Thursday, September 27, 2012

The best drug you aren’t using: Fosphenytoin

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.

Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical Pharmacokinetics and Comparative Advantages in the Acute Treatment of Seizures. Clin Pharmacokinet 2003; 42(1):33-58
Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7

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