A multicenter, open-label, observational study of testosterone gel (1%) in the treatment of adolescent boys with klinefelter syndrome or anorchia.

PURPOSE: To assess the safety and clinical outcomes of 6-month treatment with testosterone gel 1% therapy in adolescent boys with primary hypogonadism resulting from Klinefelter syndrome (KS) or anorchia. METHODS: This was a subgroup analysis of a multicenter, open-label study of adolescent boys (N = 86) with delayed puberty who received .5-5.0 g testosterone gel 1% daily for ≤6 months. Adolescent boys 12-17 years of age with KS (n = 21) or anorchia (n = 8), bone age ≥10.5 years, and baseline growth data ≥6 months were included in this analysis. Serum hormone levels (total/free testosterone, luteinizing hormone, dihydrotestosterone, follicle-stimulating hormone, and estradiol) were measured using validated assays. Safety was assessed through adverse events (AEs). RESULTS: At baseline, patients with KS were taller, weighed more, and had higher total testosterone levels (mean 174 vs. 19 ng/dL) than patients with anorchia. At 6 months, total and free testosterone and dihydrotestosterone levels increased 1.8- to 2.3-fold in the KS group and eight- to 10-fold in anorchia patients. Estradiol levels increased 1.9-fold in the anorchia group and 1.4-fold in the KS group after treatment. No clinically significant changes were noted for luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin concentrations in either group. Cough was the most common AE (eight of 29), followed by acne and headache (both four of 29). One anorchia and two KS patients discontinued prematurely. CONCLUSIONS: Once-daily testosterone gel application increased serum testosterone levels into the pubertal range and maintained pubertal testosterone levels during 6-month treatment. In this study, testosterone gel 1% raised testosterone levels and was associated with cough as the most common AE.

Effect of application site, clothing barrier, and application site washing on testosterone transfer with a 1.62% testosterone gel.

OBJECTIVES: To evaluate the effect of application site location, clothing barrier, and application site washing on testosterone transfer from males dosed with 1.62% testosterone gel to female partners. RESEARCH DESIGN AND METHODS: Open-label, randomized, parallel group, crossover study performed in 24 healthy male/female couples. 2.5 or 5.0 g of gel was applied to upper arms and shoulders or abdomens of male subjects. Skin contact occurred 2 hours after gel application between male and female subjects to compare the effect of wearing or not wearing a t-shirt, washing or not washing before contact, and the effect of differing application sites. Treatments were separated by a 1-week washout period. On each dosing day, 15 minutes of supervised skin contact occurred between the dosed male and female partner. Contact was either abdomen to abdomen (male to female), or upper arms/shoulders (male) to upper arms/shoulders, wrists and hands (female), depending on the male application site. Serum samples were collected from females at baseline and after contact to assess secondary testosterone exposure. MAIN OUTCOME MEASURES: C(max) (maximum serum concentration), AUC(0-24) (area under serum concentration-time curve from 0-24 hours), and C(av) (time-averaged concentration over 24-hour post-contact period) were assessed. Subjects were monitored for adverse events. RESULTS: Testosterone exposure (C(av) and C(max)) in females increased by up to 27% (2.5 g) or up to 280% (5.0 g) from baseline after direct skin contact at 2 hours after gel application, although C(av) remained within the female eugonadal range. Transfer from the abdomen was prevented when a t-shirt was worn (2.5-g dose). When the application site was washed before contact, mean C(av) was comparable to baseline, and C(max) was slightly higher (14%). Transfer was higher after direct skin-to-skin contact when the application and contact sites were upper arms/shoulders versus the abdomen. Testosterone concentrations returned to baseline within 48 hours after last skin contact. CONCLUSIONS: There is a risk of testosterone transfer from males using 1.62% testosterone gel to others who come into direct skin contact with the application site. This can be prevented by covering the application site with a t-shirt (2.5-g dose), or washing the application site before contact. STUDY LIMITATIONS: Women for these studies were not selected by menopausal status. The study was conducted under circumstances that were intended to simulate exaggerated conditions of contact and may not represent average contact under normal conditions. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study was not registered (first subject enrolled 28 November 2007).

Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone gel: effects of clothing barrier on testosterone absorption.

OBJECTIVE: To evaluate secondary exposure of testosterone transferred to females from a male partner, dosed with 1.62% testosterone gel after direct skin-to-skin contact with the application site, and to investigate the effect of wearing a t-shirt on testosterone transfer. RESEARCH DESIGN AND METHODS: Across three studies, a total of 72 healthy males applied 5.0 g 1.62% testosterone gel to their abdomen alone, upper arms/shoulders alone, or a combination of their upper arms/shoulders and abdomen (single dose or once daily for 7 days). Male-female contact occurred 2 or 12 hours after testosterone gel application, with males either wearing or not wearing a t-shirt. There were 15 minutes of supervised contact with the application site between the male and his female partner. Blood samples were collected over a 24 hour period in females for assessment of serum testosterone levels at baseline and after contact. MAIN OUTCOME MEASURES: Pharmacokinetic parameters included C(max) (maximum serum concentration), AUC(0-24) (area under the serum concentration-time curve from 0-24 hours), and C(av) (time-averaged concentration over the 24-hour period post-contact). Subjects were monitored for adverse events. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study 1 was not registered (first subject enrolled 8 March 2007); Study 2: 00998933; Study 3, 01130298. RESULTS: Testosterone levels (C(av) and C(max)) in females increased 86-185% from baseline after direct abdominal skin contact, although C(av) levels remained within female eugonadal range. Testosterone concentrations returned to baseline within 48 hours after last skin contact. A t-shirt barrier reduced testosterone transfer by approximately 40-48% when 5.0 g of testosterone gel was applied to the abdomen alone. A t-shirt barrier prevented transfer when 5.0 g of testosterone gel was applied to the upper arms and shoulders or to a combination of the upper arms and shoulders and the abdomen (C(max) and C(av) increased by approximately 5-11%). No major safety events were observed during the studies. CONCLUSIONS: There is a risk of testosterone transfer from males using 1.62% testosterone gel to others who come in contact with the application site for at least 12 hours after application. Secondary exposure can be mitigated by means of a t-shirt barrier. STUDY LIMITATIONS: Women for these studies were not selected by menopausal status. The study designs were intended to simulate exaggerated conditions of transfer.

Effects of skin washing on systemic absorption of testosterone in hypogonadal males after administration of 1.62% testosterone gel.

OBJECTIVE: The impact of washing on the pharmacokinetics, systemic absorption and residual testosterone on the skin after application of a 1.62% testosterone gel was investigated in an open-label, randomized, three-way crossover study in hypogonadal men. RESEARCH DESIGN AND METHODS: Twenty-four hypogonadal men (total testosterone <300 ng/dL) applied 5 g of 1.62% gel (81 mg testosterone) once daily to the shoulders/upper arms for 7 days during each of three consecutive treatment periods. On the 7th dosing day of each period, the skin was washed (soap/water) at one of the following times: 2, 6, or 10 hours post-dose. Pharmacokinetic serum samples were collected at baseline, and on days 6 (no washing) and 7 (with washing) of each treatment period. Skin stripping for determination of residual testosterone was also performed on days 6 and 7. A single location on the application site was stripped a total of 10 times. Testosterone was extracted from the tape strips using ethanol, and concentrations were determined using high performance liquid chromatography with diode array detection (HPLC-UV). MAIN OUTCOME MEASURES: Testosterone C(max), AUC(0-24), average concentration over the dosing interval (C(av)), and safety were assessed. RESULTS: Washing at 2 and 6 hours caused a 10-14% decrease in AUC(0-24) and C(av), but not C(max). Washing 10 hours after gel application had no effect on C(max), AUC(0-24), or C(av). Skin washing decreased the mean amount of testosterone remaining on the skin surface by at least 81%. CONCLUSIONS: Washing the site of gel application as soon as 2 hours after application had little impact on bioavailability and was effective in reducing residual testosterone on the skin. This finding may be important to prevent secondary transfer. STUDY LIMITATIONS: The experimental conditions using uniform timing and procedures for dose administration and washing may not fully reflect real world circumstances. CLINICAL TRIAL REGISTRATION NCT NUMBERS: Study was not registered (first subject enrolled 22 December 2006).

Pharmacokinetics and relative bioavailability of absorbed testosterone after administration of a 1.62% testosterone gel to different application sites in men with hypogonadism.

OBJECTIVE: To determine the pharmacokinetics, bioavailability, and safety of a new formulation (1.62%) of testosterone gel that produces eugonadal serum testosterone levels with use of a lower amount of gel than the currently available 1% gels. METHODS: In an open-label, randomized, 3-way crossover study, 36 male patients with hypogonadism applied 5 g of 1.62% testosterone gel (81 mg of testosterone) once daily to the abdomen, to the upper arms/shoulders, or alternating between both sites per an established schedule for 7 days. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured and used to compare the pharmacokinetics and bioavailability of the 3 treatments. RESULTS: Each application method produced average serum testosterone concentrations within the eugonadal range (300 to 1,000 ng/dL), and steady-state testosterone concentrations were achieved after 2 days of gel application to either the abdomen or the upper arms/shoulders. When testosterone gel was applied to the abdomen, approximately 30% to 40% lower bioavailability (based on area under the serum concentration-time curve from 0 to 24 hours) was observed in comparison with application to the upper arms/shoulders. The 1.62% testosterone gel was found to be safe and well tolerated in men with hypogonadism. CONCLUSION: Although lower testosterone bioavailability was observed after abdominal application of 1.62% testosterone gel in comparison with application to the upper arms/shoulders, application to either site yielded eugonadal levels of serum testosterone.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers.

INTRODUCTION: We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS: QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS: All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION: The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.

Effect of number of replicate electrocardiograms recorded at each time point in a thorough QT study on sample size and study cost.

In a "thorough QT/QTc" (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within-subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost-effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day -1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject-specific (QTcI) formulas. Within-subject and between-subject standard deviations for QTcF obtained by repeated-measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within- and between-subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per-ECG and per-subject costs.

Pharmacokinetics of fluvoxamine in relation to CYP2C19 phenotype and genotype.

OBJECTIVE: To evaluate the pharmacokinetics of fluvoxamine (FLV) in poor metabolizers (PMs) versus extensive metabolizers (EMs) of cytochrome P450 (CYP)2C19. METHODS: This was a prospective, open-label study conducted at the Clinical Research Unit School of Pharmacy. Fifty-seven healthy, nonsmoking volunteers aged 21-40 years participated. Subjects abstained from caffeinated products 12 hours prior to and during each testing period. To assess CYP2C19 activity, blood samples were collected from each subject prior to and two hours after a single dose of omeprazole 20 mg. Once PMs were identified, a sample population of EMs were selected for comparison between the two groups regarding FLV disposition. A single 100 mg FLV dose was given to EMs and PMs; blood samples for FLV analysis were obtained prior to drug administration and 0.5, 1, 2, 3, 4 6, 8, 12 and 24 hours later. A blood sample one day prior to FLV administration was also obtained for CYP2C 19 and CYP2D6. RESULTS: Four PMs were identified with the omeprazole phenotype probe and had a mean +/- SD hydroxylation index of 1.335 +/- 0.271. Nine EMs were selected based upon a hydroxylation index between 0.100 and 0.400 (mean 0.193 +/- 0.079). FLV pharmacokinetic parameters (AUC, elimination half-life, Cmax and Tmax) did not significantly differ between the two groups. Genotype analysis for CYP2C19 revealed a mutant allele for the *2 which confirmed phenotype detection of PM status. Genotype analysis for CYP2D6*3 and *4 alleles showed that all PMs of CYP2C19 were EMs of CONCLUSIONS: FLV disposition and dosing is unlikely to be affected by CYP2C19 polymorphism.