Month: September 2012

Fosphenytoin (fosPHT) is not a new drug. It was designed to improve the water solubility of phenytoin (PHT) thereby reducing the risk of cardiac arrhythmias and hypotension during administration (from lack of propylene glycol, although PHT is still a 1b antiarrhythmic). Improved water solubility also eliminates the risk of tissue necrosis if extravasation occurs. This allows for much more rapid infusion of fosPHT (150mg/min) as well as ability to administer IM.  Unfortunately, the drug failed to take-off as a PHT replacement because of its considerably higher acquisition cost.

That was 20 years ago. Today, the two drugs cost virtually the same amount of money. Even when cost is taken out of the equation, hesitance to leave PHT on the shelf still exists.

The main concern that has been expressed to me regarding replacing fosPHT with PHT is the time that it takes to convert fosPHT to active drug will negate its ability to be infused faster.  While this thought is completely logical, pharmacokinetic studies tell us otherwise.

When fosPHT is administered at appropriate infusion rates (150mg/min) and because fosPHT displaces PHT from plasma protein binding sites, the delay in conversion from prodrug to PHT will be compensated.

Let me explain.

In order for fosPHT to be activated, it must be cleaved by phosphatases in the blood and tissues and then spontaneously hydrolyses to PHT. The half-life of this process ranges from 7-15 minutes and conversion occurs faster with higher doses and faster infusions.  This evidence taken alone would certainly lead one to agree with the above concern.

The game-changing characteristic of fosPHT is that it competitively displaces PHT from plasma protein binding sites (albumin).  So after rapid IV administration, the fosPHT that has yet to be activated is increasing the amount of free PHT in the blood due to displacement.  Since only free (unbound) PHT can enter the CNS and exert its antiepileptic activity, free PHT levels are a better measure of pharmacologic activity. As a result, free PHT therapeutic concentrations are reached faster with fosPHT compared to PHT.

What advantage could PHT have now? I say none.

We use IV bisphosphonates in acute hypercalcemia with theunderstanding that they’ll help achieve a normal calcium level in about 72hours.  Aside from the importantcomponents of this treatment that will have more of an immediate effect (fluid,diuretics, steroids, calcitonin); which bisphosphonate is best?

Since oral bisphosphonates have extremely low bioavailablity(1-2%), IV agents like pamidronate and zoledronic acid become the two leadingcandidates.

Even though these drugs do reach their peak effect for days,we do want to administer them as soon as possible (often in the ED).  Zoledronic acid can be given over 15minutes; faster than pamidronate, which must be infused over 2 – 4 hours. 

There is only one study comparing the two agents head tohead (pamidronate 90mg, zoledronic acid 4mg, and zoledronic 8mg).  The study showed that zoledronic acid issuperior compared to pamidronate at achieving a “complete response” which wasdefined as a corrected serum calcium level less than 10.8 mg/dL by day 10 (88.4%vs 69.7%, respectively).  Although thisdifference reached statistical significance, its clinical significance as wellas the clinical significance of the mean nadir corrected calcium concentrations(zoledronic acid 9.8mg/dL; pamidronate 10.5mg/dL) is disputed. [Major P, et al. J Clin Oncol 19:558-567]

Regarding safety, both agents have similar incidences ofnephrotoxicity, flu-like symptoms after infusion (often, acetaminophen beforeinfusion can prevent this). Zoledronic does require dose adjustment for renalimpairment, and both should generally be avoided if GFR is less than 30 mL/min.

Cost… Zoledronic acid 4mg – $1100 per dose. Pamidronate90mg – $100 per dose.  I don’t usuallyget hung up on cost differences between drugs, but in this case with this evidence, andsafety profile, it’s hard to justify utilizing a drug that is 10x moreexpensive than it’s alternative. 

My recommendation (after adequate fluid, calciuresis,calcitonin, steroids):

First line:

Pamidronate 90mg IV in 1000mL NS, infuse over 4 hours

Second line:

Zoledronic acid 4mg IV in 100mL NS, infuse over 15 min

GFR 50-59 mL/min: 3.5 mg

GFR 40-49 mL/min: 3.3 mg

GFR 30-39 mL/min: 3.0 mg