectable form&’ and subcutaneous pellets of TG9 are not convenient because of the required frequency of injections and the necessity of surgical procedure. Oral T, free or esters, is subject to rapid breakdown in the GI tract and the liver, diminishing its subsequent bioavailability.6r7,10 Methyl-T and 17asubstituted T are orally effective, but should not be used for replacement therapy because of well-established hepatotoxicity.5t” T undecanoate is unique in that it is orally active and not hepatotoxic. However, it appears effective and acceptable only in induction of puberty because of its poor post-hepatic androgenic effects (no suppression of gonadotropins and no improvement of sexual function), disproportionate increase of dihydrotestosterone (DHT) relative to T,1°,12 and profound effects on the liver (marked decrease in the sex hormone-binding globulin and cholesterol). Transdermal patches of T, are available but must be applied to scrotal skin to achieve therapeutic levels. The long-term effect of abnormally high DHT concentrations on prostate growth is not known.5t’3-‘5 In search of a more physiological noninvasive T replacement, T complexed with hydroxypropyl$cyclodextrins have been administered sublingually and found to mimic endogenous episodic release of T in hypogonadal men.’ Theoretically, transbuccal delivery of T seems ideal as a long-term replacement because of its simplicity, acceptability, reversibility, and apparent lack of toxicity. l6 It is substantially protected from hepatic firstpass metabolism since venous drainage from the mouth is to the superior vena cava.8t16 In this respect, we investigated the bioavailability, pharmacokinetics, and metabolism of a new transbuccal delivery system of T in five eugonadal men.

Materials

and Methods

Buccal Testosterone (Buccal T)

Testosterone was administered via the buccal cavity in a novel delivery system (Buccal T; Zetachron, Inc., ISSN 0010.7824/95/$9 SSDI OOlO-7824(95)00216-2

50

314

Kim et al

Contraception 1995;52:313-316

State College, PA). The buccal matrix is comprised primarily of a blend of water-soluble polymers that melt near body temperature. High surface area colloidal silicon dioxide dispersed in the matrix imparts the characteristics of a thixotropic gel to the material in the molten state. Testosterone is partially dispersed in the matrix. When placed in the buccal cavity, the matrix melts and disperses in 3-5 minutes, exposing the mucosal tissue to testosterone in a comparatively non-aqueous environment. Each tablet contained 10 mg testosterone USP micronized (Upjohn, Kalamazoo, MI) as an active ingredient.

DHT determination, the kit employed an oxidative destruction of T step; this procedure eliminated the need for chromatographic separation of T and DHT. We have previously verified that this DHT kit yields results comparable to those obtained with a procedure employing column chromatography for the separation of T and DHT. The sensitivity of the T, DHT, and SHBG assays were 63 pg/mL, 125 pg/mL and 10 nmol/L, respectively. The intra- and interassay coefficients of variation for the T, DHT, and SHBG assays were ~8.0% and <8.0%, ~12.0% and <12.0%, and ~7.0% and <6.0%, respectively.

Participants Five healthy eugonadal men were recruited for this study. Their ages ranged from 44-57 years (median, 55) and body weights were within -+ 20% of their ideal weights. No subject had any contraindications to androgen therapy and had not been treated with any other hormonal drugs for at least 30 days. Blood count, biochemical studies, and urinalysis were normal. They gave written informed consent to participate in the study. The protocol and consent were approved by the Institutional Review Board (IRB) of the Eastern Virginia Medical School (EVMS).

Statistical Analysis Mean change of values from day 1 to day 2 at each time point was used to determine the T tion half-life), C,,, (maximal concent~a!ti($;“‘a”,“d~ T,,, (time to C ,,,) for T and DHT. Student’s paired t-test was used to compare repeated measurements at each sampling time. Elimination half-life was estimated graphically. PcO.05 was considered significant.

Study Protocol The study was performed in an outpatient setting on two consecutive days. On day 1, subjects reported to the Clinical Research Unit at 8:00 a.m. for blood sampling to determine baseline total unconjugated T, DHT, and sex hormone-binding globulin (SHBG) concentrations. All subjects fasted overnight. Blood samples were obtained at 8:00 a.m. and again 30 min and 1, 2, 3, 4, 6, and 12 h later. After a zero h sample at 8:00 a.m. on the following morning, each subject was given one Buccal T (Zetachron, Inc., State College, PA) and allowed to dissolve it in the buccal space. Blood samples were then drawn at 30 min and 1,2,3,4, 6, 12 and 24 h. The sera were frozen at - 20°C and held for analysis at the end of the study. Safety was monitored by vital signs and adverse reactions during the study period. Methods Commercially available, radioimmunoassay kits were utilized for the determination of serum concentrations of total serum unconjugated T (RSL/ICN; Carson, CA), DHT (Amersham; Arlington Heights, IL) and SHBG (Techland; Brussels, Belgium). The DHT kit employed a single antibody methodology with a charcoal separation step. The T and SHBG assays utilized double antibody procedures. For the

Results Before administration of drugs, the mean 24 h serum T (Figure 1) and DHT (Figure 2) were normal in these five eugonadal men. Serum T levels of two men below 50 years old were higher than that of three men older than 50 (P
1

I 77

20 ^ E a 5

”

T

I”

01’ 0

’ 4

3

’ 8

’ 12

’ 16

’

’ 20

’ 24

Hours

Figure 1. Total unconjugated serum T concentrations (means + SD) before (W) and after (0) administration of 10 mg Buccal T (conversion factor to SI units: 3.467).

Contraception 1995;52:313-316

Buccal

1 a00

1600

1400

g & a f

1200

1000

0

i

I

I

T r! I’ \ -

f

-

I I i -t

l

600 I 0

4

I 12

a

I 16

8

I 20

I 24

HOLIE

Figure 2. Total serum DHT concentrations (means * SD] before (m) and after (0) administration of Buccal T (conversion factor to SI units: 3.4481. DHT (Figure 2) concentrations (means 2 SD). The maximal concentratilon (C,,,] of T was 19.56 2 7.64 ng/mL (5.3-fold increase from the baseline) at 30 & 6

min (T,,,) after administration (conversion factor to SI units: 3.467). The serum T levels remained higher than the baseline levels at each particular time of day from 1 to 24 h (4.56 + 0.40 vs 4.10 5 0.27 ng/mL). These increments were statistically significant up to 4 h ( 1.53-fold increase from the baseline; PcO.05) but not significant at 6-24 h. The elimination half-life of Buccal T was about 1.75 h. Serum DHT paralleled the

rise in serum T. It peaked at 2 ? 2 h (1.46 ? 0.20 ng/mL; 2.3-fold increase from baseline) and remained significantly above thie baseline for up to 6 h (1.22-fold increase from the baseline: P < 0.05) (conversion factor to SI units: 3.448). The DHT:T ratio, which was normal prior to Buccal T, was significantly decreased at 30 min (P
Discussion These five eugonadal men showed normal baseline profiles of serum T, DHT, and SHBGj T concentration showed intact diurnal variation.“‘i8 The men above 50 years had lower T and higher SHBG profiles over 24 h compared to the men below 50. This finding is in accord with an age-related T decrease and SHBG increase,5,18,19 and suggests that this physiologic transition of testicular

fuuction

ages of 45 to 55, similar

may occur between the

to the female

climacteric.

testosterone

315

The pharmacokinetics as a result of a single 10 mg Buccal T suggests b.i.d to t.i.d dosing for replacement therapy. The DHT:T ratio was normal except for the first 2 h during which metabolic conversion of excessive T to DHT increased. Compared to other preparations 6J7,10t13J14Buccal T was associated with a more normai DHT:T ratio. This single dose bioavailability study could not determine the impact of Buccal T on SHBG suppression. Historically, SHBG suppression is evident after 1 week of oral synthetic androgens” and 3 months after intramuscular T therapy,‘l but not after either 1 week of sublingual T complexed with hydroxypropyl-bcyclodextrins’ or 6 months of T pellet implantation.’ This suggests that SHBG may not be suppressed by buccal or sublingual T because of hepatic sparing effect. To confirm the absence of hepatic first-pass metabolism and/or hepatotoxicity, a long-term clinical study will be required. Because of the small number of subjects in this study, no conclusions can be drawn about patient acceptance or adverse effects. However, because of the simplicity and reversibility of transbuccal administration, patient acceptance is most likely to be favorable. This study suggests that Buccal T delivery warrants

further exploration

especially

for forthcoming

indica-

tions of T therapy such as combined regimens with

contraceptive

GnRH

ment therapy

in aging men4s,17 and women,23-25

where suitable

antagonists4J5,22

and noninvasive

and replace-

long-term

replace-

ment therapy may be beneficial.

Acknowledgment The authors would like to thank Ms. Dara WillettLeary for her editorial support and manuscript preparation.

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