Abirapro Actions

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Actions of Abirapro in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacotherapeutic Group: Endocrine therapy, other hormone antagonists and related agents. ATC Code: L02BX03.

Pharmacology: Pharmacodynamics: Mechanism of Action: Abirapro is converted in vivo to Abirapro, an androgen biosynthesis inhibitor. Specifically, Abirapro selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals.

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies eg, treatment with luteinising hormone-releasing hormone (LHRH) agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with Abirapro decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy).

Pharmacodynamic Effects: Abirapro decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer. In a phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with Abirapro, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.

Clinical Efficacy and Safety: Efficacy was established in a randomised placebo-controlled multicentre phase 3 clinical study of patients with metastatic advanced prostate cancer (castration resistant prostate cancer) who had received prior chemotherapy containing a taxane. Enrolled patients had received prior docetaxel. Patients were not required to show disease progression on docetaxel, as toxicity from this chemotherapy may have led to discontinuation. Patients were using an LHRH agonist or were previously treated with orchiectomy (N=1195). In the active treatment arm, Abirapro was administered at a dose of 1000 mg daily in combination with low-dose prednisone or prednisolone 5 mg twice daily (N=797). Control patients received placebo and low-dose prednisone or prednisolone 5 mg twice daily (N=398).

Changes in either radiographic findings or PSA serum concentration independently do not always predict clinical benefit. Therefore, in this study, it was recommended that patients be maintained on their study treatments until there was PSA progression (confirmed 25% increase over the patient's baseline/nadir) together with protocol-defined radiographic progression and symptomatic or clinical progression. Patients with prior ketoconazole treatment for prostate cancer were excluded from this study. The primary efficacy endpoint was overall survival (OS).

The median age of enrolled patients was 69 years (range 39-95). The number of patients treated with Abirapro by racial group was Caucasian 737 (93.2%), Black 28 (3.5%), Asian 11 (1.4%) and other 14 (1.8%). Eleven percent (11%) of patients enrolled had an Eastern Cooperative Oncology Group (ECOG) performance score of 2; 70% had radiographic evidence of disease progression with or without PSA progression; 70% had received 1 prior cytotoxic chemotherapy and 30% received 2. Liver metastasis was present in 11% of patients treated with Abirapro.

In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treated with Abirapro compared with 55% (219 of 398) of patients treated with placebo, had died. A statistically significant improvement in median OS was seen in patients treated with Abirapro.

At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with Abirapro remained alive, compared with the proportion of patients treated with placebo.

Subgroup survival analyses showed a consistent survival benefit for treatment with Abirapro.

In addition to the observed improvement in OS, all secondary study endpoints favoured Abirapro and were statistically significant after adjusting for multiple testing as follows: Patients receiving Abirapro demonstrated a significantly higher total PSA response rate (defined as a ≥50% reduction from baseline), compared with patients receiving placebo, 38% versus 10%, p<0.0001.

The median time to PSA progression was 10.2 months for patients treated with Abirapro and 6.6 months for patients treated with placebo [HR=0.58; 95% CI: (0.462; 0.728), p<0.0001].

The median radiographic progression-free survival was 5.6 months for patients treated with Abirapro and 3.6 months for patients who received placebo [HR=0.673; 95% CI: (0.585; 0.776), p<0.0001].

Pain: The proportion of patients with pain palliation was statistically significantly higher in the Abirapro group than in the placebo group (44% vs 27%, p=0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst pain intensity score over the last 24 hrs without any increase in analgesic usage score observed at 2 consecutive evaluations 4 weeks apart. Only patients with a baseline pain score of ≥4 and at least 1 post-baseline pain score were analysed (N=512) for pain palliation.

A lower proportion of patients treated with Abirapro had pain progression compared to patients taking placebo at 6 (22% vs 28%), 12 (30% vs 38%) and 18 months (35% vs 46%). Pain progression was defined as an increase from baseline of ≥30% in the BPI-SF worst pain intensity score over the previous 24 hrs without a decrease in analgesic usage score observed at 2 consecutive visits, or an increase of ≥30% in analgesic usage score observed at 2 consecutive visits. The time-to-pain progression at the 25th percentile was 7.4 months in the Abirapro group, versus 4.7 months in the placebo group.

Skeletal-Related Events: A lower proportion of patients in the Abirapro group had skeletal-related events compared with the placebo group at 6 months (18% vs 28%), 12 months (30% vs 40%), and 18 months (35% vs 40%). The time to first skeletal-related event at the 25th percentile in the Abirapro group was twice that of the control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation or surgery to bone.

Pharmacokinetics: Following administration of Abirapro, the pharmacokinetics of Abirapro and Abirapro have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abirapro is rapidly converted in vivo to Abirapro, an androgen biosynthesis inhibitor.

Absorption: Following oral administration of Abirapro in the fasting state, the time to reach maximum plasma Abirapro concentration is approximately 2 hrs.

Administration of Abirapro with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of Abirapro, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking Abirapro with meals has the potential to result in highly variable exposures. Therefore, Abirapro must not be taken with food. It should be taken at least 2 hrs after eating and no food should be eaten for at least 1 hr after taking Abirapro. The tablets should be swallowed whole with water.

Distribution: The plasma protein-binding of 14C-Abirapro in human plasma is 99.8%. The apparent volume of distribution is approximately 5630 L, suggesting that Abirapro extensively distributes to peripheral tissues.

Biotransformation: Following oral administration of 14C-Abirapro as capsules, Abirapro is hydrolysed to Abirapro, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of Abirapro. Of 15 detectable metabolites, 2 main metabolites, Abirapro sulphate and N-oxide Abirapro sulphate, each represents approximately 43% of total radioactivity.

Elimination: The mean half-life (t½) of Abirapro in plasma is approximately 15 hrs based on data from healthy subjects. Following oral administration of 14C-Abirapro 1000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged Abirapro and Abirapro (approximately 55% and 22% of the administered dose, respectively).

Patients with Hepatic Impairment: The pharmacokinetics of Abirapro was examined in subjects with preexisting mild or moderate hepatic impairment (Child-Pugh class A and B, respectively) and in healthy control subjects. Systemic exposure to Abirapro after a single oral 1000-mg dose increased by approximately 11% and 260% in subjects with mild and moderate preexisting hepatic impairment, respectively. The mean t½ of Abirapro is prolonged to approximately 18 hrs in subjects with mild hepatic impairment and to approximately 19 hrs in subjects with moderate hepatic impairment. No dose adjustment is necessary for patients with preexisting mild hepatic impairment. Abirapro should not be used in patients with preexisting moderate or severe hepatic impairment.

For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required.

Patients with Renal Impairment: The pharmacokinetics of Abirapro was compared in patients with end-stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to Abirapro after a single oral 1000-mg dose did not increase in subjects with end-stage renal disease on dialysis. Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction. However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.

Toxicology: Preclinical Safety Data: Developmental or reproductive toxicology studies were not conducted with Abirapro; however, in all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of Abirapro. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period. Abirapro is contraindicated in pregnancy.

Aside from reproductive organ changes seen in all animal toxicology studies, nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity. Carcinogenicity studies were not conducted.

How should I take Abirapro?

Take Abirapro only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

Abirapro comes with a patient information leaflet. Read the information carefully and make sure you understand it before taking Abirapro. If you have any questions, ask your doctor.

Swallow the tablets whole with water. Do not break, crush, or chew it.

It is best to take Abirapro on an empty stomach. Do not eat 2 hours before or 1 hour after taking Abirapro.

Dosing

The dose of Abirapro will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Abirapro. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Missed Dose

If you miss a dose of Abirapro, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you missed a dose of Abirapro, take your normal dose on the following day. If more than one daily dose is missed, call your doctor.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Abirapro administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Follow all directions on your prescription label. Abirapro is usually taken once per day while also taking prednisone two times per day. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your prednisone dosage needs may change if you have surgery, are ill, or are under stress. Do not change your medication dose or schedule without your doctor's advice.

Take this medicine with a full glass of water. Swallow the Abirapro tablet whole.

Take Abirapro on an empty stomach. Do not eat anything for at least 2 hours before you take Abirapro and for at least 1 hour after you have taken the medicine.

Your blood pressure will need to be checked often, and you may need frequent blood tests at your doctor's office.

You should not stop using Abirapro or prednisone suddenly. Follow your doctor's instructions about tapering your prednisone dose.

Store at room temperature away from moisture and heat.

Abirapro pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.

Mechanism of Action

Abirapro is converted in vivo to Abirapro, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17, 20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by Abirapro can also result in increased mineralocorticoid production by the adrenals.

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.

Abirapro decreased serum testosterone and other androgens in patients in the placebo-controlled phase 3 clinical trial. It is not necessary to monitor the effect of Abirapro on serum testosterone levels.

Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.

Pharmacodynamics

In a clinical study in patients with metastatic CRPC who were treated with Abirapro 500 mg once daily and methylprednisolone 4 mg twice daily for 84 days, the average serum testosterone level ± standard deviation (SD) on days 9 and 10 of treatment was 0.33 ± 0.09 ng/dL.

Pharmacokinetics

Following administration of Abirapro, the pharmacokinetics of Abirapro and Abirapro have been studied in healthy volunteers and in patients with metastatic CRPC. In vivo, Abirapro is converted to Abirapro. In clinical studies of other Abirapro formulations, Abirapro plasma concentrations were below detectable levels (< 0.2 ng/mL) in > 99% of the analyzed samples.

Geometric mean ±SD Abirapro Cmax was 73 ± 44 ng/mL and AUCINF was 373 ± 249 ng·hr/mL following a single dose of Abirapro 500 mg in overnight fasted healthy volunteers. Dose proportionality was observed in single doses of Abirapro in a range of 125 mg to 625 mg.

Absorption

Following oral administration of Abirapro to healthy volunteers and patients with metastatic CRPC, the mean time to reach maximum plasma Abirapro concentrations is approximately 2 hours.

Effect of Food

Abirapro Cmax was approximately 6.5-fold higher and AUCINF was 4.4-fold higher when a single dose of Abirapro 500 mg was administered with a high-fat meal (56-60% fat, 900-1,000 calories) compared to overnight fasting in healthy volunteers.

Other formulations of Abirapro may differ in their food effects and dose. This may impact the ability to take other Abirapro formulations with food. Abirapro can be taken with or without food.

Distribution and Protein Binding

Abirapro is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, Abirapro and Abirapro are not substrates of P-glycoprotein (P-gp) and that Abirapro is an inhibitor of P-gp.

Metabolism

Following oral administration of 14C-Abirapro as capsules, Abirapro is hydrolyzed to Abirapro (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of Abirapro in human plasma are Abirapro sulphate (inactive) and N-oxide Abirapro sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide Abirapro sulphate and SULT2A1 is involved in the formation of Abirapro sulphate.

Excretion

In patients with metastatic CRPC, the mean terminal half-life of Abirapro in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-Abirapro, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged Abirapro and Abirapro (approximately 55% and 22% of the administered dose, respectively).

Patients with Hepatic Impairment

The pharmacokinetics of Abirapro was examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to Abirapro after a single oral 1,000 mg dose of another Abirapro product given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of Abirapro is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.

In another trial, the pharmacokinetics of Abirapro were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of Abirapro increased by approximately 7-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment.

Patients with Renal Impairment

The pharmacokinetics of Abirapro were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg dose of another Abirapro product was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to Abirapro after a single oral 1,000 mg dose of another Abirapro product did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function.

Drug Interactions

In vitro studies with human hepatic microsomes showed that Abirapro has the potential to inhibit CYP1A2, CYP2D6 and CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5.

In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with 1,000 mg daily of another Abirapro product (plus a different corticosteroid twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.

In a clinical study to determine the effects of 1,000 mg daily of another Abirapro product (plus a different corticosteroid twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.

Abirapro is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction study of healthy subjects, pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of 1,000 mg of another Abirapro product, the mean plasma AUCINF of Abirapro was decreased by 55%.

In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of Abirapro.

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg of another Abirapro product.

In vitro, Abirapro and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.

QT Prolongation

In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received a dose of 1,000 mg once daily orally of another Abirapro product at least 1 hour before or 2 hours after a meal in combination with a different corticosteroid orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to Abirapro cannot be excluded due to study design limitations.


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References

  1. NCIt. "Abiraterone: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).

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