Sunday 28 October 2012
Zytiga Makes Lupron Redundant
Clinical trials are ongoing to evaluate the effects of Zytiga as first line therapy when given 3 weekely Lupron injections as well. Lupron is an LHRH agonist which lowers testosterone levels, whilst Zytiga is able to completely block testosterone production throughout the body, which makes the use of Lupron redundant. So Zytiga blocks all testosterone production anyway and the hormone injection is superfluous. Why do these doctors continue to inject hormones when they know that they are doing nothing more to control the disease. Surely the continued use of Lupron whilst on Zytiga is questionable and there is no evidence that continued use of Lupron with Zytiga is beneficial to the patient. The best neoadjuvant use of Zytiga is therefore as a single agent without Lupron perhaps combined with a low dose of a corticosteroid such as prednisone to offset hyopkalemic side effects.
Xgeva Zytiga Combo
Denosumab (Xgeva) is an antibody injection that targets the RANK ligand and has shown to be effective against bone metastases. Xgeva is now licensed for treating metastatic cancer and Zytiga is licensed for treating metastatic prostate cancer so the combination of these 2 approaches can now be clinically evaluated. The 2 are compatible since Zytiga is taken once daily orally and Xgeva is given as a monthly injection. Combining Xgeva with Zytiga respresents a logical approach to treating metastatic prostate cancer and the results of using this combination in clinical practise will be interesting.
Friday 26 October 2012
AMG 386 Zytiga Combo
AMG 386 is a new antibody injection that targets a protein involved in blood vessel formation to the tumours. Disrupting this blood supply causes the tumours to die off. Zytiga is now a new standard of care for prostate cancer therapy and so other promising agents are being trialed in combination with Zytiga. Combining AMG 386 with Zytiga offers a multitargetted approach which should have a powerful combined effect and this combination is now under clinical investigation.
AMG 386 has already demonstrated its efficacy against ovarian cancer and its effects against prostate cancer will be very interesting.
AMG 386 is a first-in-class investigational “peptibody” (i.e., a combination of a peptide + an antibody) that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 & Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play roles in angiogenesis, and the maturation of blood vessels appears to be controlled by their precise balance.
Associate Professor of Medicine at Monash University in Australia, Gary Richardson, presented data from phase 2 clinical trials against ovarian cancer showing that AMG 386 in combination with paclitaxel not only extends survival, but is well tolerated and reduces the risk of serious complications.
“Currently the prognosis for ovarian cancer patients is poor,” Professor Richardson said. “Over 75% of patients diagnosed with ovarian cancer present with advanced disease. Current treatments will cure only about a quarter of these patients.”
“The phase 2 trials show that AMG 386 combined with paclitaxel extends survival of heavily pre-treated patients by almost two thirds (4.6 to 7.2 months). In practical terms, this does not add significantly to survival time for terminal patients, but importantly indicates real potential as a first line treatment immediately following surgery.”
Professor Richardson said the treatment worked by inhibiting angiogenesis, the process by which new blood vessels grow from existing blood vessels. “By starving the cancer cells of blood supply, they will die in greater numbers. This form of therapy is complementary to current chemotherapy treatment as it uses a different mechanism to target the cancer.”
AMG 386 has already demonstrated its efficacy against ovarian cancer and its effects against prostate cancer will be very interesting.
AMG 386 is a first-in-class investigational “peptibody” (i.e., a combination of a peptide + an antibody) that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 & Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play roles in angiogenesis, and the maturation of blood vessels appears to be controlled by their precise balance.
Associate Professor of Medicine at Monash University in Australia, Gary Richardson, presented data from phase 2 clinical trials against ovarian cancer showing that AMG 386 in combination with paclitaxel not only extends survival, but is well tolerated and reduces the risk of serious complications.
“Currently the prognosis for ovarian cancer patients is poor,” Professor Richardson said. “Over 75% of patients diagnosed with ovarian cancer present with advanced disease. Current treatments will cure only about a quarter of these patients.”
“The phase 2 trials show that AMG 386 combined with paclitaxel extends survival of heavily pre-treated patients by almost two thirds (4.6 to 7.2 months). In practical terms, this does not add significantly to survival time for terminal patients, but importantly indicates real potential as a first line treatment immediately following surgery.”
Professor Richardson said the treatment worked by inhibiting angiogenesis, the process by which new blood vessels grow from existing blood vessels. “By starving the cancer cells of blood supply, they will die in greater numbers. This form of therapy is complementary to current chemotherapy treatment as it uses a different mechanism to target the cancer.”
Zytiga Receives Award From German Urologists
Zytiga has received an award from the German Society of Urologists for being the most innovative product in oncology for 2012. Zytiga beat competitors Cialis and Xgeva to be recognised as the most significant development in the treatment of prostate cancer as judged by the urologists. The "Innovative Product 2012" (Das Inovativ Produkt 2012) award was presented to Gerd Czekalla of Jannsen-Cilag who received the award on behalf of the company which is the European branch of Johnson & Johnson who manufacture Zytiga.
http://www.youtube.com/watch?v=rL40cfdiyS4
http://www.youtube.com/watch?v=rL40cfdiyS4
Tuesday 23 October 2012
Could Zytiga be Used for Colon Cancer ?
Exciting new research results are revealing a crucial role of testosterone in the development and progression of colon cancer. Colorectal cancer is on the increase in the western world and is often fatal. Surgery leads to debiltating side effects such as the use of colostomy bags and so an effective treatment for colon cancer is really needed. Zytiga effectively blocks testosterone biosynthesis and reduces plasma testosterone level to zero. Could Zytiga be therefore used to treat colon cancer by starving the colon cancer cells of testosterone ? This is an interesting proposition and is worthy of a clinical trial. Perhaps Johnson & Johnson should now investigate this intriguing possibility. A clinical trial of Zytiga against colon cancer would be really interesting scientifically.
Exclusive Interview with Prof Potter the Creator of Zytiga
Dr Hembury caught up with Professor Potter the Creator of the new prostate cancer drug Zytiga at the complimentary and alternative medicine CAM conference in London this weekend and managed to record an exclusive interview which shows amazing insights into the search for a cure for cancer that has led to the discoveries of Zytiga, Idoxifene, Stilserene and Salvestrols.
Dr Hembury: You must be absolutely delighted that Zytiga is now a blockbuster drug.
Prof Potter: Yes this is fantastic news at last I might get something out of it. I've waited 22 years for this. I'm set to receive royalties from the sales of Zytiga so it will be nice at long last to actually receive some financial reward for discovering this important anticancer agent. I knew when I first discovered Zytiga that it would one day become a blockbuster. The results were so good it couldn't fail. Extreme Potency. No toxicity. Very well tolerated so you cant go wrong. What more do you want, this is the perfect cure for Prostate Cancer. What has been frustrating is the length of time that it takes to develop a new drug. I discovered Zytiga 22 years ago almost to this day on the 1 st of November 1990 and here we are in 2012 and only in June this year was it approved for use in NHS hospital in the UK where it was discovered. It is ironic that it has taken US dollars and American Corporate backing to be sold back to the UK at an enormous premium. This could have been taken straight out of my lab in the Institute of Cancer Research within the Royal Marsden Hospital and given to the patients in the Hospital 20 years ago if we didnt live in such a crazy screwed up corporate society.
.....tbc
Dr Hembury: You must be absolutely delighted that Zytiga is now a blockbuster drug.
Prof Potter: Yes this is fantastic news at last I might get something out of it. I've waited 22 years for this. I'm set to receive royalties from the sales of Zytiga so it will be nice at long last to actually receive some financial reward for discovering this important anticancer agent. I knew when I first discovered Zytiga that it would one day become a blockbuster. The results were so good it couldn't fail. Extreme Potency. No toxicity. Very well tolerated so you cant go wrong. What more do you want, this is the perfect cure for Prostate Cancer. What has been frustrating is the length of time that it takes to develop a new drug. I discovered Zytiga 22 years ago almost to this day on the 1 st of November 1990 and here we are in 2012 and only in June this year was it approved for use in NHS hospital in the UK where it was discovered. It is ironic that it has taken US dollars and American Corporate backing to be sold back to the UK at an enormous premium. This could have been taken straight out of my lab in the Institute of Cancer Research within the Royal Marsden Hospital and given to the patients in the Hospital 20 years ago if we didnt live in such a crazy screwed up corporate society.
.....tbc
How Long Does Zytiga Work ?
The question of how long does Zytiga work comes up frequently on traffic sources for this website so I thought I would do my best to answer this.
First it is important to realise that trials showed that 80 % of patients responded to treatment with Abiraterone Acetate (Zytiga). This means that for 20 % of prostate cancer patients Zytiga simply does not work. So in reality for 20 % of patients (i.e. 1 in 5) Zytiga will not work at all.
For the majority that do respond (i.e. 4 out of 5) the reponses can vary enormously. Some men respond dramatically and feel better within a few days with PSA levels declining fast. Other men see a sharp PSA increase for a few months before the levels eventually decline. Others see a slow but steady decline in PSA levels.
20 % of patients show a very good response to Zytiga
20% show a medium response
20% show an initial rise in PSA before it declines
20% show a slow response
The duration of the response also varies from around 6 months up to 6 years. The average response duration from the Phase III clinical trials was 1 year.
i.e. the answer to the question is
On average Zytiga works for 1 year.
When used earlier in the treatment of prostate cancer before chemotherapy the trials showed that Zytiga worked for an average of 2 years.
If used before chemotherapy Zytiga works for 2 years.
The longest Zytiga survivor is 8 years from the Phase I clinical trials in 2004.
There are several 6 year survivors still taking Zytiga from the Phase II clinical trials.
There are hundreds of 4 year survivors on Zytiga from the 1000 cohort of the Phase III trials.
I hope this helps you to understand the soughts of responses that you get with Zytiga, Jez
First it is important to realise that trials showed that 80 % of patients responded to treatment with Abiraterone Acetate (Zytiga). This means that for 20 % of prostate cancer patients Zytiga simply does not work. So in reality for 20 % of patients (i.e. 1 in 5) Zytiga will not work at all.
For the majority that do respond (i.e. 4 out of 5) the reponses can vary enormously. Some men respond dramatically and feel better within a few days with PSA levels declining fast. Other men see a sharp PSA increase for a few months before the levels eventually decline. Others see a slow but steady decline in PSA levels.
20 % of patients show a very good response to Zytiga
20% show a medium response
20% show an initial rise in PSA before it declines
20% show a slow response
The duration of the response also varies from around 6 months up to 6 years. The average response duration from the Phase III clinical trials was 1 year.
i.e. the answer to the question is
On average Zytiga works for 1 year.
When used earlier in the treatment of prostate cancer before chemotherapy the trials showed that Zytiga worked for an average of 2 years.
If used before chemotherapy Zytiga works for 2 years.
The longest Zytiga survivor is 8 years from the Phase I clinical trials in 2004.
There are several 6 year survivors still taking Zytiga from the Phase II clinical trials.
There are hundreds of 4 year survivors on Zytiga from the 1000 cohort of the Phase III trials.
I hope this helps you to understand the soughts of responses that you get with Zytiga, Jez
Monday 22 October 2012
Zytiga is a Blockbuster Drug
Zytiga the new drug for prostate cancer has now reached blockbuster status surpassing the billion dollar annual sales rate. Johnson & Johnson third quarter sales of Zytiga have now broken through the $ 250 M barrier reaching $ 265 M for this last quarter of a year.
These are remarkable sales figures that have been reached in a short space of time since the drug was only FDA approved in April last year. The rapid uptake of Zytiga reflects the medical oncologists confidence in its efficacy and safety profile. The drug is very well tolerated and the responses in many cases are phenomenal.
Over half the sales were accounted for from the United States alone and European sales are set to increase yet further. Zytiga is now on the national formulary in many European countries and has been approved for prescription use on the NHS in the UK which paves the way for more widespread usage.
These are remarkable sales figures that have been reached in a short space of time since the drug was only FDA approved in April last year. The rapid uptake of Zytiga reflects the medical oncologists confidence in its efficacy and safety profile. The drug is very well tolerated and the responses in many cases are phenomenal.
Over half the sales were accounted for from the United States alone and European sales are set to increase yet further. Zytiga is now on the national formulary in many European countries and has been approved for prescription use on the NHS in the UK which paves the way for more widespread usage.
Monday 15 October 2012
Cabozantinib Effective Against Bone Mets
Cabozantinib is a VEGFR inhibitor that prevents blood supply to the tumour and combats bone metastases. Clinical trials have now shown that a low dose of 40 mg of Cabozantinib is still effective in combatting metastatic prostate cancer.
The ultimate combination of Cabozantinib with Zytiga offers a powerful approach to the treatment of metastatic prostate cancer.
Results have been released from a clinical trial of 51 patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases receiving a 40 mg daily dose of cabozantinib (XL-184). The data suggests that the 40 mg daily dose has similar clinical activity to the 100 mg daily dose previously reported from this trial. The key parameters used included measurement of reduction of metastatic bone disease and soft tissue disease, and reduction of bone-related pain and narcotic use, with apparent improvement in adverse event rates and tolerability at the lower dose.
Professor Johann de Bono, M.D., Ph.D., leader of the prostate cancer targeted therapy team at The Institute of Cancer Research, London, and honorary consultant at The Royal Marsden Hospital presented the data today in an oral presentation session on prostate cancer at the European Society for Medical Oncology (ESMO) 2012 Annual Meeting in Vienna, Austria.
"The results presented today at ESMO are consistent with interim data previously reported for the 40 mg cohort of an ongoing investigator-sponsored trial evaluating low-dose cabozantinib in men with CRPC and bone metastases," said Dr Michael Morrissey, Ph.D., president and chief executive officer of Exelixis. "The data suggest that the 40 mg daily dose has activity with respect to a number of key metrics, including bone and soft tissue responses, as well as changes in pain scores and narcotic use. Additionally, the 40 mg daily dose appears to be well-tolerated in patients with metastatic CRPC."
Initial results from ongoing efforts focused on documenting the direct impact of cabozantinib on tumor lesions in the bone of prostate cancer patients were presented, and suggest that cabozantinib's effects on bone scan may be linked to induction of tumor necrosis in bone metastases. In a patient with complete resolution of pelvic metastatic lesions on bone scan, diffusion-weighted magnetic resonance imaging (MRI) findings were consistent with tumor necrosis occurring within the bone metastases. Additional evidence for the tumor selective effect of cabozantinib on bone scans was also presented, based on an analysis of a patient with concurrent osteoarthritis. In this patient, near complete resolution of bone scan tracer uptake at sites of metastatic tumor lesions was observed, while bone scan tracer uptake was maintained at sites of osteoarthritis. To gain further insights into the effects of cabozantinib on bone lesions, there are other ongoing clinical trials using MRI, other imaging techniques, and bone-metastatic tumor biopsies.
Soft Tissue Response. Twenty-one patients had measurable soft tissue or visceral lesions at baseline and 19 patients had at least one post-baseline assessment. Evidence of tumor regression was seen in 79% of the 19 patients with at least one post-baseline assessment. Overall response by RECIST among 21 patients with at least baseline data was partial response in 10%, stable disease in 71%, and progressive disease in 10%. Soft tissue responses were independent of prior therapy.
The ultimate combination of Cabozantinib with Zytiga offers a powerful approach to the treatment of metastatic prostate cancer.
Results have been released from a clinical trial of 51 patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases receiving a 40 mg daily dose of cabozantinib (XL-184). The data suggests that the 40 mg daily dose has similar clinical activity to the 100 mg daily dose previously reported from this trial. The key parameters used included measurement of reduction of metastatic bone disease and soft tissue disease, and reduction of bone-related pain and narcotic use, with apparent improvement in adverse event rates and tolerability at the lower dose.
Professor Johann de Bono, M.D., Ph.D., leader of the prostate cancer targeted therapy team at The Institute of Cancer Research, London, and honorary consultant at The Royal Marsden Hospital presented the data today in an oral presentation session on prostate cancer at the European Society for Medical Oncology (ESMO) 2012 Annual Meeting in Vienna, Austria.
"The results presented today at ESMO are consistent with interim data previously reported for the 40 mg cohort of an ongoing investigator-sponsored trial evaluating low-dose cabozantinib in men with CRPC and bone metastases," said Dr Michael Morrissey, Ph.D., president and chief executive officer of Exelixis. "The data suggest that the 40 mg daily dose has activity with respect to a number of key metrics, including bone and soft tissue responses, as well as changes in pain scores and narcotic use. Additionally, the 40 mg daily dose appears to be well-tolerated in patients with metastatic CRPC."
Initial results from ongoing efforts focused on documenting the direct impact of cabozantinib on tumor lesions in the bone of prostate cancer patients were presented, and suggest that cabozantinib's effects on bone scan may be linked to induction of tumor necrosis in bone metastases. In a patient with complete resolution of pelvic metastatic lesions on bone scan, diffusion-weighted magnetic resonance imaging (MRI) findings were consistent with tumor necrosis occurring within the bone metastases. Additional evidence for the tumor selective effect of cabozantinib on bone scans was also presented, based on an analysis of a patient with concurrent osteoarthritis. In this patient, near complete resolution of bone scan tracer uptake at sites of metastatic tumor lesions was observed, while bone scan tracer uptake was maintained at sites of osteoarthritis. To gain further insights into the effects of cabozantinib on bone lesions, there are other ongoing clinical trials using MRI, other imaging techniques, and bone-metastatic tumor biopsies.
Soft Tissue Response. Twenty-one patients had measurable soft tissue or visceral lesions at baseline and 19 patients had at least one post-baseline assessment. Evidence of tumor regression was seen in 79% of the 19 patients with at least one post-baseline assessment. Overall response by RECIST among 21 patients with at least baseline data was partial response in 10%, stable disease in 71%, and progressive disease in 10%. Soft tissue responses were independent of prior therapy.
Saturday 13 October 2012
Tasquinimod Looks Promising in Trials
Tasquinimod is a small molecule with anti angiogenic activity that interupts blood vessel formation in tumours and cuts off their blood supply. Current Phase 2 clinical trials look promising and demonstrate that Tasquinimod has significant anticancer activity and showed antimetastatic activity. Tasquinimod is active at very low doses and a dose of 1 mg daily was the maximum used in the trials. It has dose limiting toxcity above 1 mg daily so this is the maximum that can be safely used.
Molecular structure of Tasquinimod which is a quinoline carboxamide.
Tasquinimod is an analogue of the drug Roquinimex also known as Linomide. Roquinimex has immunostimulant actvity as well as anti angiogenic activity. It also inhibits TNF alpha production. It is deactivated by metabolic 4-hydroxylation, a process that is blocked by a trifluoromethyl group in Tasquinimod.
Molecular Structure of Roquinimex
The precise mechanism of action of Tasquinimod is not known but it does have anti angiogenic activity and stops the development of new vasculature to the tumours.
Molecular structure of Tasquinimod which is a quinoline carboxamide.
Tasquinimod is an analogue of the drug Roquinimex also known as Linomide. Roquinimex has immunostimulant actvity as well as anti angiogenic activity. It also inhibits TNF alpha production. It is deactivated by metabolic 4-hydroxylation, a process that is blocked by a trifluoromethyl group in Tasquinimod.
Molecular Structure of Roquinimex
The precise mechanism of action of Tasquinimod is not known but it does have anti angiogenic activity and stops the development of new vasculature to the tumours.
Tasquinimod phase II clinical trial in men with minimally symptomatic metastatic castrate-resistant prostate cancer. A randomized, double-blind, placebo-controlled phase II trial was conducted in men assigned (at a ratio of two to one) to either oral once-daily tasquinimod (TASQ) 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, or pain criteria, excluding prostate-specific antigen. Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively, and median progression-free survival (PFS) was 7.6 versus 3.3 months. TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.
Sunday 7 October 2012
Docetaxel Therapy for Prostate Cancer
Docetaxel is a type of chemotherapy otherwise known as Taxotere. It is a derivative of Taxol (Paclitaxel) that has improved activity and is widely used in the treatment of advanced prostate cancer. Docetaxel is usually given in combination with prednisone which helps aleviate side effects.
The molecular structure of Docetaxel is shown below and it is an ester of Phenylpropanoic acid and Baccatinol. The raw material for the synthesis of Docetaxel is Baccatin which comes from the Yew tree needles.
Since Docetaxel is a form of chemotherapy it comes with all the side effects of chemotherapy such as nausea, hair loss, liver toxicity, etc so compared to Docetaxel, Zytiga has few side effects.
Zytiga represents the logical choice in patients that have relapsed on current androgen deprivation strategies since it can achieve total androgen blockade. Docetaxel should be seen as the second choice when Zytiga therapy has failed.
When both Zytiga and Docetaxel have failed then Jevtana (Cabazitaxel) can be considered which is a newer version of Docetaxel. It has been shown to have activity in post Docetaxel treated patients.
Molecular structure of the steroidal compound Abiraterone the key ingredient of Zytiga.
The molecular structure of Docetaxel is shown below and it is an ester of Phenylpropanoic acid and Baccatinol. The raw material for the synthesis of Docetaxel is Baccatin which comes from the Yew tree needles.
Zytiga represents the logical choice in patients that have relapsed on current androgen deprivation strategies since it can achieve total androgen blockade. Docetaxel should be seen as the second choice when Zytiga therapy has failed.
When both Zytiga and Docetaxel have failed then Jevtana (Cabazitaxel) can be considered which is a newer version of Docetaxel. It has been shown to have activity in post Docetaxel treated patients.
Molecular structure of the steroidal compound Abiraterone the key ingredient of Zytiga.
Tuesday 2 October 2012
Fate of Zytiga in the Human Body
What is the fate of Zytiga when it enters the human body ? How is it processed by the human enzymes ? This all depends on metabolism and the drug metabolism of Zytiga has been thoroughly investigated. This takes place as part of the overall ADME process involving Absorption, Distribution, Metabolism, and Excretion.
For Zytiga (Abiraterone Acetate) only about 5 % is absorbed by the intestine in an unfed state. This means that for a 1000 mg (4 tablet) dose only about 50 mg is being absorbed. The absorption of Zytiga greatly increases when taken with food and a single tablet dose of 250 mg taken shortly after eating results in the absorption of 60 mg of drug which is higher than the full dose taken on an empty stomach.
Absorption of Zytiga
Zytiga as Abiraterone Acetate is taken orally and enters the stomach where it is solubalised by bile acids which are released after eating a meal. The Zytiga tablets disintegrate in the stomach and the released Abiraterone Acetate passes along the small intestine where it is absorbed across the intestinal wall and enters the bloodstream.
Cleavage by Plasma Esterases
The intestinal bloodstream passes through the liver where Abiraterone Acetate escapes first pass metabolism and enters the bloodstream to the rest of the body. In the bloodstream plasma esterases cleave Abiraterone Acetate which is an ester to liberate free Abiraterone.
Binding of Abiraterone to CYP17
The free Abiraterone is then delivered by the bloodstream to the organs of the body including the prostate, the gonads, and the adrenal glands. Here Abiraterone binds tightly to the enzyme CYP17 preventing it from working. This enzyme CYP17 is responsible for making all of the androgens in the human body and so inhibiting CYP17 with Abiraterone causes all androgen production to stop and testosterone levels reduce to zero. This starves the prostate tumours of testosterone and they cease multiplying and start regressing.
Metabolism of Abiraterone by CYP3A4
CYP3A4 makes the inactive metabolite Abiraterone N-oxide. With its pyridyl nitrogen oxidised to the N-oxide Abiraterone is unable to block CYP17 and is rendered inactive.
Metabolsim of Abiraterone N-oxide by SULT2A1
The steroid sulfatase enzyme SULT2A1 puts a sulfate group onto the 3-hydroxy group of Abiraterone N-oxide to make the water soluble Abiraterone N-Oxide Sulfate which is excreted in the urine. About 4 % of Zytiga ends up in this way as the fully metabolised Abiraterone N-oxide Sulfate.
So the Zytiga that enters the human body is processed in a very precise way that allows Zytiga sufficient time to work and yet clears the drug safely from the system.
Molecular Structur of Abiraterone
For Zytiga (Abiraterone Acetate) only about 5 % is absorbed by the intestine in an unfed state. This means that for a 1000 mg (4 tablet) dose only about 50 mg is being absorbed. The absorption of Zytiga greatly increases when taken with food and a single tablet dose of 250 mg taken shortly after eating results in the absorption of 60 mg of drug which is higher than the full dose taken on an empty stomach.
Absorption of Zytiga
Zytiga as Abiraterone Acetate is taken orally and enters the stomach where it is solubalised by bile acids which are released after eating a meal. The Zytiga tablets disintegrate in the stomach and the released Abiraterone Acetate passes along the small intestine where it is absorbed across the intestinal wall and enters the bloodstream.
Cleavage by Plasma Esterases
The intestinal bloodstream passes through the liver where Abiraterone Acetate escapes first pass metabolism and enters the bloodstream to the rest of the body. In the bloodstream plasma esterases cleave Abiraterone Acetate which is an ester to liberate free Abiraterone.
Binding of Abiraterone to CYP17
The free Abiraterone is then delivered by the bloodstream to the organs of the body including the prostate, the gonads, and the adrenal glands. Here Abiraterone binds tightly to the enzyme CYP17 preventing it from working. This enzyme CYP17 is responsible for making all of the androgens in the human body and so inhibiting CYP17 with Abiraterone causes all androgen production to stop and testosterone levels reduce to zero. This starves the prostate tumours of testosterone and they cease multiplying and start regressing.
Metabolism of Abiraterone by CYP3A4
CYP3A4 makes the inactive metabolite Abiraterone N-oxide. With its pyridyl nitrogen oxidised to the N-oxide Abiraterone is unable to block CYP17 and is rendered inactive.
Metabolsim of Abiraterone N-oxide by SULT2A1
The steroid sulfatase enzyme SULT2A1 puts a sulfate group onto the 3-hydroxy group of Abiraterone N-oxide to make the water soluble Abiraterone N-Oxide Sulfate which is excreted in the urine. About 4 % of Zytiga ends up in this way as the fully metabolised Abiraterone N-oxide Sulfate.
So the Zytiga that enters the human body is processed in a very precise way that allows Zytiga sufficient time to work and yet clears the drug safely from the system.
Molecular Structur of Abiraterone
Dasatinib Zytiga Combo
Dasatinib (Sprycel) is an inhibitor of the Src tyrosine kinase. This enzyme mediates signal transduction from the growth factor receptors to the downstream MAP kinase cascade. Blocking Src stops the meassage to grow that is sent from the growth factor to the cell nucleus. So the nuclear signals to grow are blocked by a Src inhibitor and this should have synergistic effects with total androgen ablation obtained with Zytiga.
The combination of Dasatinib and Zytiga represents a logical combination in the treatment of advanced prostate cancer and is currently undergoing clinical trials to test its safety and efficacy.
Molecular Structure of Dasatinib (Sprycel)
Molecular Structure of Abiraterone (Zytiga)
This looks like a good combination of drugs and we look forward to the results of the clinical trials.
The combination of Dasatinib and Zytiga represents a logical combination in the treatment of advanced prostate cancer and is currently undergoing clinical trials to test its safety and efficacy.
Molecular Structure of Dasatinib (Sprycel)
Molecular Structure of Abiraterone (Zytiga)
Monday 1 October 2012
Sunitinib Zytiga Combo
Sunitinib (Sutent) is a combined PDGFR and VEGFR inhibitor that is undergoing clinical trials in combination with Zytiga and Prednisone. VEGFR is inolved in metastatic tumour growth and so an inhibitor of this enzyme will be useful in stopping the spread of the cancer and reducing the growth of existing metastases.
Other VEGFR inhibitors that could be combined with Zytiga are:
Cabozantinib (Exelexis) VEGFR2 & Met Kinase
Sorafenib (Nexavar) VEGFR, PDGFR, Raf Kinase
Regorafenib (Stivarga) VEGFR, PDGFR, B-Raf
Vandetanib (Caprelsa, Astra Zeneca) VEGFR, EGFR, Ret Kinase
Cediranib (Recentin, Astra Zeneca) VEGFR
Pazopanib (Votrient, GSK) VEGFR, PDGFR, c-Kit Kinase
Linifanib (Abbot) VEGFR, PDGFR
Tivozanib (AV-951) VEGFR
Dovitinib (TKI-258) VEGFR, FGFR, c-Kit
Axitinib (Inlyta, Pfizer) VEGFR
Other VEGFR inhibitors that could be combined with Zytiga are:
Cabozantinib (Exelexis) VEGFR2 & Met Kinase
Sorafenib (Nexavar) VEGFR, PDGFR, Raf Kinase
Regorafenib (Stivarga) VEGFR, PDGFR, B-Raf
Vandetanib (Caprelsa, Astra Zeneca) VEGFR, EGFR, Ret Kinase
Cediranib (Recentin, Astra Zeneca) VEGFR
Pazopanib (Votrient, GSK) VEGFR, PDGFR, c-Kit Kinase
Linifanib (Abbot) VEGFR, PDGFR
Tivozanib (AV-951) VEGFR
Dovitinib (TKI-258) VEGFR, FGFR, c-Kit
Axitinib (Inlyta, Pfizer) VEGFR
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