Pharmacology: Mechanism of Action: Rokfos belongs to the class of nitrogen-containing bisphosphonates which acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
Pharmacodynamic Effects: The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, Rokfos inhibits bone resorption without adversely affecting the formation, mineralization or mechanical properties of bone.
In addition to being a very potent inhibitor of bone resorption, Rokfos also possesses several antitumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies: In Vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment making it less conducive to tumour cell growth, antiangiogenic activity, antipain activity.
In Vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumor cells, synergistic cytostatic effect with other anticancer drugs, antiadhesion/invasion activity.
Pharmacokinetics: Single and multiple 5- and 15-min infusions of 2, 4, 8 and 16 mg Rokfos in 64 patients with bone metastases yielded the following pharmacokinetic data, which were found to be dose-independent.
After initiation of the Rokfos infusion, the plasma concentrations of Rokfos rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hrs and <1% of peak after 24 hrs, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the 2nd infusion of Rokfos on day 28.
IV administered Rokfos is eliminated via a triphasic process: Rapid biphasic disappearance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hrs, followed by a long elimination phase with a terminal elimination half-life of t½γ 146 hrs. There was no accumulation of Rokfos in plasma after multiple doses of the drug given every 28 days. Rokfos is not metabolised and is excreted unchanged via the kidney. Over the 1st 24 hrs, 39±16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue, it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04±2.5 L/hr, independent of dose, and unaffected by gender, age, race and bodyweight. Increasing the infusion time from 5-15 min caused a 30% decrease in Rokfos concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.
The interpatient variability in pharmacokinetic parameters for Rokfos was high, as seen with other biphosphonates.
No pharmacokinetic data for Rokfos are available in patients with hypercalcaemia or in patients with hepatic insufficiency. Rokfos does not inhibit human P-450 enzymes in vitro, shows no biotransformation and in animal studies <3% of the administered dose was recovered in the faeces, suggesting no relevant role of liver function in the pharmacokinetics of Rokfos.
The renal clearance of Rokfos was correlated with creatinine clearance (CrCl), renal clearance representing 75±33% of the CrCl, which showed a mean of 84±29 mL/min (range 22-143 mL/min) in the 64 cancer patients studied. Population analysis showed that for a patient with CrCl of 20 mL/min (severe renal impairment), or 50 mL/min (moderate impairment), the corresponding predicted clearance of Rokfos would be 37 or 72%, respectively of that of a patient showing CrCl of 84 mL/min. Only limited pharmacokinetic data are available in patients with severe renal insufficiency (CrCl <30 mL/min).
Rokfos shows no affinity for the cellular components of blood and plasma protein-binding is low (approximately 56%) and independent of the concentration of Rokfos.
Special Populations: Pediatric Patients: Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that Rokfos pharmacokinetics in children 3-17 years of age are similar to those in adults at a similar mg/kg dose level. Age, bodyweight, gender and CrCl appear to have no effect on Rokfos systemic exposure.
A nurse or other trained health professional will give you Rokfos. Rokfos is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for at least 15 minutes.
For hypercalcemia, Rokfos is usually given only once. If your doctor decides that you need additional doses, you will receive the medicine again after at least 7 days have passed. This treatment will continue until your body responds to the medicine.
For bone cancer and multiple myeloma, Rokfos is usually given every 3 to 4 weeks. This treatment will continue until your body responds to the medicine.
For osteoporosis, Rokfos is usually given once a year and will continue until your body responds to the medicine.
You may also receive other medicines to help keep your body from losing too much fluid.
Your doctor may also give you vitamins containing Vitamin D and calcium. Tell your doctor if you are unable to take these supplements.
Drink extra fluids so you will pass more urine while you are using Rokfos. This will keep your kidneys working well and help prevent kidney problems. However, it is very important to not drink too much liquid. Talk to your doctor about the right amount of liquids for you.
Rokfos comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.
Rokfos is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Rokfos must be given slowly, and the IV infusion can take at least 15 minutes to complete.
Rokfos is sometimes given only once per year. Follow your doctor's instructions.
Drink at least 2 glasses of water within a few hours before your injection to keep from getting dehydrated.
Your doctor may want you to take a calcium and/or vitamin D supplement while you are being treated with Rokfos. Carefully follow your doctor's instructions about the type and strength of calcium to take.
To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Your kidney function may also need to be tested. You may not need to use Rokfos for longer than 3 to 5 years if you use it for osteoporosis. Visit your doctor regularly.
Rokfos Injection is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.
The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone.
Intravenously administered Rokfos rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of Rokfos in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of Rokfos is attributable to its high binding affinity to bone mineral.
Pharmacokinetic data in patients with Paget's disease of bone are not available.
Distribution: Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Rokfos were given to 64 patients with cancer and bone metastases. The post-infusion decline of Rokfos concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end-of-infusion to less than 1% of Cmax 24 hours post infusion with population half-lives of t1/2α 0.24 hour and t1/2β 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of Rokfos was prolonged, with very low concentrations in plasma between Days 2 and 28 post infusion, and a terminal elimination half-life t1/2γ of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of Rokfos was dose proportional from 2 to 16 mg. The accumulation of Rokfos measured over three cycles was low, with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.
In vitro and ex vivo studies showed low affinity of Rokfos for the cellular components of human blood. In vitro mean Rokfos protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL.
Metabolism: Rokfos does not inhibit human P450 enzymes in vitro. Rokfos does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14C-Rokfos in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that Rokfos is not metabolized.
Excretion: In 64 patients with cancer and bone metastases on average (± SD) 39 ± 16% of the administered Rokfos dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post Day 2. The cumulative percent of drug excreted in the urine over 0 to 24 hours was independent of dose. The balance of drug not recovered in urine over 0 to 24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0 to 24 hour renal clearance of Rokfos was 3.7 ± 2 L/h.
Rokfos clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4 mg dose of Rokfos from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the Rokfos concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL vs. 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL vs. 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.
Pediatrics: Rokfos Injection is not indicated for use in children.
Geriatrics: The pharmacokinetics of Rokfos was not affected by age in patients with cancer and bone metastases whose age ranged from 38 years to 84 years.
Race: The pharmacokinetics of Rokfos was not affected by race in patients with cancer and bone metastases.
Hepatic Impairment: No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Rokfos.
Renal Impairment: The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately-impaired renal function. Compared to patients with creatinine clearance greater than 80 mL/min (N=37), patients with creatinine clearance = 50 to 80 mL/min (N=15) showed an average increase in plasma AUC of 15%, whereas patients with creatinine clearance = 30 to 50 mL/min (N=11) showed an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min. Rokfos Injection is contraindicated in patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [see,,.
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Information checked by Dr. Sachin Kumar, MD Pharmacology