A novel formulation of the prostate cancer drug abiraterone acetate – currently marketed as Zytiga – will dramatically improve the quality of life for people suffering from prostate cancer, as pre-clinical trials by the University of South Australia show the new formulation improves the drug’s effectiveness by 40 per cent.
Developed by Professor Clive Prestidge’s Nanostructure and Drug Delivery research group at UniSA’s Cancer Research Institute, the breakthrough discovery uses an oil-based oral formulation that not only enables a smaller dose of the drug to be effective, but also has the potential to dramatically reduce possible side effects, such as joint swelling and diarrhoea.
Despite Zytiga being the leading formulation to treat prostate cancer, lead researcher, Dr. Hayley Schultz says the new formulation will ultimately provide a better treatment for patients with prostate cancer.
Prostate cancer is the most commonly diagnosed cancer in men, with one in six at risk of diagnosis before the age of 85. In 2019, more than 19,500 cases of prostate cancer were diagnosed in Australia. Globally, prostate cancer cases reached 1.28 million in 2018.
“Many drugs are poorly water soluble, so when they’re ingested, they enter the gut but don’t dissolve, which means that their therapeutic effect is limited,” Dr. Schultz says.
“This is the case for Zytiga. Here, only 10 per cent of the dose is absorbed, leaving the other 90 per cent undissolved, where it simply passes through the body as waste.
“On top of this, patients taking Zytiga must fast for two hours prior to taking the drug, and another hour after taking the drug to achieve predictable absorption. And as you can imagine, this can be painstakingly inconvenient.
“Our new formulation changes this. By using oils to mimic pharmaceutical food effects, we’re able to significantly increase the drug’s solubilisation and absorption, making it more effective and a far less invasive treatment for patients.”
The new formulation uses very high levels of abiraterone acetate dissolved within a specific oil and encapsulated within porous silica microparticles to form a powder that can be made into tablets or filled into capsules.
Applied to human treatment, it could reduce the dose from 1000mg to 700mg per day, without the need for fasting.
Prof Prestidge says if the team can secure funding, clinical trials in humans could be just two years away.
“Based on our knowledge of this drug’s pharmaceutical food effect, we hypothesise its absorption in humans will be extensively improved using this technology”, Prof Prestidge says.
“Anything we can do to contribute to the development of a commercialised product to improve the lives of patients, is invaluable.
“This novel formulation is flexible enough to be adopted by thousands of different medicines; its potential to help patients of all kinds is exponential.”
Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges.
Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5–10-fold). Hence, a large dose of abiraterone acetate (1000 mg per day) is prescribed to patients who must fast for at least 1 h before and 2 h after administration.
The recent expiry of Zytiga®s’ patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product.
Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.
Before taking ZYTIGA®, tell your healthcare provider about all of your medical conditions, including if you:
- Have heart problems
- Have liver problems
- Have a history of adrenal problems
- Have a history of pituitary problems
- Are receiving any other treatment for prostate cancer
- Are pregnant or plan to become pregnant. ZYTIGA® can cause harm to your unborn baby and loss of pregnancy (miscarriage). Females who are or may become pregnant should not handle ZYTIGA® uncoated tablets or other ZYTIGA® tablets if broken, crushed, or damaged without protection, such as gloves
- Have a partner who is pregnant or may become pregnant
- Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ZYTIGA® and for 3 weeks after the last dose of ZYTIGA®
- Are breastfeeding or plan to breastfeed. It is not known if ZYTIGA® passes into your breast milk
Tell your healthcare provider about all the medicines you take or treatments you receive including prescription and over-the-counter medicines, vitamins, and herbal supplements. ZYTIGA® can interact with many other medicines.
How should I take ZYTIGA®?
- Take ZYTIGA® and prednisone exactly as your healthcare provider tells you
- Take your prescribed dose of ZYTIGA® one time a day. Your healthcare provider may change your dose if needed
- Do not change or stop taking your prescribed dose of ZYTIGA® or prednisone without talking to your healthcare provider first
- Take ZYTIGA® on an empty stomach, at least 1 hour before or at least 2 hours after a meal. Do not take ZYTIGA® with food. Taking ZYTIGA® with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects
- Swallow ZYTIGA® tablets whole. Do not crush or chew tablets
- Take ZYTIGA® tablets with water
- If you miss a dose of ZYTIGA® or prednisone, take your prescribed dose the following day. If you miss more than 1 dose, tell your healthcare provider right away
- Your healthcare provider will do blood tests to check for side effects
What are the possible side effects of ZYTIGA®?
ZYTIGA® may cause serious side effects including:
- High blood pressure (hypertension), low blood potassium levels (hypokalemia), fluid retention (edema), and irregular heartbeats can happen during treatment with ZYTIGA®. This can be life-threatening. To decrease the chance of this happening, you must take prednisone with ZYTIGA® exactly as your healthcare provider tells you. Your healthcare provider will check your blood pressure, do blood tests to check your potassium levels, and check for any signs and symptoms of fluid retention every month during treatment with ZYTIGA®
- Tell your healthcare provider if you get any of the following symptoms:
- Fast or irregular heartbeats
- Feel faint or lightheaded
- Muscle weakness
- Pain in your legs
- Swelling in your legs or feet
- Adrenal problems may happen if you stop taking prednisone, get an infection, or are under stress
- Liver problems. You may develop changes in liver function blood tests. Your healthcare provider will do blood tests to check your liver before treatment with ZYTIGA® and during treatment with ZYTIGA®. Liver failure may occur, which can lead to death. Tell your healthcare provider if you notice any of the following changes:
- Yellowing of the skin or eyes
- Darkening of the urine
- Severe nausea or vomiting
- Increased risk of bone fracture and death when ZYTIGA® and prednisone or prednisolone is used in combination with a type of radiation called radium Ra 223 dichloride. Tell your healthcare provider about any other treatments you are taking for prostate cancer
- The most common side effects of ZYTIGA® include:
- Feeling very tired
- Joint pain
- High blood pressure
- Swelling in your legs or feet
- Low blood potassium levels
- Hot flushes
- Infected nose, sinuses, or throat
- Low red blood cells (anemia)
- High blood cholesterol and triglycerides
- High blood sugar levels
- Certain other abnormal blood tests
ZYTIGA® may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility.
THESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF ZYTIGA®.
ZYTIGA® can interact with other medicines.
You should not start or stop any medicine before you talk with the healthcare provider who prescribed ZYTIGA®.
Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist when you get a new medicine.
Call your healthcare provider for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch, or call 1-800-FDA-1088 (1-800-332-1088).
More information: Hayley B. Schultz et al, Enhancement of abiraterone acetate oral bioavailability by supersaturated-silica lipid hybrids, International Journal of Pharmaceutics (2020). DOI: 10.1016/j.ijpharm.2020.119264