Pharmacokinetics of Testosterone Gel for Hypogonadism
Pharmacokinetics of Testosterone Gel for Hypogonadism
This 14-day study assessed testosterone 2% gel in men with hypogonadism to determine gel drying time, time to achieve eugonadal testosterone concentrations and time to achieve steady-state testosterone concentrations. These measures provide valuable information for both clinicians and patients regarding the practicality and effectiveness of treatment.
In this study, patients (n=31) reported rapid gel drying at the application site (2.4 min; 95% CI, 1.7–3.4 min), suggesting that men can incorporate testosterone 2% gel application into their daily routine with minimal disruption. Although there was a substantial range in drying time, from 0.5 to 17.8 min, >80% of patients reported drying times under 4 min. The longer reported drying times were likely because of the patient's own subjective determination as to when the application site was dry. This determination can be influenced by differences in technique and perception of dryness. Interindividual variations in skin (for example, dryness and thickness) may also have contributed to the variation in reported drying times. Importantly, patients with a longer drying time did not take longer to reach maximum serum concentrations.
There is a paucity of published literature regarding treatment adherence among men with hypogonadism receiving testosterone therapy, but the few published reports using medical chart review data suggest that up to one-third of men prescribed testosterone therapy will discontinue treatment within 1 year. Prescription claims data for testosterone gels suggest that treatment adherence may be substantially lower than reported in the medical chart review studies. Although the role of drying time in treatment discontinuation or suboptimal compliance is unclear, it seems reasonable to assume that gel characteristics that minimize patient inconvenience, such as rapid drying times, may improve treatment adherence, and consequently, improve clinical outcomes. We are unaware of prior literature investigating drying times for this gel or other testosterone gels.
Eugonadal serum TT concentrations were achieved rapidly in this study, at a mean of 2.9 h (95% CI, 1.9–4.3 h)). Maximum serum TT and FT concentrations were reached at 4 h after initial application of testosterone 2% gel (40 mg), with a single peak in TT concentration observed over 24 h. In contrast, two commercially available testosterone 1% gels (50 mg) each showed a triphasic release pattern over 24 h, with maximum serum TT and FT concentrations achieved between 18.0- and 24.0-h postapplication, although the eugonadal range was reached during the earlier nonmaximal peaks. Substantial intraindividual variation in PKs was noted for both of the 1% gels, as was noted with testosterone 2% gel in this study and previously.
Mean steady-state serum TT concentration with testosterone 2% gel was achieved by the first day following initiation of treatment (1.1 days). Furthermore, all men in this study received the recommended starting dose (40 mg) of testosterone 2% gel and no titration was allowed, in contrast to how the drug may be used in clinical practice, where the dose may be titrated to enable patients to achieve target testosterone concentrations based on individual response. Wang et al. estimated that steady-state testosterone levels with testosterone 1% gel (100 mg, split between 1 and 4 sites on the trunk) were achieved at day 2 and maintained after daily administration for up to 32 months. These findings suggest that testosterone 2% gel and testosterone 1% gel may achieve steady state around the same time. However, several factors, including study design, dose applied, laboratory-specific factors (for example, blood collection procedures), patient factors (for example, exercise before blood draws) and other environmental factors could potentially have influenced measurement of testosterone in these two studies. Furthermore, these studies do not account for titration of dose, which likely occurs regularly in clinical practice. Indeed, differences do exist between testosterone gels in how finely the dose can be titrated based on the gel delivery system. Based on a patient's preferences and response to treatment, physicians and patients may find testosterone 2% gel a suitable option because of the ability to titrate in smaller doses (10-mg doses), the low volume and its application site (that is, front and inner thighs). Compared with other testosterone gels, the thigh application site for testosterone 2% gel is unique. Although the impact of this application site on transference to women and children has not been studied in comparison with other topical testosterone products, we believe this location could minimize transference risk and may also provide psychological comfort to potential patients in this regard. Nonetheless, testosterone 2% gel does have a black box warning for potential transference to other individuals in the prescribing information.
In conclusion, testosterone 2% gel is generally well tolerated and effectively maintained testosterone concentration in the eugonadal range in men with hypogonadism in this 14-day PK and drying-time study. Testosterone 2% gel dried quickly, with a median drying time of 2.4 min. Eugonadal serum TT concentrations were achieved within 3 h of initial gel application, and steady-state serum TT concentrations were observed in slightly >1 day. All reported treatment-related AEs were minor, and no SAEs were reported.
Discussion
This 14-day study assessed testosterone 2% gel in men with hypogonadism to determine gel drying time, time to achieve eugonadal testosterone concentrations and time to achieve steady-state testosterone concentrations. These measures provide valuable information for both clinicians and patients regarding the practicality and effectiveness of treatment.
In this study, patients (n=31) reported rapid gel drying at the application site (2.4 min; 95% CI, 1.7–3.4 min), suggesting that men can incorporate testosterone 2% gel application into their daily routine with minimal disruption. Although there was a substantial range in drying time, from 0.5 to 17.8 min, >80% of patients reported drying times under 4 min. The longer reported drying times were likely because of the patient's own subjective determination as to when the application site was dry. This determination can be influenced by differences in technique and perception of dryness. Interindividual variations in skin (for example, dryness and thickness) may also have contributed to the variation in reported drying times. Importantly, patients with a longer drying time did not take longer to reach maximum serum concentrations.
There is a paucity of published literature regarding treatment adherence among men with hypogonadism receiving testosterone therapy, but the few published reports using medical chart review data suggest that up to one-third of men prescribed testosterone therapy will discontinue treatment within 1 year. Prescription claims data for testosterone gels suggest that treatment adherence may be substantially lower than reported in the medical chart review studies. Although the role of drying time in treatment discontinuation or suboptimal compliance is unclear, it seems reasonable to assume that gel characteristics that minimize patient inconvenience, such as rapid drying times, may improve treatment adherence, and consequently, improve clinical outcomes. We are unaware of prior literature investigating drying times for this gel or other testosterone gels.
Eugonadal serum TT concentrations were achieved rapidly in this study, at a mean of 2.9 h (95% CI, 1.9–4.3 h)). Maximum serum TT and FT concentrations were reached at 4 h after initial application of testosterone 2% gel (40 mg), with a single peak in TT concentration observed over 24 h. In contrast, two commercially available testosterone 1% gels (50 mg) each showed a triphasic release pattern over 24 h, with maximum serum TT and FT concentrations achieved between 18.0- and 24.0-h postapplication, although the eugonadal range was reached during the earlier nonmaximal peaks. Substantial intraindividual variation in PKs was noted for both of the 1% gels, as was noted with testosterone 2% gel in this study and previously.
Mean steady-state serum TT concentration with testosterone 2% gel was achieved by the first day following initiation of treatment (1.1 days). Furthermore, all men in this study received the recommended starting dose (40 mg) of testosterone 2% gel and no titration was allowed, in contrast to how the drug may be used in clinical practice, where the dose may be titrated to enable patients to achieve target testosterone concentrations based on individual response. Wang et al. estimated that steady-state testosterone levels with testosterone 1% gel (100 mg, split between 1 and 4 sites on the trunk) were achieved at day 2 and maintained after daily administration for up to 32 months. These findings suggest that testosterone 2% gel and testosterone 1% gel may achieve steady state around the same time. However, several factors, including study design, dose applied, laboratory-specific factors (for example, blood collection procedures), patient factors (for example, exercise before blood draws) and other environmental factors could potentially have influenced measurement of testosterone in these two studies. Furthermore, these studies do not account for titration of dose, which likely occurs regularly in clinical practice. Indeed, differences do exist between testosterone gels in how finely the dose can be titrated based on the gel delivery system. Based on a patient's preferences and response to treatment, physicians and patients may find testosterone 2% gel a suitable option because of the ability to titrate in smaller doses (10-mg doses), the low volume and its application site (that is, front and inner thighs). Compared with other testosterone gels, the thigh application site for testosterone 2% gel is unique. Although the impact of this application site on transference to women and children has not been studied in comparison with other topical testosterone products, we believe this location could minimize transference risk and may also provide psychological comfort to potential patients in this regard. Nonetheless, testosterone 2% gel does have a black box warning for potential transference to other individuals in the prescribing information.
In conclusion, testosterone 2% gel is generally well tolerated and effectively maintained testosterone concentration in the eugonadal range in men with hypogonadism in this 14-day PK and drying-time study. Testosterone 2% gel dried quickly, with a median drying time of 2.4 min. Eugonadal serum TT concentrations were achieved within 3 h of initial gel application, and steady-state serum TT concentrations were observed in slightly >1 day. All reported treatment-related AEs were minor, and no SAEs were reported.
