DRUG PROFILE Long-acting testosterone undecanoate for parenteral testosterone therapy Aksam A Yassin†, Testosterone as a compound for the treatment of testosterone deficiency has been Doris Huebler & available for almost 70 years; however, the pharmaceutical formulations have been less Farid Saad than ideal. Injectable testosterone esters have been used traditionally for treatment, but †Author for correspondence Clinic of Urology/Andrology, they generate supranormal testosterone levels shortly after the 2–3-weekly injections, Segeberger Kliniken, when testosterone levels then decline very rapidly becoming subnormal in the days Department of Urology, before the next injection. Testosterone undecanoate is a new injectable testosterone Rathausallee 94 a, 22846 Norderstedt-Hamburg, preparation with a considerably better pharmacokinetic profile. After two initial Germany; and Gulf Medical injections with a 6-week interval, the following intervals between two injections are College School of Medicine, almost always 12 weeks. Plasma testosterone levels with this preparation are almost Ajman, United Arab Emirates always in the normal range. Side effects experienced with conventional testosterone Tel.: +49 405 262 157 Fax: +49 405 262 820 esters are almost nil with this preparation. [email protected] Soon after its chemical identification more than Most forms of oral testosterone are alkylated 70 years ago, the male hormone testosterone at the 17α-carbon position, greatly reducing became pharmaceutically available. However, it their hepatic metabolism and improving their has taken a considerable time for convenient oral bioavailability. Unfortunately, these com- and safe preparations to be developed. The low pounds, such as 17α-methyl testosterone, are bioavailability, after both oral and parenteral associated with an unacceptably high rate of administration due to the short circulating half- hepatotoxic effects, including cholestatic jaun- life of testosterone, hampered its therapeutic use dice, peliosis hepatis and even liver tumors in a [1,2]. Among ways to circumvent these limita- third to half of long-term users [9–11]. As a result, tions, chemical modifications of the testoster- such 17α-alkylated forms of testosterone are not one molecule were developed allowing oral use, considered safe for long-term use by most although part some these turned out to be hepa- experts in the field [12]. totoxic. Subsequently, various parenteral testo- The only oral administration of testosterone sterone preparations were developed. Among that is currently safe is testosterone undecanoate the earliest were intramuscular injectable for- (TU), which is commercially available in many mulations of testosterone esterified with fatty countries. When administered orally, a portion of acids dissolved in a vegetable oil vehicle [3]. TU is absorbed via lymphatics and thereby These preparations remain the most cost-effec- bypasses hepatic first-pass metabolism [13–15]. TU tive and widely used worldwide. However, is lymphatically absorbed due to its long lipophilic injections of conventional testosterone fatty side chain. However, the absolute bioavailability acid esters (enanthate, cypionate, decanoate and of testosterone after oral TU administration is propionate) have an effective duration of action only approximately 6% [15], implying that most of of 1–2 weeks [4], as wider or narrower spacing an oral TU dose is absorbed via the portal circula- between injections leads to progressively more tion and metabolized by the liver. TU must be extreme excursions in serum testosterone con- administered orally in doses of 120–240 mg/day Keywords: injection interval, centrations with substantial supra- and sub- (divided in two-to-three administrations per day). pharmacokinetic profile, physiological serum concentrations, less well- The transdermal route for testosterone admin- testosterone esters, [5] testosterone treatment, sustained gonadotropin suppression and istration generates excellent pharmacokinetic testosterone undecanoate greater subjective symptoms of these wide fluc- profiles; however, patches can cause moderate to tuations [2]. Subdermal testosterone pellet severe skin reaction due to the vehicles (enhanc- implants or biodegradable microspheres allow ers) that facilitate testosterone absorption across longer application intervals, although handling the skin [16]. The newly available testosterone Future Drugs Ltd of these preparations is relatively difficult [6–8]. gels are safe and effective, but must be applied to 10.1586/14750708.3.6.709 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(6), 709–721 709 DRUG PROFILE – Yassin, Huebler & Saad a fairly large area of skin and care must be taken able to develop a suitable intramuscular testo- to avoid inadvertent exposure to women and sterone preparation with a volume of 4 ml con- children [17–21]. taining 1000 mg of TU. At present, the Sustained- and controlled-release testoster- stability in climate zone II (25oC) lasts one buccal systems, including mucoadhesive 60 months [37]. Intramuscular TU is currently excipients, are now available in some countries not approved for use in the USA, but is pre- but require twice-daily administration. Venous scribed in Europe, Latin America and Asia drainage from the oral cavity flows directly to under the trade name Nebido®, and in Aus- the superior vena cava and, thus, hepatic first- tralia under the trade name Reandron 1000® pass metabolism is circumvented with these for the treatment of male hypogonadism. preparations [22–25]. In summary, each of these modes of testoster- Toxicology & pharmacology one delivery has drawbacks. The recent discov- The active pharmacological principle of LA-TU ery of steroidal and nonsteroidal selective is testosterone itself. After entering the periph- androgen receptor modulators (SARMs) could eral circulation, TU (molecular weight provide a promising alternative for testosterone 456.7 Da) is hydrolyzed to testosterone, which therapy, including hormonal male contracep- exerts its androgenic activity [14,38]. Therefore, tion. The identification of an orally bioavailable the toxicology of TU is the same as for other SARM with the ability to mimic the desired cleavable testosterone fatty acid esters, such as central and peripheral androgenic and anabolic testosterone propionate (three carbon atoms), effects of testosterone in a tissue-specific manner testosterone enanthate (TE; seven carbon atoms) and simultaneously avoid the undesirable or testosterone cypionate (eight carbon atoms). androgen effects (e.g., on prostate and skin) In contrast to these fatty acid esters, the kinetics would represent an important step in androgen for side-chain cleavage of the saturated aliphatic therapy [26–30]. However, most of these com- fatty acid undecanoic acid with 11 carbon atoms pounds are in very early phases of pharmaceuti- turned out to be considerably longer, permitting cal development and the availability on the much longer injection intervals and at the same market is expected in the more or less distant time preventing supra- or subphysiological future. That also applies to microencapsulation serum testosterone levels. of Leydig cells [31] and some possibilities of stem Nahrendorf and colleagues evaluated the influ- cell technology. ence of LA-TU treatment on left ventricular In a search for medium-term solutions to key remodeling following experimental myocardial problems of testosterone therapy, TU, for intra- infarction in male rats, as assessed by magnetic res- muscular administration was developed by onance imaging and in vivo hemodynamics [39]. Jenapharm GmbH & Co. KG, a subsidiary of The authors found no evidence for cardiac toxic- Schering AG in Berlin, Germany. The develop- ity of testosterone administration, despite a ten- ment of this long-acting TU (LA-TU) will now fold increase in testosterone serum levels, after be presented and discussed. TU administration compared with placebo administration. Neither infarct size nor proce- Development of LA-TU dure-related mortality was influenced by TU. For the development of an intramuscular long- On the contrary, there was a tendency to an acting testosterone preparation for male contra- improved hemodynamic outcome: left ventricu- ception, the WHO Special Programme of lar end diastolic pressure was reduced signifi- Research, Development and Research Training cantly in TU-treated animals together with wall in Human Reproduction initiated search activi- stress without differences in diastolic filling rates ties for identifying suitable fatty acid side chains following myocardial infarction. for esterification of testosterone [32]. It appeared Despite the fact that, after oral administra- that testosterone esterified with undecanoic acid tion, TU is well tolerated, the bioavailability shows ideal long-term kinetics [4,33–34]. The first leaves much to be desired. Täuber and colleagues TU preparation was developed in China [35–36]. reported that the mean absolute bioavailability Unfortunately, the injection volume of 8 ml for of testosterone after oral administration of TU to TU 1000 mg caused some problems at the local women was 6.83 ± 3.32%, whereas the mean injection site. Therefore, by use of a special absolute bioavailability of orally administered galenic formulation based on benzyl benzoate free testosterone was 3.64 ± 2.45% [15]. The and refined castor oil, Jenapharm/Schering were absorption of TU by the gut is erratic, resulting 710 Therapy (2006) 3(6) Testosterone