Sponsored by an educational grant from Schering
Today I want to talk about the comparison of kinetics, efficiency and safety of two testosterone formulations for intramuscular injection. One of them most of you have used in the past which is testosterone undecanoate for intramuscular injection and recently in Europe and in some countries in Asia, testosterone undecanoate for intramuscular injection has been approved for treatment of hypogonadal men.
So, as you know, there are and have heard in this meeting, there are a lot of testosterone formulations on the market for the treatment of hypogonadal men. There are transdermal systems like patches, gels, there are other formulations, buccal formulations, as well as pellets for subcutaneous implantation.
But today I want to just focus on intramuscular testosterone esters and, indeed, on two of them. This is testosterone enanthate and if you buy a vial of testosterone enanthate, you get a 1 ml oily solution containing 250 mix of testosterone enanthate. So this is totally different if you buy a vial of testosterone undecanoate. There are 4 ml containing 1,000 mg testosterone undecanoate. So as we started 9 years ago to use this formulation, um, we had a little concern about this large injection volume. So during the first 5 years of using this formulation, the doctors actually did the injections at our department, so now the nurses are doing them and we didn’t see any local, several local side effect. During our experience, there was one hematoma and if you ask the patient who received testosterone inundate before, they say it is not much difference between these two types of injections. And I am going to talk today about testosterone undecanoate for intramuscular injections remain the solution using castor oil. There is another solution or another preparation Professor Nieschlag talked about which using tree seed oil solvents. This is not meant. This is just Nebido® here.
If we take a look and Dr. Zitzmann has shown this already, he has a comparison of these two testosterone formulations. You see after injection of testosterone enanthate 250 mg, testosterone levels sharply rise and dropping the second week after the injection and reaching already hypogonadal levels in the third week after the injection. So even if you use a two-week injection interval you get fluctuating serum testosterone levels which often causes discomfort in the patient. So and here you see the single-dose kinetic published by Behre a couple of years ago of 1,000 mg testosterone undecanoate and as you can see here after the injection, during the first one-and-a-half and two weeks, testosterone levels rise reaching middle-normal values and then slightly drop and even after 12 weeks after the injections, we have still testosterone levels somewhere in the lower normal parameter, really low normal range. So 9 years ago, we used this information, this single-dose kinetic study in a computerized model to predict multi-dose kinetic. So actually this system proved us wrong in real life.
But based on this prediction we initiated a trial in Cologne where we randomised 40 hypogonadal men. Twenty received testosterone enanthate intramuscular and in this group, 7 patients suffered from primary hypogonadism, 13 from secondary hypogonadism. In the testosterone undecanoate group, 5 men had primary hypogonadism and 15 secondary. So all men investigated here, are really hypogonadal. Everybody had testosterone levels below 5 nmol/L at base line.
So let us take a look at our study design. So these are the two groups and we have two phases in that study. We had a main study, a comparative part for 30 weeks and then we had a follow-up phase for 30 months. So we randomised in these two groups, a TE group received 250 mg TE every three weeks, 16 of these 20 men switched to TU 1,000 mg every three months. So there was a little difference here, but the TE group, the first two injection intervals were 6 weeks, then we prolonged to 9 weeks and in the follow-up phase to 12 weeks. So why did we do this?
And this becomes clear if we take a look at our multi-dose pharmacokinetics in that study. So here you see total serum testosterone levels and in grey is the TE group, in red the TU group and our time for dose sampling was every 3 weeks. So we did not see this sharp increase and coming down of testosterone levels in the TE group, so these are really trough levels. This was a little different from the TE group. So prior the next injection, the phase of testosterone level raised close and then we decided to actually use a 9 week interval and still the levels prior to the next injection rose, so we decided to use a 12 week interval and as we used the 12 week injection interval in the follow-up phase, we actually reached a steady state. So our computerized model was wrong. The prolongation of the serum testosterone level was much longer than predicted. So of course we were interested in parameter of sufficiency.
And here you see the gonadotropins, FSH and LH levels, so due to testosterone treatment, FSH and LH levels dropped without any significant difference between the two therapy groups. And in the follow-up, we reached a somehow stable level. This is a mixed state of primary and secondary hypogonadal men.
So of course we wanted to see estradiol levels and SHBG levels and the estradiol level pretty much mirrored the testosterone curve with trough levels in the TE group and rising levels in the TU group and then stable levels in the normal lower range using a 12 week injection interval after U in the follow-up phase of our study. Pretty much the same you see if you look at the behaviour of SHBG levels. So you see due to testosterone treatment, a man can decrease in SHBG levels without any significant difference between the two therapy arms and in the follow-up phase, the levels looked somehow pretty much stable in the lower normal range.
So of course we were interested to see parameters of erythropoesis, as Dr. Zitzmann pointed out before. You can see here the hemoglobin hematocrit levels and due to testosterone treatment you see a rise during the first 12 months of therapy. Without any difference between the two therapy arms and using the 12 week injection interval in the follow-up phase, that is pretty fine and our hemoglobin levels stayed stable. We have an average increase of 1.5 g/dl, we had an average increase in hematocrit at 2% and here you can see the same behaviour. We have an increase over the first year and then it pretty much stays stable throughout the follow-up phase of our study.
So we were keen to see lipid parameters, not only for safety reasons. Here are the total cholesterol levels and this slide is a little different, so you see here the comparative part of the study and here on the right-hand side the follow-up phase and this small table are the mean values measured for total cholesterol at every time point we measured. So we are starting, it is pretty much the same for total cholesterol values and then we dropped down a little bit after the comparative part after switching the man to TU, we reach about 202 mg/dL, so total cholesterol level dropped slightly.
So we wanted to see, of course, HDL and LDL levels and here again this small table shows you the base line levels and then HDL levels slightly drop during the whole study, but in the follow-up phase it stays pretty much stable without any larger differences. So we take a look at the LDL level. Here again, the comparative part of our study. We are starting at the same levels, around about 160 mg/dL, then we dropped slightly during the first 30 weeks and then this continues to drop for the whole trial. So we do not know if this is any significant for cardiovascular risk or something, but at least it confirms some of the data which are currently out there.
We measured body composition in our patients and here the first phase, the first 30 weeks of our study, you see the fat-free man and here are changes in kilogram and as you can see here, due to testosterone treatment, about, well, 3 to 4 kg fat-free mass increases and the fat mass changes, as well, to give a decrease in fat mass about here 2.5, 2.6 to 2.2 kg. There were no significant differences between the two therapy groups. What happens in the long run?
And here you can see the changes in fat mass and these are the changes in kilogram and here are indicated the relative changes in percent and you see that we, somewhere around 12% to 18% in the long run of fat mass in our trial. During the first phase of our study here are 6 months data; we do not see any significant difference between the two therapy arms.
So if we do have body composition data, we should have bone mineral density data, so here is the lumbar spine and you might be a little disappointed because of the relatively low relative increase in bone marrow density, but we do have to keep in mind that most of our patients in this trial have been treated before and our wash-out phase was only 3 months. So we get about an increase of 4% in bone mineral density over time.
So what happened to prostate parameters like PSA? In our trial, PSA of course increases after initiating of testosterone therapy about the maximum of 0.5%, 5 mg/dL and then is pretty much stable and these are the prostate volume data using transrectal ultrasonography and, as you can see in both therapy groups during the first 30 weeks of the therapy, prostate volume increases about 4 to 5 ml and what happens now in the long run?
PSA levels increase directly after initiation of testosterone therapy and using a 12 week injection interval after U, they stopped pretty much stable throughout the follow-up phase of our study.
So what happens to prostate volume in the long run? You see here during the first 6 months of therapy prostate volume increases and then it stays stable throughout the follow-up phase of our study where we used the 12 week injection interval.
So, furthermore, we measured sexual and psychological parameters in our patients. So we used (inaudible) questionnaire based on (inaudible) analog scales so these were a scale 10 cm long and if you make a cross on the very left-hand side, the score is zero which is the lowest thinkable value for the patient, and if you make a cross on the very right side, this is the highest thinkable level we set at 100, and what you see here are the scores for sexual thoughts, fantasy, sexual interest and desire and satisfaction with sex life. And as you can see here, after our, this is the screening phase, this is the first injections after the beginning of the testosterone treatment in both therapy groups, the scores substantially raised and this yields statistical significance after 3 weeks of therapy. And then during the 30 weeks of the comparative part of the study, this is pretty much stable and this is true for all parameters. There might be some little difference you see here in satisfaction with sex life because of lower initial scores in the testosterone enanthate group, but we do not think this is really a difference because a relative increase in those groups is pretty much the same so we think both therapy forms are equally effective.
We asked for sexual parameters by waking erections, total erections, ejaculations and here you see as well, already after 3 weeks of therapy, you have a substantial increase in the total numbers which stay stable throughout the comparative part of our study. So here again, a little lower baseline level in the TE group but the relatively increase is pretty much the same.
We asked for psychological parameters and here you see the scores for the depression, fatigue, anxiety and aggression and as you can see here, to yield, to get significant results and the decreased scores, you need about 6 weeks of testosterone therapy again. There are no significant differences between the two therapy forms. The same is true for fatigue, the scores drop, reaching significance about 6 weeks after initiating of testosterone therapy and then it stays pretty much stable. We did not see any significant results or changes in scores for anxiety and aggression.
So let me now conclude our results. We think testosterone undecanoate, 1,000 mg intramuscular, is as effective and as safe as the older testosterone enanthate regime using 200 mg intramuscular and last but not least and I feel most important, you need 3 to 4 times less injection to achieve sufficient and physiological testosterone replacement therapy in hypogonadal men using testosterone undecanoate, 1,000 mg.
And last and most importantly, I want to acknowledge all the people who initiated this study and were working in it because without these people, it would never have been possible. Professor Jockenhövel for initiating this study and a lot of work was performed by Professor Oettel to actually make this preparation work. Thank you very much for your attention.
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