DOI

10.17077/etd.1cwx630j

Document Type

Dissertation

Date of Degree

Summer 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Murry, Daryl J.

First Committee Member

Fleckenstein, Lawrence L.

Second Committee Member

Milavetz, Gary

Third Committee Member

Brogden, Nicole K.

Fourth Committee Member

Smith, Brian J.

Abstract

Depot intramuscularly administered testosterone cypionate (TC) is indicated for treatment of hypogonadism in males. However, illegal use of TC and other anabolic steroids in athletic competition has been occurring for over 50 years. A randomized three-arm clinical trial was conducted to investigate side effects of long-term abuse of testosterone cypionate. The objective of the thesis is to apply modeling approach to characterize pharmacokinetics of long-term TC injections as well as identify its side effects on healthy male volunteers. A linear one-compartment model with first-order absorption best described the concentration-time profile of testosterone obtained from 31 healthy males. The population clearance estimates for total and free testosterone were 2.42*103 and 6.03*105 L/day, respectively. Weight and albumin were identified as significant covariates for total testosterone. Given the known inhibitory effect of testosterone on HPG axis, an indirect effect model was applied to describe the suppression of luteinizing hormone and spermatogenesis. The estimated potency of total testosterone with respect to LH suppression was 9.38ng/ml. Model simulation showed that suppression of luteinizing hormone and spermatogenesis after TC injection was more severe and of greater duration in the highest dose level. A polynomial change point mixed effects model was successfully built to describe the change in weight and lipid profiles after weekly injection of testosterone cypionate. Model simulation showed that both 250mg and 500mg would incur an average increase of body weight of 3.5kg at 8 weeks after dosing. A polynomial change point model also identifies that there is a tendency for lipid decrease after TC administration. However, no difference was found in the lipid change between three dose groups, which precludes any definite conclusion on the effect of long-term TC administration on lipid profiles.

Keywords

Abuse of steroids, Luteinizing hormone, Population pharmacokinetic/pharmacodynamic (PK/PD) modeling, Spermatogenesis, Testosterone cypionate

Pages

xiv, 136 pages

Bibliography

Includes bibliographical references (pages 126-136).

Copyright

Copyright © 2016 Youwei Bi

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