Long-acting testosterone undecanoate for parenteral testosterone

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Transcript of Long-acting testosterone undecanoate for parenteral testosterone

  • Future Drugs Ltd

    10.1586/14750708.3.6.709 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(6), 709721 709


    Long-acting testosterone undecanoate for parenteral testosterone therapyAksam A Yassin, Doris Huebler & Farid Saad Author for correspondenceClinic of Urology/Andrology, Segeberger Kliniken, Department of Urology, Rathausallee 94 a, 22846 Norderstedt-Hamburg, Germany; and Gulf Medical College School of Medicine, Ajman, United Arab EmiratesTel.: +49 405 262 157 Fax: +49 405 262 820 yassin@t-online.de

    Keywords: injection interval, pharmacokinetic profile, testosterone esters, testosterone treatment, testosterone undecanoate

    Testosterone as a compound for the treatment of testosterone deficiency has been available for almost 70 years; however, the pharmaceutical formulations have been less than ideal. Injectable testosterone esters have been used traditionally for treatment, but they generate supranormal testosterone levels shortly after the 23-weekly injections, when testosterone levels then decline very rapidly becoming subnormal in the days before the next injection. Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After two initial injections with a 6-week interval, the following intervals between two injections are almost always 12 weeks. Plasma testosterone levels with this preparation are almost always in the normal range. Side effects experienced with conventional testosterone esters are almost nil with this preparation.

    Soon after its chemical identification more than70 years ago, the male hormone testosteronebecame pharmaceutically available. However, ithas taken a considerable time for convenientand safe preparations to be developed. The lowbioavailability, after both oral and parenteraladministration due to the short circulating half-life of testosterone, hampered its therapeutic use[1,2]. Among ways to circumvent these limita-tions, chemical modifications of the testoster-one molecule were developed allowing oral use,although part some these turned out to be hepa-totoxic. Subsequently, various parenteral testo-sterone preparations were developed. Amongthe earliest were intramuscular injectable for-mulations of testosterone esterified with fattyacids dissolved in a vegetable oil vehicle [3].These preparations remain the most cost-effec-tive and widely used worldwide. However,injections of conventional testosterone fattyacid esters (enanthate, cypionate, decanoate andpropionate) have an effective duration of actionof 12 weeks [4], as wider or narrower spacingbetween injections leads to progressively moreextreme excursions in serum testosterone con-centrations with substantial supra- and sub-physiological serum concentrations, less well-sustained gonadotropin suppression [5] andgreater subjective symptoms of these wide fluc-tuations [2]. Subdermal testosterone pelletimplants or biodegradable microspheres allowlonger application intervals, although handlingof these preparations is relatively difficult [68].

    Most forms of oral testosterone are alkylatedat the 17-carbon position, greatly reducingtheir hepatic metabolism and improving theiroral bioavailability. Unfortunately, these com-pounds, such as 17-methyl testosterone, areassociated with an unacceptably high rate ofhepatotoxic effects, including cholestatic jaun-dice, peliosis hepatis and even liver tumors in athird to half of long-term users [911]. As a result,such 17-alkylated forms of testosterone are notconsidered safe for long-term use by mostexperts in the field [12].

    The only oral administration of testosteronethat is currently safe is testosterone undecanoate(TU), which is commercially available in manycountries. When administered orally, a portion ofTU is absorbed via lymphatics and therebybypasses hepatic first-pass metabolism [1315]. TUis lymphatically absorbed due to its long lipophilicside chain. However, the absolute bioavailabilityof testosterone after oral TU administration isonly approximately 6% [15], implying that most ofan oral TU dose is absorbed via the portal circula-tion and metabolized by the liver. TU must beadministered orally in doses of 120240 mg/day(divided in two-to-three administrations per day).

    The transdermal route for testosterone admin-istration generates excellent pharmacokineticprofiles; however, patches can cause moderate tosevere skin reaction due to the vehicles (enhanc-ers) that facilitate testosterone absorption acrossthe skin [16]. The newly available testosteronegels are safe and effective, but must be applied to

  • DRUG PROFILE Yassin, Huebler & Saad

    710 Therapy (2006) 3(6)

    a fairly large area of skin and care must be takento avoid inadvertent exposure to women andchildren [1721].

    Sustained- and controlled-release testoster-one buccal systems, including mucoadhesiveexcipients, are now available in some countriesbut require twice-daily administration. Venousdrainage from the oral cavity flows directly tothe superior vena cava and, thus, hepatic first-pass metabolism is circumvented with thesepreparations [2225].

    In summary, each of these modes of testoster-one delivery has drawbacks. The recent discov-ery of steroidal and nonsteroidal selectiveandrogen receptor modulators (SARMs) couldprovide a promising alternative for testosteronetherapy, including hormonal male contracep-tion. The identification of an orally bioavailableSARM with the ability to mimic the desiredcentral and peripheral androgenic and anaboliceffects of testosterone in a tissue-specific mannerand simultaneously avoid the undesirableandrogen effects (e.g., on prostate and skin)would represent an important step in androgentherapy [2630]. However, most of these com-pounds are in very early phases of pharmaceuti-cal development and the availability on themarket is expected in the more or less distantfuture. That also applies to microencapsulationof Leydig cells [31] and some possibilities of stemcell technology.

    In a search for medium-term solutions to keyproblems of testosterone therapy, TU, for intra-muscular administration was developed byJenapharm GmbH & Co. KG, a subsidiary ofSchering AG in Berlin, Germany. The develop-ment of this long-acting TU (LA-TU) will nowbe presented and discussed.

    Development of LA-TU For the development of an intramuscular long-acting testosterone preparation for male contra-ception, the WHO Special Programme ofResearch, Development and Research Trainingin Human Reproduction initiated search activi-ties for identifying suitable fatty acid side chainsfor esterification of testosterone [32]. It appearedthat testosterone esterified with undecanoic acidshows ideal long-term kinetics [4,3334]. The firstTU preparation was developed in China [3536].Unfortunately, the injection volume of 8 ml forTU 1000 mg caused some problems at the localinjection site. Therefore, by use of a specialgalenic formulation based on benzyl benzoateand refined castor oil, Jenapharm/Schering were

    able to develop a suitable intramuscular testo-sterone preparation with a volume of 4 ml con-taining 1000 mg of TU. At present, thestability in climate zone II (25oC) lasts60 months [37]. Intramuscular TU is currentlynot approved for use in the USA, but is pre-scribed in Europe, Latin America and Asiaunder the trade name Nebido, and in Aus-tralia under the trade name Reandron 1000

    for the treatment of male hypogonadism.

    Toxicology & pharmacologyThe active pharmacological principle of LA-TUis testosterone itself. After entering the periph-eral circulation, TU (molecular weight456.7 Da) is hydrolyzed to testosterone, whichexerts its androgenic activity [14,38]. Therefore,the toxicology of TU is the same as for othercleavable testosterone fatty acid esters, such astestosterone propionate (three carbon atoms),testosterone enanthate (TE; seven carbon atoms)or testosterone cypionate (eight carbon atoms).In contrast to these fatty acid esters, the kineticsfor side-chain cleavage of the saturated aliphaticfatty acid undecanoic acid with 11 carbon atomsturned out to be considerably longer, permittingmuch longer injection intervals and at the sametime preventing supra- or subphysiologicalserum testosterone levels.

    Nahrendorf and colleagues evaluated the influ-ence of LA-TU treatment on left ventricularremodeling following experimental myocardialinfarction in male rats, as assessed by magnetic res-onance imaging and in vivo hemodynamics [39].The authors found no evidence for cardiac toxic-ity of testosterone administration, despite a ten-fold increase in testosterone serum levels, afterTU administration compared with placeboadministration. Neither infarct size nor proce-dure-related mortality was influenced by TU.On the contrary, there was a tendency to animproved hemodynamic outcome: left ventricu-lar end diastolic pressure was reduced signifi-cantly in TU-treated animals together with wallstress without differences in diastolic filling ratesfollowing myocardial infarction.

    Despite the fact that, after oral administra-tion, TU is well tolerated, the bioavailabilityleaves much to be desired. Tuber and colleaguesreported that the mean absolute bioavailabilityof testosterone after oral administration of TU towomen was 6.83 3.32%, whereas the meanabsolute bioavailability of orally administeredfree testosterone was 3.64 2.45% [15]. Theabsorption of TU by the gut is erratic, resulting

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    Testosterone undecanoate DRUG PROFILE

    in a great inter- as well as intra-individual varia-bility in serum levels. TU is metabolized partlyin the intestinal wall [14].

    With the present state of available testosteronepreparations, the parenteral administration ofTU will receive growing interest.

    PharmacokineticsThe relationships between intramuscular TUdos