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Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration) (2023)
Maria G. Vogiatzi, Jonathan S. Jaffe, Takugo Amy, and Alan D. Rogol
Abstract
Context
Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents.
Objective
An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups.
Methods
Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens.
Results
The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases.
Conclusion
SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce the size of fluctuations in serum T and related symptoms.
Normal male pubertal maturation occurs between ages 9 and 14 years, after which puberty is considered delayed [1]. Delayed puberty affects approximately 2% of adolescents and has been associated with considerable psychosocial distress [1, 2]. Delays in puberty due to hypogonadism or constitutional delay in males may be treated with testosterone, which is used to promote the development of secondary sexual characteristics, growth, and normal bone and muscle mass [3, 4]. Although many testosterone formulations are approved for the treatment of hypogonadism in adult men, only intramuscular (IM) testosterone enanthate (TE) and testosterone pellets have been approved for adolescent males. These approvals were issued before the 1962 Kefauver-Harris Drug Control Act requiring that drugs prove safe and efficacious [5-7]. It is unclear whether there was clinical trial evidence supporting the safety and efficacy of these drugs at the time of their approval, and the US Food and Drug Administration has cautioned that evidence for IM TE and testosterone pellets may not align with current pediatric drug-approval standards [5]. Furthermore, improper use of testosterone therapies approved for adult males in adolescent males may lead in the latter group to disproportionate advancements in bone maturation, fusion of the epiphyseal growth centers, and early termination of linear growth [6, 7].
Testosterone therapy in adolescent males with delayed puberty starts with the administration of small doses of testosterone, typically IM TE, to induce puberty. In hypogonadism, doses are gradually increased to reach adult male testosterone replacement over a course of approximately 3 years and in a process that mimics physiologic male pubertal progression [1]. Intramuscular TE injections are easy to titrate, and TE given IM is the most commonly used preparation for induction and progression of puberty [8]. However, the injections can be painful, may require frequent office visits if not self-administered, and may be associated with nonphysiologic fluctuations in serum testosterone levels [3, 7]. Many new testosterone formulations have been developed to overcome difficulties with administration and adverse events, but these are supported only by expert opinion and are not evidence-based [3, 4]. Oral testosterone esters and transdermal testosterone gel have been used for puberty induction. However, the use of oral therapy has been limited by concerns about bioavailability and difficulties with dose titration, while the use of transdermal testosterone gel in pediatrics is limited by dosing variability [1, 9]. Since there is little evidence to guide optimal testosterone dosing in adolescent males, the efficacy and safety of testosterone administration may be supported by extrapolation from adult pharmacokinetics (PK) data, which have previously been used to augment pediatric drug development [4, 5, 10]. Extrapolation of adult data and scaling to pediatric patients may be completed through the use of allometry, which is the study of how the characteristics of living creatures change with size [11]. Differences in physiology and biochemistry lead to different rates of metabolism and renal clearance of drugs in different age groups of pediatric patients compared to adults. These differences necessitate the use of allometric modeling to scale drug clearance from adults to pediatric patients.
The goal of the present study is to design a nonlinear mixed effect (NLME) model to characterize the PK of IM and subcutaneous (SC) TE in adult patients with hypogonadism, to identify potential covariates affecting the PK of TE, and to scale these data to adolescent patients. Adult models were allometrically scaled to adolescent patients (aged 12 to < 18 years) at typical body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly IM and SC administration of 12.5, 25, 50, 75, and 100 mg TE regimens to project an optimal dose and schedule for adolescent patients with hypogonadism whose pubertal maturation is induced with testosterone.
Materials and Methods
Study Design
This PK study is an analysis of data from a previously published 3-arm, open-label, multidose, parallel-group phase 2 study (NCT01887418) [12]. The phase 2 study design was approved by the institutional review boards of participating centers and conducted in accordance with the Declaration of Helsinki and in compliance with Good Clinical Practice Guidelines. Informed consent was obtained from all patients.
12. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: a phase II study. Sex Med. 2015;3(4):269-279.
Considering the results of this PK analysis, one may propose the use of SC TE 12.5 mg monthly as appropriate for puberty initiation as both Cave and Cmax values correspond to those seen in early puberty. While dosing regimens modeled for monthly and EOW administration produced unphysiological testosterone concentrations, these regimens were used as a starting point to understand adolescent testosterone PK. These dosing regimens are used by pediatric endocrinologists initiating testosterone therapy in adolescents and are increased to adult dosing regimens of weekly or biweekly administration as adolescents go through pubertal maturation [1]. The results of these dosing regimens provide important context for IM and SC dosing, as adolescent patients tend to prefer nondaily testosterone formulations such as IM and SC, which produce variable and unphysiological testosterone PK in adolescents. While transdermal testosterone may be more physiological, it does not show individual pulsations or diurnal variation. Despite this, all forms of testosterone are unphysiological, and many have been used for testosterone therapy in hypogonadal men and boys. The use of IM TE at 12.5 mg monthly, as well as the SC and IM TE regimen of 25 mg monthly, may result in Cmax values that reach mid- and advanced puberty, especially in lighter-weight adolescents, a fact that may lead to undesirable rapid skeletal maturation during puberty induction. As the simulated adolescent Cmax and Cave values for SC TE were found to be approximately 75% of the respective IM TE values, the use of SC TE may assist with a more gradual and physiologic advancement of pubertal development compared to IM TE. The use of average testosterone exposures over a dosing interval may be limited in clinical applicability, but these methods were necessary to determine total exposure and provide practical context for IM and SC dosing in adolescent patients.
This paucity of data, coupled with a lack of evidence-based guidelines for the treatment of hypogonadism in adolescents, suggests that additional clinical trials are required to explore treatment regimens for adolescents requiring testosterone therapy [4]. Furthermore, individual patient factors and treatment goals must be considered when selecting testosterone therapy in adolescents [1].
As a model created to provide simulated SC and IM TE regimens in adolescents, our findings have several limitations that should be carefully considered when addressing clinical applicability. This model was generated from men with physician-diagnosed hypogonadism of any etiology and not organic testosterone deficiency, which may explain the high variability in PK data for patients receiving 50 mg SC TE, who may have experienced postdose endogenous testosterone production. Endogenous testosterone production in adult patients forming the basis of this model confounds extrapolation to adolescents with delayed puberty, where there is decreased endogenous testosterone production. Subsequent pediatric clinical trial data would provide more valuable insight as to the applicability of concentration-guided testosterone dosing in pediatric patients with delayed puberty. Despite adolescent simulations predicting higher serum testosterone concentrations in lighter- compared to heavier-weight groups with reliable increases in Cave, interpretations about the testosterone exposure-response relationship cannot be determined. This relationship is a function of the allometric equations used during modeling, as smaller-weight groups will have lower clearance and volume of distribution, and thus a higher concentration. Also, the adult model did not find weight to be a significant covariate on PK parameters, further limiting the interpretation of exposure-response results. Finally, the lowest monthly dose evaluated in this PK analysis may not prove to be appropriate in the smallest and least mature patients, but for a majority of adolescent patients being treated for hypogonadism, this dosing is predicted to produce typical Cave exposures and permit dose progression to foster growth and maturation [5, 19].
Conclusion
Testosterone PK following SC and IM administration of TE is best described by one-compartment models with first-order absorption and elimination kinetics in adult males. Because there are insufficient data on adolescents to derive a PK model, this male model was allometrically scaled to adolescents based on weight groups of 30 to 60 kg. For simulations in 30- to 60-kg adolescent males, SC TE Cave values approximated 75% of IM TE Cave values following regimens of 12.5, 25, 50, 75, and 100 mg TE administered weekly, EOW, or monthly. Therefore, SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in this population of simulated adolescent hypogonadal males. This simulation provides valuable PK data for adolescents of varying weight groups following SC TE administration that may be used alongside future studies to support the use of SC TE in adolescent patients with hypogonadism. Scaling the adult model to adolescents predicted that 12.5 SC TE monthly could produce serum testosterone levels indicative of early puberty and showed pubertal stage progression following multiple subsequent testosterone doses. Therefore, SC TE may represent an effective and convenient treatment option for male adolescents with hypogonadism.
Maria G. Vogiatzi, Jonathan S. Jaffe, Takugo Amy, and Alan D. Rogol
Abstract
Context
Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents.
Objective
An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups.
Methods
Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens.
Results
The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases.
Conclusion
SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce the size of fluctuations in serum T and related symptoms.
Normal male pubertal maturation occurs between ages 9 and 14 years, after which puberty is considered delayed [1]. Delayed puberty affects approximately 2% of adolescents and has been associated with considerable psychosocial distress [1, 2]. Delays in puberty due to hypogonadism or constitutional delay in males may be treated with testosterone, which is used to promote the development of secondary sexual characteristics, growth, and normal bone and muscle mass [3, 4]. Although many testosterone formulations are approved for the treatment of hypogonadism in adult men, only intramuscular (IM) testosterone enanthate (TE) and testosterone pellets have been approved for adolescent males. These approvals were issued before the 1962 Kefauver-Harris Drug Control Act requiring that drugs prove safe and efficacious [5-7]. It is unclear whether there was clinical trial evidence supporting the safety and efficacy of these drugs at the time of their approval, and the US Food and Drug Administration has cautioned that evidence for IM TE and testosterone pellets may not align with current pediatric drug-approval standards [5]. Furthermore, improper use of testosterone therapies approved for adult males in adolescent males may lead in the latter group to disproportionate advancements in bone maturation, fusion of the epiphyseal growth centers, and early termination of linear growth [6, 7].
Testosterone therapy in adolescent males with delayed puberty starts with the administration of small doses of testosterone, typically IM TE, to induce puberty. In hypogonadism, doses are gradually increased to reach adult male testosterone replacement over a course of approximately 3 years and in a process that mimics physiologic male pubertal progression [1]. Intramuscular TE injections are easy to titrate, and TE given IM is the most commonly used preparation for induction and progression of puberty [8]. However, the injections can be painful, may require frequent office visits if not self-administered, and may be associated with nonphysiologic fluctuations in serum testosterone levels [3, 7]. Many new testosterone formulations have been developed to overcome difficulties with administration and adverse events, but these are supported only by expert opinion and are not evidence-based [3, 4]. Oral testosterone esters and transdermal testosterone gel have been used for puberty induction. However, the use of oral therapy has been limited by concerns about bioavailability and difficulties with dose titration, while the use of transdermal testosterone gel in pediatrics is limited by dosing variability [1, 9]. Since there is little evidence to guide optimal testosterone dosing in adolescent males, the efficacy and safety of testosterone administration may be supported by extrapolation from adult pharmacokinetics (PK) data, which have previously been used to augment pediatric drug development [4, 5, 10]. Extrapolation of adult data and scaling to pediatric patients may be completed through the use of allometry, which is the study of how the characteristics of living creatures change with size [11]. Differences in physiology and biochemistry lead to different rates of metabolism and renal clearance of drugs in different age groups of pediatric patients compared to adults. These differences necessitate the use of allometric modeling to scale drug clearance from adults to pediatric patients.
The goal of the present study is to design a nonlinear mixed effect (NLME) model to characterize the PK of IM and subcutaneous (SC) TE in adult patients with hypogonadism, to identify potential covariates affecting the PK of TE, and to scale these data to adolescent patients. Adult models were allometrically scaled to adolescent patients (aged 12 to < 18 years) at typical body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly IM and SC administration of 12.5, 25, 50, 75, and 100 mg TE regimens to project an optimal dose and schedule for adolescent patients with hypogonadism whose pubertal maturation is induced with testosterone.
Materials and Methods
Study Design
This PK study is an analysis of data from a previously published 3-arm, open-label, multidose, parallel-group phase 2 study (NCT01887418) [12]. The phase 2 study design was approved by the institutional review boards of participating centers and conducted in accordance with the Declaration of Helsinki and in compliance with Good Clinical Practice Guidelines. Informed consent was obtained from all patients.
12. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: a phase II study. Sex Med. 2015;3(4):269-279.
Considering the results of this PK analysis, one may propose the use of SC TE 12.5 mg monthly as appropriate for puberty initiation as both Cave and Cmax values correspond to those seen in early puberty. While dosing regimens modeled for monthly and EOW administration produced unphysiological testosterone concentrations, these regimens were used as a starting point to understand adolescent testosterone PK. These dosing regimens are used by pediatric endocrinologists initiating testosterone therapy in adolescents and are increased to adult dosing regimens of weekly or biweekly administration as adolescents go through pubertal maturation [1]. The results of these dosing regimens provide important context for IM and SC dosing, as adolescent patients tend to prefer nondaily testosterone formulations such as IM and SC, which produce variable and unphysiological testosterone PK in adolescents. While transdermal testosterone may be more physiological, it does not show individual pulsations or diurnal variation. Despite this, all forms of testosterone are unphysiological, and many have been used for testosterone therapy in hypogonadal men and boys. The use of IM TE at 12.5 mg monthly, as well as the SC and IM TE regimen of 25 mg monthly, may result in Cmax values that reach mid- and advanced puberty, especially in lighter-weight adolescents, a fact that may lead to undesirable rapid skeletal maturation during puberty induction. As the simulated adolescent Cmax and Cave values for SC TE were found to be approximately 75% of the respective IM TE values, the use of SC TE may assist with a more gradual and physiologic advancement of pubertal development compared to IM TE. The use of average testosterone exposures over a dosing interval may be limited in clinical applicability, but these methods were necessary to determine total exposure and provide practical context for IM and SC dosing in adolescent patients.
This paucity of data, coupled with a lack of evidence-based guidelines for the treatment of hypogonadism in adolescents, suggests that additional clinical trials are required to explore treatment regimens for adolescents requiring testosterone therapy [4]. Furthermore, individual patient factors and treatment goals must be considered when selecting testosterone therapy in adolescents [1].
As a model created to provide simulated SC and IM TE regimens in adolescents, our findings have several limitations that should be carefully considered when addressing clinical applicability. This model was generated from men with physician-diagnosed hypogonadism of any etiology and not organic testosterone deficiency, which may explain the high variability in PK data for patients receiving 50 mg SC TE, who may have experienced postdose endogenous testosterone production. Endogenous testosterone production in adult patients forming the basis of this model confounds extrapolation to adolescents with delayed puberty, where there is decreased endogenous testosterone production. Subsequent pediatric clinical trial data would provide more valuable insight as to the applicability of concentration-guided testosterone dosing in pediatric patients with delayed puberty. Despite adolescent simulations predicting higher serum testosterone concentrations in lighter- compared to heavier-weight groups with reliable increases in Cave, interpretations about the testosterone exposure-response relationship cannot be determined. This relationship is a function of the allometric equations used during modeling, as smaller-weight groups will have lower clearance and volume of distribution, and thus a higher concentration. Also, the adult model did not find weight to be a significant covariate on PK parameters, further limiting the interpretation of exposure-response results. Finally, the lowest monthly dose evaluated in this PK analysis may not prove to be appropriate in the smallest and least mature patients, but for a majority of adolescent patients being treated for hypogonadism, this dosing is predicted to produce typical Cave exposures and permit dose progression to foster growth and maturation [5, 19].
Conclusion
Testosterone PK following SC and IM administration of TE is best described by one-compartment models with first-order absorption and elimination kinetics in adult males. Because there are insufficient data on adolescents to derive a PK model, this male model was allometrically scaled to adolescents based on weight groups of 30 to 60 kg. For simulations in 30- to 60-kg adolescent males, SC TE Cave values approximated 75% of IM TE Cave values following regimens of 12.5, 25, 50, 75, and 100 mg TE administered weekly, EOW, or monthly. Therefore, SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in this population of simulated adolescent hypogonadal males. This simulation provides valuable PK data for adolescents of varying weight groups following SC TE administration that may be used alongside future studies to support the use of SC TE in adolescent patients with hypogonadism. Scaling the adult model to adolescents predicted that 12.5 SC TE monthly could produce serum testosterone levels indicative of early puberty and showed pubertal stage progression following multiple subsequent testosterone doses. Therefore, SC TE may represent an effective and convenient treatment option for male adolescents with hypogonadism.
