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Abstract
We used a randomized, double-blind, crossover design to evaluate the pharmacokinetics, safety, and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to <5·38 nmol/l with leuprorelin acetate, took BATT (10, 20, or 30 mg) daily for 10 days. There was a 4-day washout between treatments. Substantial testosterone absorption occurred from BATT, and mean serum testosterone, free testosterone, and dihydrotestosterone (DHT) concentrations over 24 hours showed circadian variations. Steady state was reached by day 5. Average 24-h concentrations for the three BATT doses were within the normal range for eugonadal men: testosterone 11·67–14·57 nmol/l, free testosterone 0·026–0·33 nmol/l and DHT 1·66–2·03 nmol/l. On all three doses, peak testosterone and free testosterone were reached 8–9 h after tablet application; DHT peaked about 1–2 h later and declined more slowly. Hormone concentrations increased with BATT dose, but increases were less than dose-proportional. There was no evidence of testosterone accumulation. BATT was well tolerated.
Introduction
Testosterone, the main circulating androgen in men, is secreted predominantly by the testes. Normal serum testosterone concentrations are 10·41–34·70 nmol/l and show circadian variation with peak concentrations in the morning (Bremner et al. 1983, Place & Nichols 1991).In extragonadal tissues, circulating testosterone is enzymatically converted to dihydrotestosterone (DHT) by 5α-reductase.
The main indication for androgen replacement therapy in men is primary or secondary hypogonadism associated with a deficiency of endogenous testosterone (Bhasin1992, Snyder, et al. 2000). The restoration of testosterone concentrations to normal maintains or induces male secondary sexual characteristics, sexual behavior, energy, mood and muscle development (Matsumoto 1994, Dobset al. 1999, Wang et al. 2000b, Basaria & Dobs 2001). Various exogenous testosterone formulations have been developed, including injectable, oral, and dermal preparations. Intramuscular injections often yield testosterone concentrations greatly above normal during the first few days after administration, and do not produce daily variation in testosterone concentrations (Behre et al. 1994, Matsumoto 1994, Dobs et al. 1999). Oral testosterone undecanoate, used in Europe, is a lipid-soluble preparation that is absorbed directly into the lymphatic system, thereby avoiding first-pass metabolism in the liver (Conway et al.1988). However, because of the poor oral bioavailability of testosterone, the levels of circulating testosterone obtained in such treatment are unpredictable (Cantrill et al. 1984, Conway et al. 1988, Bagatelle & Bremner 1996). Transdermal delivery of testosterone, widely prescribed in the USA as either a patch or gel can yield physiological concentrations of testosterone, and a circadian pattern close to that of healthy men (Meikle et al. 1996, Dobs et al.1999). Transdermal patches often cause local skin reactions(Arver et al. 1997, Parker & Armitage 1999), and the scrotal patch produces very high concentrations of DHT, owing to high 5α-reductase activity in scrotal skin (Cunningham et al. 1989, Meikle et al. 1992). Testosterone gel causes only minimal skin irritation (Wang et al.2000a), but it must be applied over a large surface area of skin (Wang et al. 2000a,b), and thus may not be acceptable to all patients.
In this study, we evaluated the pharmacokinetics, tolerability, and safety of three dosage strengths of a buccal adhesive testosterone tablet (BATT), under development by Abbott Laboratories (Abbotts Park, IL, USA). Buccal administration ‘bypasses’ the liver and so avoids first-pass clearance (Dobs et al. 1998). To study BATT, we used a model of artificial hypogonadism in healthy men, by temporarily suppressing their endogenous testosterone secretion with a gonadotrophin-releasing hormone agonist, leuprorelin acetate (Linde et al. 1981, Frick & Aulitzky1986, Leibenluft et al. 1997). We evaluated serum testosterone, free testosterone, and DHT concentrations on 10, 20, and 30 mg BATT.
BATT treatment
Subjects applied the BATT to the gingiva, in the region of the infranasal fossa, at 0800 h each day, for 10 consecutive days. They were asked to eat breakfast and brush their teeth before applying BATT, and to avoid drinking for 30 min afterwards.
Subjects were resident from 12 hours before to 24 hours after dosing, during the baseline phase, and on days 1 and 10 of each period. On days 5–9, subjects attended each morning for pre-dose blood samples, and then applied BATT.
Hormone assays
We measured testosterone, free testosterone, and DHT in serum samples taken at the following times: before dosing and 1·5, 3, 4, 5, 6, 8, 12, 15, 18, and 24 h after dosing day –1 (baseline phase) and on days 1 and 10 of each period, before dosing on days 5–9 of each period.
The serum was separated and stored at 20 C or below until assayed. Hormone concentrations were measured by validated, radioimmunological assays (RIA) using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX, USA). Lower limits of quantitation were 0·35 nmol/l (testosterone), 0·001 nmol/l (free testosterone), and 0·09 nmol/l (DHT). Intra-assay and interassay coefficients of variation for all assays were <9% and <12% respectively
RIA is not as good as equilibrium dialysis for measuring absolute concentrations of free testosterone. However, with respect to free testosterone, we were mainly concerned with relative concentrations on different doses of BATT, so we believe the method to be adequate for our purposes.
Pharmacokinetic analyses
For all BATT doses, we determined the following pharmacokinetic parameters of each hormone: maximum concentration (Cmax), minimum concentration (Cmin), time of maximum concentration (Tmax), the area under the concentration curve from 0 to 24 h (AUC0–24), and time-average concentration (Cavg, equal to AUC0–24/24).
In addition, we calculated baseline-adjusted pharmacokinetic parameters for each hormone, by subtracting the subject’s baseline (day –1) serum concentrations from the corresponding concentrations on days 1 and 10. We obtained baseline-adjusted AUC0–24 by deducting the subject's baseline AUC0–24 from the observed AUC0–24
Lastly, we calculated free testosterone/testosterone andtestosterone/DHT ratios, using the baseline-adjusted concentrations of each hormone.
Safety and tolerability assessments
We assessed BATT safety and tolerability by: dental assessment, ECG, vital signs, physical examination, and laboratory safety tests before and after dosing, and by adverse events.
In addition, we examined the subject’s gingiva and lip mucosa before and 12 h after BATT application, at baseline (day –1), and on days 1 and 10 of each treatment period. Subjects were also asked to assess tablet acceptability and tolerability.
Pharmacokinetics of BATT
Mean serum testosterone, free testosterone, and DHT concentrations over 24 h were similar on the three doses of BATT (Fig. 1). At steady state, all BATT doses produced an early increase in mean testosterone and free testosterone, with maximum concentrations about 8–9 h after tablet application, and a slow decline thereafter. DHT concentrations peaked about 2 h later and declined more gradually, than those of testosterone and free testosterone.
Summary statistics of the baseline-adjusted pharmacokinetic parameters of each hormone are shown in Table 1. Mean pre-dose testosterone, free testosterone, and DHT did not differ significantly between successive days, on days 5–9, indicating that a steady state had been reached by day 5. At steady state, mean Cmax and AUC0–24 of each hormone increased with dose. However, dose-normalised, mean Cmax and AUC0–24 of each hormone were significantly lower in the 30 mg than in the 10 mg dose group, on both day 1 and day 10 (P<0·001). Thus, the increase in testosterone, free testosterone, and DHT was less than dose-proportional.
In the 20 and 30 mg dose groups, the mean Cmax and AUC0–24 of each hormone were higher on day 1 than on day 10, indicating that none of the hormones accumulated. Furthermore, mean Tmax and dose-normalized AUC0–24 of testosterone and free testosterone, and Tmax of DHT, were significantly lower on day 10 than on day 1 (P=0·02to <0·001). Age had no statistically significant effect on mean baseline-adjusted pharmacokinetic parameters of testosterone, free testosterone, or DHT (P=0·06 to 0·96). Carryover effects were not significant in most of the statistical analyses
Cavg of testosterone, free testosterone, and DHT are shown in Fig. 2, with the associated normal ranges. Hormone concentrations were within the normal range in most subjects on all BATT doses. Free testosterone/testosterone ratios averaged about 0·02, on all BATTdoses, and on placebo. On the 10 and 20 mg tablets, average testosterone/DHT ratios were between 4 and 14 during the 24 h after dosing, compared with 4 to 8 on placebo. However, on BATT (30 mg), average testosterone/DHT ratios fluctuated more widely with time, ranging between 3 and 23.
Although Cavg of testosterone was <34·70 nmol/l in all subjects, concentrations in some blood samples were supraphysiological. Testosterone concentrations were>41·64 nmol/l in at least one blood sample in three subjects on BATT (20 mg) and in five subjects on BATT (30 mg). DHT concentrations were >3·45 nmol/l in at least one blood sample in six, eleven, and thirteen subjects BATT (10, 20, and 30 mg) respectively. In most subjects, such high hormone concentrations were observed at about two to four sampling times.
Safety and tolerability
There were no clinically significant changes in vital signs, physical examination, ECG, or laboratory safety values. Minor adverse events were experienced by several subjects; however, none was considered to be related to treatment.
Localized hyperemia at the BATT application site was noted in two subjects on day 10 of the last treatment period. Thirteen and twelve subjects reported local discomfort on BATT and placebo respectively; most subjects experienced that discomfort in the first treatment period.
In summary, physiological concentrations of testosterone, free testosterone, and DHT were reached on all three doses of BATT, and a circadian rhythm in hormone concentrations was produced. Steady-state was rapidly attained, and hormone levels quickly returned to baseline after tablet removal. Furthermore, BATT was well-tolerated. Studies in hypogonadal men are warranted.
Abstract
We used a randomized, double-blind, crossover design to evaluate the pharmacokinetics, safety, and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to <5·38 nmol/l with leuprorelin acetate, took BATT (10, 20, or 30 mg) daily for 10 days. There was a 4-day washout between treatments. Substantial testosterone absorption occurred from BATT, and mean serum testosterone, free testosterone, and dihydrotestosterone (DHT) concentrations over 24 hours showed circadian variations. Steady state was reached by day 5. Average 24-h concentrations for the three BATT doses were within the normal range for eugonadal men: testosterone 11·67–14·57 nmol/l, free testosterone 0·026–0·33 nmol/l and DHT 1·66–2·03 nmol/l. On all three doses, peak testosterone and free testosterone were reached 8–9 h after tablet application; DHT peaked about 1–2 h later and declined more slowly. Hormone concentrations increased with BATT dose, but increases were less than dose-proportional. There was no evidence of testosterone accumulation. BATT was well tolerated.
Introduction
Testosterone, the main circulating androgen in men, is secreted predominantly by the testes. Normal serum testosterone concentrations are 10·41–34·70 nmol/l and show circadian variation with peak concentrations in the morning (Bremner et al. 1983, Place & Nichols 1991).In extragonadal tissues, circulating testosterone is enzymatically converted to dihydrotestosterone (DHT) by 5α-reductase.
The main indication for androgen replacement therapy in men is primary or secondary hypogonadism associated with a deficiency of endogenous testosterone (Bhasin1992, Snyder, et al. 2000). The restoration of testosterone concentrations to normal maintains or induces male secondary sexual characteristics, sexual behavior, energy, mood and muscle development (Matsumoto 1994, Dobset al. 1999, Wang et al. 2000b, Basaria & Dobs 2001). Various exogenous testosterone formulations have been developed, including injectable, oral, and dermal preparations. Intramuscular injections often yield testosterone concentrations greatly above normal during the first few days after administration, and do not produce daily variation in testosterone concentrations (Behre et al. 1994, Matsumoto 1994, Dobs et al. 1999). Oral testosterone undecanoate, used in Europe, is a lipid-soluble preparation that is absorbed directly into the lymphatic system, thereby avoiding first-pass metabolism in the liver (Conway et al.1988). However, because of the poor oral bioavailability of testosterone, the levels of circulating testosterone obtained in such treatment are unpredictable (Cantrill et al. 1984, Conway et al. 1988, Bagatelle & Bremner 1996). Transdermal delivery of testosterone, widely prescribed in the USA as either a patch or gel can yield physiological concentrations of testosterone, and a circadian pattern close to that of healthy men (Meikle et al. 1996, Dobs et al.1999). Transdermal patches often cause local skin reactions(Arver et al. 1997, Parker & Armitage 1999), and the scrotal patch produces very high concentrations of DHT, owing to high 5α-reductase activity in scrotal skin (Cunningham et al. 1989, Meikle et al. 1992). Testosterone gel causes only minimal skin irritation (Wang et al.2000a), but it must be applied over a large surface area of skin (Wang et al. 2000a,b), and thus may not be acceptable to all patients.
In this study, we evaluated the pharmacokinetics, tolerability, and safety of three dosage strengths of a buccal adhesive testosterone tablet (BATT), under development by Abbott Laboratories (Abbotts Park, IL, USA). Buccal administration ‘bypasses’ the liver and so avoids first-pass clearance (Dobs et al. 1998). To study BATT, we used a model of artificial hypogonadism in healthy men, by temporarily suppressing their endogenous testosterone secretion with a gonadotrophin-releasing hormone agonist, leuprorelin acetate (Linde et al. 1981, Frick & Aulitzky1986, Leibenluft et al. 1997). We evaluated serum testosterone, free testosterone, and DHT concentrations on 10, 20, and 30 mg BATT.
BATT treatment
Subjects applied the BATT to the gingiva, in the region of the infranasal fossa, at 0800 h each day, for 10 consecutive days. They were asked to eat breakfast and brush their teeth before applying BATT, and to avoid drinking for 30 min afterwards.
Subjects were resident from 12 hours before to 24 hours after dosing, during the baseline phase, and on days 1 and 10 of each period. On days 5–9, subjects attended each morning for pre-dose blood samples, and then applied BATT.
Hormone assays
We measured testosterone, free testosterone, and DHT in serum samples taken at the following times: before dosing and 1·5, 3, 4, 5, 6, 8, 12, 15, 18, and 24 h after dosing day –1 (baseline phase) and on days 1 and 10 of each period, before dosing on days 5–9 of each period.
The serum was separated and stored at 20 C or below until assayed. Hormone concentrations were measured by validated, radioimmunological assays (RIA) using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX, USA). Lower limits of quantitation were 0·35 nmol/l (testosterone), 0·001 nmol/l (free testosterone), and 0·09 nmol/l (DHT). Intra-assay and interassay coefficients of variation for all assays were <9% and <12% respectively
RIA is not as good as equilibrium dialysis for measuring absolute concentrations of free testosterone. However, with respect to free testosterone, we were mainly concerned with relative concentrations on different doses of BATT, so we believe the method to be adequate for our purposes.
Pharmacokinetic analyses
For all BATT doses, we determined the following pharmacokinetic parameters of each hormone: maximum concentration (Cmax), minimum concentration (Cmin), time of maximum concentration (Tmax), the area under the concentration curve from 0 to 24 h (AUC0–24), and time-average concentration (Cavg, equal to AUC0–24/24).
In addition, we calculated baseline-adjusted pharmacokinetic parameters for each hormone, by subtracting the subject’s baseline (day –1) serum concentrations from the corresponding concentrations on days 1 and 10. We obtained baseline-adjusted AUC0–24 by deducting the subject's baseline AUC0–24 from the observed AUC0–24
Lastly, we calculated free testosterone/testosterone andtestosterone/DHT ratios, using the baseline-adjusted concentrations of each hormone.
Safety and tolerability assessments
We assessed BATT safety and tolerability by: dental assessment, ECG, vital signs, physical examination, and laboratory safety tests before and after dosing, and by adverse events.
In addition, we examined the subject’s gingiva and lip mucosa before and 12 h after BATT application, at baseline (day –1), and on days 1 and 10 of each treatment period. Subjects were also asked to assess tablet acceptability and tolerability.
Pharmacokinetics of BATT
Mean serum testosterone, free testosterone, and DHT concentrations over 24 h were similar on the three doses of BATT (Fig. 1). At steady state, all BATT doses produced an early increase in mean testosterone and free testosterone, with maximum concentrations about 8–9 h after tablet application, and a slow decline thereafter. DHT concentrations peaked about 2 h later and declined more gradually, than those of testosterone and free testosterone.
Summary statistics of the baseline-adjusted pharmacokinetic parameters of each hormone are shown in Table 1. Mean pre-dose testosterone, free testosterone, and DHT did not differ significantly between successive days, on days 5–9, indicating that a steady state had been reached by day 5. At steady state, mean Cmax and AUC0–24 of each hormone increased with dose. However, dose-normalised, mean Cmax and AUC0–24 of each hormone were significantly lower in the 30 mg than in the 10 mg dose group, on both day 1 and day 10 (P<0·001). Thus, the increase in testosterone, free testosterone, and DHT was less than dose-proportional.
In the 20 and 30 mg dose groups, the mean Cmax and AUC0–24 of each hormone were higher on day 1 than on day 10, indicating that none of the hormones accumulated. Furthermore, mean Tmax and dose-normalized AUC0–24 of testosterone and free testosterone, and Tmax of DHT, were significantly lower on day 10 than on day 1 (P=0·02to <0·001). Age had no statistically significant effect on mean baseline-adjusted pharmacokinetic parameters of testosterone, free testosterone, or DHT (P=0·06 to 0·96). Carryover effects were not significant in most of the statistical analyses
Cavg of testosterone, free testosterone, and DHT are shown in Fig. 2, with the associated normal ranges. Hormone concentrations were within the normal range in most subjects on all BATT doses. Free testosterone/testosterone ratios averaged about 0·02, on all BATTdoses, and on placebo. On the 10 and 20 mg tablets, average testosterone/DHT ratios were between 4 and 14 during the 24 h after dosing, compared with 4 to 8 on placebo. However, on BATT (30 mg), average testosterone/DHT ratios fluctuated more widely with time, ranging between 3 and 23.
Although Cavg of testosterone was <34·70 nmol/l in all subjects, concentrations in some blood samples were supraphysiological. Testosterone concentrations were>41·64 nmol/l in at least one blood sample in three subjects on BATT (20 mg) and in five subjects on BATT (30 mg). DHT concentrations were >3·45 nmol/l in at least one blood sample in six, eleven, and thirteen subjects BATT (10, 20, and 30 mg) respectively. In most subjects, such high hormone concentrations were observed at about two to four sampling times.
Safety and tolerability
There were no clinically significant changes in vital signs, physical examination, ECG, or laboratory safety values. Minor adverse events were experienced by several subjects; however, none was considered to be related to treatment.
Localized hyperemia at the BATT application site was noted in two subjects on day 10 of the last treatment period. Thirteen and twelve subjects reported local discomfort on BATT and placebo respectively; most subjects experienced that discomfort in the first treatment period.
In summary, physiological concentrations of testosterone, free testosterone, and DHT were reached on all three doses of BATT, and a circadian rhythm in hormone concentrations was produced. Steady-state was rapidly attained, and hormone levels quickly returned to baseline after tablet removal. Furthermore, BATT was well-tolerated. Studies in hypogonadal men are warranted.
