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Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects

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Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects Touro Scholar Faculty Publications & Research of the TUC College of Pharmacy College of Pharmacy 2018 Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects Youwei Bi Paul J. Perry Touro University California, [email protected] Michael Ellerby Touro University California, [email protected] Daryl J. Murry Follow this and additional works at: https://touroscholar.touro.edu/tuccop_pubs Part of the Hormones, Hormone Substitutes, and Hormone Antagonists Commons Recommended Citation Bi, Y., Perry, P. J., Ellerby, M., & Murry, D. J. (2018). Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects. CPT: Pharmacometrics & Systems Pharmacology, 7 (4), 259-268. https://doi.org/10.1002/psp4.12287 Citation: CPT Pharmacometrics Syst. Pharmacol. (2018) 7, 259–268; doi:10.1002/psp4.12287 VC 2018 ASCPT All rights reserved ORIGINAL ARTICLE Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects Youwei Bi1, Paul J. Perry1,2, Michael Ellerby2 and Daryl J. Murry3* A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate (TC). Thirty-one healthy men were randomized into a dose group of 100, 250, or 500 mg/wk and received 14 weekly injections of TC. A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one- compartment model best described the concentration-time profile of total testosterone. The population mean estimates for testosterone were 2.6 kL/day for clearance and 14.4 kL for volume of distribution. Weight, albumin, and their changes from baseline were identified as significant covariates for testosterone. The estimated potency of total testosterone (tT) with respect to suppression of luteinizing hormone (LH) synthesis was 9.33 ng/mL. Simulation based on the indirect response model suggests the suppression of endogenous testosterone secretion, LH synthesis, and spermatogenesis was more severe and of greater duration in the 250 mg and the 500 mg dose groups. CPT Pharmacometrics Syst. Pharmacol. (2018) 7, 259–268; doi:10.1002/psp4.12287; published online 1 March 2018. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE clinical trial, which quantified the relationship between TOPIC? testosterone exposure after exogenous administration þ Long-term excessive dosing of anabolic steroids can and suppression of LH and spermatogenesis. Model lead to serious health risks. One of the most significant results showed that the suppression of endogenous tes- physiologic changes induced by the use of testosterone tosterone secretion, LH synthesis, and spermatogenesis esters is a dose-dependent impairment of normal tes- was more severe and of greater duration in the 250 mg ticular androgen secretion and spermatogenesis. andthe500mgdosegroups. WHAT QUESTION DID THIS STUDY ADDRESS? HOW MIGHT THIS CHANGE DRUG DISCOVERY, þ This study characterizes and quantifies changes in DEVELOPMENT, AND/OR THERAPEUTICS testosterone and LH concentration, and spermatogene- þ This PK/PD model provides a framework to quantify sis following long-term TC administration. and predict the change in LH and spermatogenesis WHAT DOES THIS STUDY ADD TO OUR after exogenous testosterone administration. The aver- KNOWLEDGE? age concentration of tT in the past 18 weeks was found þ The study developed a PK/PD model based on a ran- to have the strongest association with suppression of domized three-arm (100 mg, 250 mg, and 500 mg/week) spermatogenesis. Endogenous testosterone is responsible for stimulation and over 50 years.4–6 Numerous studies have shown that long- development of male sex organs and for maintenance of term use or excessive dosing of anabolic steroids can lead 1 secondary male characteristics. An abnormally low level of to serious health risks. One physiologic change is a dose- testosterone is referred to as hypoandrogenism, in men it dependent impairment of normal testicular androgen secre- may result in decreased sex hormone production and defi- tion and spermatogenesis.7–9 This effect is believed to ciency in gamete production and regulation. Depot- result from the suppression of circulating luteinizing hor- testosterone (testosterone cypionate (TC)) is an oil-soluble mone (LH) and follicle stimulating hormone through a feed- ester of the hormone testosterone and is indicated for back loop system of the hypothalamic-pituitary-gonadal hormone replacement therapy in men who have symptoms (HPG) axis.9,10 Most studies evaluating anabolic steroid 2 of deficiency or absence of endogenous testosterone. use are observational and retrospective with studied doses It can be used to treat both congenital and acquired substantially lower than the dose commonly used by illicit 3 hypoandrogenism. steroid users.11–14 Aside from the therapeutic indications, the illegal use of A randomized, double-blind, placebo-controlled study was TC and other anabolic steroids by athletes to gain an unfair conducted by MacIndoe et al.11 to investigate the effects of advantage in athletic competitions have been reported for 1University of Iowa, College of Pharmacy, Iowa City, Iowa, USA; 2Touro University-California, College of Pharmacy, Vallejo (Mare Island), California, USA; 3University of Nebraska Medical Center, College of Pharmacy, Omaha, Nebraska. *Correspondence: DJ Murry ([email protected]) Received 4 December 2017; accepted 18 January 2018; published online on 1 March 2018. doi:10.1002/psp4.12287 PK/PD Modeling of Depot Testosterone Cypionate Bi et al. 260 Table 1 Baseline demographic characteristics, protein levels, and laboratory test values of 31 healthy volunteers. Median (range) Characteristic 100 mg (N 5 10) 250 mg (N 5 10) 500 mg (N 5 11) Baseline tT, ng/mL 6.44 (4.04–9.5) 5.93 (4.2–10.6) 5.78 (2.31–9.48) Baseline fT, ng/dL 2.41 (1.58–4.17) 2.38 (0.28–3.55) 2.44 (1.08–3.09) Age, years 26.5 (22–32) 25.5 (22–39) 30 (21–39) Weight, kg 82.2 (61.7–115) 88.8 (61.7–105) 84.7 (60.7–115) Blood urea nitrogen, mg/dL 14.5 (10–17) 15 (9–18) 15 (8–19) Serum creatinine, mg/dL 1.05 (0.8–1.5) 1.1 (1–1.2) 1 (0.9–1.2) Creatinine clearance, mL/min 124 (89.6–179) 123 (90.4–153) 125 (84.3–166) Albumin, g/dL 4.55 (4.4–6.9) 4.55 (4.3–5.1) 4.6 (1.6–5) Globulin, g/dL 2.75 (2–3.1) 2.9 (2.4–3.5) 3 (2.8–3.2) Thyroxine-binding globulin, ug/mL 19.5 (10–31) 18.5 (11–26) 21 (14–26) Sex hormone-binding globulin, nmol/L 26 (17–46) 24.5 (11–48) 22 (13–47) Alkaline phosphatase, IU/L 63.5 (52–89) 52 (41–97) 67 (50–98) Lactate dehydrogenase, IU/L 157 (141–194) 158 (121–196) 143 (111–184) AST, IU/L 23 (17–32) 20.5 (14–53) 18 (12–34) ALT, IU/L 22 (16–52) 27.5 (12–47) 19 (10–40) GGT, IU/L 22 (10–54) 20 (10–54) 18 (10–58) Total bilirubin, mg/dL 7.25 (6.9–8.1) 7.5 (6.8–8.4) 7.6 (7.1–8) Direct bilirubin, mg/dL 0.2 (0.2–0.4) 0.25 (0.1–0.4) 0.3 (0.1–0.5) Triglyceride, mg/dL 110 (40–335) 122 (43–532) 123 (58–538) Cholesterol, mg/dL 199 (140–238) 184 (139–224) 198 (162–241) HDL, mg/dL 39 (27–70) 39 (21–54) 33 (22–47) LDL, mg/dL 125 (65–186) 116 (79–162) 136 (79–181) ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipopro- tein; fT, free testosterone; tT, free testosterone. weekly TC injections upon the HPG axis. Our main objective 8 hours, and then daily for 26 consecutive days after the of developing a pharmacokinetic/pharmacodynamic (PK/PD) last active TC injection were used to determine their elimi- model based on these data is to characterize and quantify nation. Biweekly luteinizing hormone releasing hormone the effect of long-term administration of supratherapeutic (LHRH) stimulation tests were performed 7 days after the doses of TC on suppression of LH synthesis and spermato- last injection of either placebo or testosterone to assess genesis. This information may help us better understand the pituitary gonadotropin secretion. Venous blood samples for effect of the illegal use of anabolic steroids on the impair- LH and follicle stimulating hormone were obtained before ment of testicular androgen secretion. and 30, 60, and 120 minutes after the intravenous infusion of 100 mcg LHRH. Semen samples were obtained by mas- turbation at baseline (week 0), and weeks 2, 16, 21, 28, METHODS and, in some subjects, at week 40, and assessed for total Study design and motile sperm concentrations. Subjects were asked to The study design of the trial has been published else- be sexually abstinent for 24 hours before sample collection. where.11 In summary, this is a randomized, double-blind clinical trial in which 31 healthy male subjects were ran- Model building domized into the 100 mg/wk (n 5 10), 250 mg/wk (n 5 10), Nonlinear mixed effects modeling was performed using and 500 mg/wk (n 5 11) dose groups. The high dosing regi- NONMEM version 7.2. The PK/PD data analysis was per- mens of 250 mg/week and 500 mg/week resemble doses formed sequentially. The PK model for tT was first fitted to illegally used by athletes. The study included two consecu- the data, and the PD model for suppression of LH synthesis, tive weekly injections of TC placebo, followed by 14 con- and spermatogenesis was then sequentially fitted conditional secutive weekly TC injections.
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