Troy L. ZumBrunnen

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.

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.

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

Abstract 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 Cmax (maximum serum concentration), AUC0–24 (area under the serum concentration–time curve from 0–24 hours), and Cav (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 (Cav and Cmax) in females increased 86–185% from baseline after direct abdominal skin contact, although Cav 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 (Cmax and Cav 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.

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.

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

Abstract 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: Cmax (maximum serum concentration), AUC0–24 (area under serum concentration-time curve from 0–24 hours), and Cav (time-averaged concentration over 24-hour post-contact period) were assessed. Subjects were monitored for adverse events. Results: Testosterone exposure (Cav and Cmax) 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 Cav 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 Cav was comparable to baseline, and Cmax 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)

The pharmacokinetics and pharmacodynamics of 17-d-norgestimate and ethinyl estradiol alone and in the presence of cilansetron 2 mg TID, in healthy females

To assess the effects of cilansetron (CIL) 2 mg on the blood concentrations of ethinyl estradiol (EE), 17‐d‐Norgestimate (NG), progesterone (P), lutenizing hormone (LH), and follicle stimulating hormone (FSH) in healthy females receiving an oral contraceptive(OC).

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

Abstract 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 Cmax, AUC0–24, average concentration over the dosing interval (Cav), and safety were assessed. Results: Washing at 2 and 6 hours caused a 10–14% decrease in AUC0–24 and Cav, but not Cmax. Washing 10 hours after gel application had no effect on Cmax, AUC0–24, or Cav. 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)

Effect of fluvoxamine, paroxetine and ketoconazole on the multiple dose pharmacokinetics of cilansetron in healthy male and female volunteers

To investigate the effects of a CYP1A2 inhibitor (fluvoxamine, FLV), a CYP2D6 inhibitor (paroxetine, PAR), and a CYP3A4 inhibitor (ketoconazole, KET) on the multiple dose pharmacokinetics (PK) of cilansetron(CIL).

The effect of washing and the absence of interindividual transfer of estradiol gel

AimThe primary objective of this study was to evaluate the extent of interindividual transfer and subsequent exposure to estradiol, estrone and estrone sulfate in non-treated postmenopausal women after repeated daily direct skin-to-skin contact with postmenopausal women treated with estradiol gel. The secondary objective was to evaluate the effect on serum estradiol, estrone and estrone sulfate concentrations of washing the application site 1 hour after estradiol gel was applied.MethodsThis was a single-center, randomized, open-label, crossover, multiple-dose study. A total of 48 healthy, postmenopausal women were assigned to either the treated (application of 1.25g of transdermal estradiol gel 0.06%) or non-treated (secondary exposure) group in matched pairs. The study comprised two treatment periods each of 14 days, separated by a washout period of 14 days. Those randomized to the treated group received estradiol gel every day in both treatment periods, but in a crossover design were further randomized to thoroughly wash (or not wash) the application site 1 hour after gel administration for the duration of one of the treatment periods. To determine the extent of transfer of estradiol gel to non-treated women, a 15-minute direct skin-to-skin contact test was conducted daily 1 hour after gel application to the treated test partner (with or without washing of the application site). Serum estradiol, estrone and estrone sulfate concentrations were measured over a 24-hour period at baseline and on day 14 of each study period to determine the extent of transfer of estradiol gel and subsequent absorption in the non-treated group, and the extent of absorption of estradiol and the effect of washing (compared with not washing) the application site after gel administration in the treated group.ResultsIn the non-treated group, mean pharmacokinetic parameters for estradiol, estrone and estrone sulfate after 14 days of daily direct skin-to-skin contact with the women treated with estradiol gel were not statistically different from baseline. In the treated group, washing the application site 1 hour after gel administration reduced the serum concentrations of estradiol, estrone, and estrone sulfate throughout the 24-hour blood sampling interval. These reductions were small but statistically significant.ConclusionInterindividual transfer of estradiol gel 1 hour after application from treated to non-treated individuals and subsequent absorption of estradiol, as determined by the area under the serum concentration-time curve and maximum serum concentration of estradiol, estrone and estrone sulfate, was not statistically significant and clinically unimportant. Washing of the application site at 1 hour after daily transdermal administration of the gel reduced the extent of absorption of estradiol in treated individuals.

Secondary exposure to testosterone from patients receiving replacement therapy with transdermal testosterone gels

Accepted: 19 December 2011; published online: 20 January 2012 Citation: Curr Med Res Opin 2012; 28:267–69 The potential for unintended transfer of testosterone to others from adult men receiving transdermal testosterone gel treatment for hypogonadism is a recognized safety concern, due to the undesirable pharmacologic ffects of testosterone in women and children. The following three papers present the results from five phase 1 studies that investigated the transfer of testosterone to adult women from male partners who applied a 1.62% testosterone gel (AndroGel 1.62%, Abbott). There are four gel products currently marketed in the United States for testosterone replacement therapy in hypogonadal males: AndroGel 1%, AndroGel 1.62% (Abbott, North Chicago, IL), Testim (Auxilium Pharmaceuticals, Malvern, PA), and Fortesta (Endo Pharmaceuticals, Chadds Ford, PA). In addition a 2% topical solution is available (Axiron, Lilly, Indianapolis, IN). These products are applied topically and deliver testosterone to increase serum concentrations to eugonadal levels in men with low testosterone levels. Testosterone gels are applied daily to the skin of the upper arms/shoulders and/or abdomen, or thighs of male patients, depending on their dosing instructions. Since only a low fraction of testosterone is absorbed transdermally from the gels, there exists a significant reservoir of steroid on the surface of the skin, and this residual testosterone could be transferred to others who come into direct skin contact with the patient’s site of gel application. Transfer of testosterone to women or children via skin contact with the application site following gel application has been reported. Even small quantities of testosterone transferred on a repeated basis to these individuals may result in the clinical signs and symptoms of hyperandrogenism, sexual precocity, or inappropriate virilization. The signs and symptoms of secondary testosterone exposure in children include the development of pubic hair, enlargement of the penis or clitoris, increased number of erections and libido, advanced bone age, and aggressive behavior. Usually these signs regress once the testosterone source is removed, although there are instances when the genitalia do not completely return to normal size, and bone age remains slightly greater than chronological age. The signs and symptoms of testosterone exposure in women are the development of acne, changes in body hair distribution or other signs of virilization, or menstrual irregularity. Testosterone product labeling states that testosterone is teratogenic and may cause fetal harm. Fetal exposure to androgens can cause virilization, so testosterone exposure should be particularly avoided during pregnancy. The United States Food and Drug Administration (FDA) addressed the issue of testosterone gel safety in May 2009. It reported the receipt of eight reports of secondary exposure to testosterone in children ranging in age from 9 months