There are some new things going on with proton pump inhibitors (PPIs) and our job is going to be to try and talk about some of these. I get the envious job of talking about the pharmacokinetics/ pharmacodynamics of these drugs.

I think many of you know something about PPIs and their pharmacology, but I find these to be a fascinating group of drugs; this is really an interesting compound class and not just from their pharmacology, but also from their kinetics and their dynamics. The pharmacology of these drugs is fairly similar; all of these drugs are prodrugs, they're not active in the form that's administered to the patient. This prodrug has to be absorbed into the systemic circulation, find its way to the parietal cell, and get into the canalicular space, where it then is activated, and only then is it able to bind to the proton pumps and shut those pumps down, which is, of course, the purpose of these compounds.

These drugs also are a little unusual from their formulation standpoint; they are weak bases, they're rather insoluble in water ( the negative logarithm of the acid ionization constant [pKa] values are shown). And that's actually a useful thing. I never knew much about pKa when I was in school; we spent a lot of time learning about it and then I immediately forgot about it. But this actually is an important group of drugs when it comes to pKa, because you need to have these compounds exposed to acid, because of their weak bases, to protonate. And the pKa tells us what the pH range is that these compounds will protonate over, and it's the protonation that is the first step in the activation of the prodrug to the active compound.

If you take a PPI in its raw form and expose it to the acid in your stomach, it will protonate in your stomach and not be absorbed; it will be degraded in the stomach. So all of these drugs, all of the compounds that have come to market up until now, have been protected from stomach acid, either through coating of the tablet or coating of the contents within the capsules, the small beads. That is a delayed-release formulation (it's not really a sustained-release formulation) designed to get through the pylorus into the small intestine before the drug gets released. Therefore the drug can be absorbed without protonating -- you don't want these drugs to protonate until they get to the site of action, which is at the secretory canalicular space.

The other part that's interesting about these drugs is that the receptor, in this case the proton pump that they bind to, unlike many of our drug-binding receptors, comes and goes. It's a very fluctuating and active receptor and if you are having breakfast you have turned your proton pumps on, but later in the day when you're not eating, they're going to go back to sleep. So as you're going to see as we go through this, it's really important to have these drugs at the receptor when the receptor is available; having the drug available but no receptor doesn't buy you much because the drug has nothing to which it can bind. And it's stimulation of the parietal cell, by food for example, that is very important in enhancing the activity of these compounds.

Here's a stylized picture of a parietal cell, and there are a number of different receptors that turn on and off parietal cells -- histamine, gastrin, acetylcholine, and probably others. In the cytoplasm of the parietal cell are proton pumps; these pumps can migrate to the wall of the canalicular space (which are the indents shown here into the cell) and these pumps then secrete hydrogen ion into the canalicular space. Hydrogen ion then is carried out into the gastric lumen where it combines with chloride and makes hydrochloric acid, and that's really the simple function of the parietal cell. It's those pumps that are active at the wall of the canalicular space that are available to be bound by PPIs, so you have to have pumps turned on and active for the PPI to be maximally effective.

One of the things that we realized as we learned about these drugs is that simply eating is a good thing to do if you're going to take a PPI. This was a study done some years ago that looked at the effect of a meal on the pharmacodynamics of 2 of the PPIs, omeprazole and lansoprazole, with drug given fasting and before breakfast. By simply feeding the patients before you give the PPI, you enhance the response. This is in spite of the fact that for some of these drugs, particularly lansoprazole, you markedly reduce the bioavailability. Absorption is reduced, but response is better. That's an interesting phenomenon and it shows how important it is to have an active pump when the PPI is present at the canalicular space.

Omeprazole has been around since the early to mid-1980s and when this drug was first developed as the prototype of the PPIs, one of the things that was learned early on was this was a rather unstable compound. If you put it into a pH of less than 4, it degrades very quickly. On the other hand, at an alkaline pH, the drug is very stable. So there was a choice to be made, and they had 2 choices. They could either buffer the compound to try and get it through the stomach without degradation, or they could coat the compounds to prevent exposure to acid until it got out of the stomach into the small intestine where it could be absorbed. Early in the development of omeprazole, both of those opportunities were examined.

I'm just going to show a little bit of data; they are old data. It's almost not in the literature but there are some interesting things out there. This was an early study done using pentagastrin to stimulate acid secretion in the parietal cells. It was using a powdered formulation of omeprazole by itself or with sodium bicarbonate to buffer it. They used a 15-mg dose of omeprazole with the buffer and a 30-mg dose of enteric-coated granules, so these were granules that were protected from the acids. These were the 2 options that they had at the time. It was a steady-state study essentially with 5 or more doses. The response is percent inhibition of acid secretion. Following the first dose, there was about a 50% reduction in acid secretion with the buffered product and only a 20% reduction with the enteric-coated product. After 3 or 4 doses, the response for both products had increased, and at steady state, there still was an advantage to the buffered product over the enteric-coatedproduct.

So early on, it looked like either one of these approaches would work, particularly at steady state; the differences were smaller at steady state than they were early on. Well, history is history and the decision was made to simply protect the product from acid and all the formulations that came out were delayed-release coated products.

There has been of course, as we've used omeprazole and PPIs, an interest amongst practitioners to find new ways to administer these drugs. We always get questions: How do I get this drug down a nasogastric (NG) tube, for example? So there were some studies done and some things published during the 1990s that looked at alternative ways to administer PPIs, ways that they could be given to patients who would have difficulty swallowing. There were a number of extemporaneously prepared compounds used. Following the guidelines that were published by a couple of different groups, the most common thing was to use the 8.4% sodium bicarbonate for injection syringes, squeeze that out, grind up the capsules or the tablets, and make a messy suspension and put it into an NG tube. And that was done for quite some time. In 2001, a new company called Santarus, Inc. acquired the rights to omeprazole powder, thinking that this might provide a better product or formulation, and that finally came tofruition this year with a product that actually came to market.

There were a number of different formulations tried to develop a product that would be a commercially available compound. This was one of the studies using 2 different antacids, bicarbonate and calcium carbonate combined. This shows the kinetic data and the pharmacodynamic data, which is integrated gastric acidity, and the area under the curve (AUC), the area under the gastric acid curve, for omeprazole 40 mg and omeprazole 40 mg plus 30 mEq of antacid. There's a marked difference in the peak concentrations and there also was a pretty big difference in the AUCs, which was reflected by a somewhat modest effect of omeprazole alone on the gastric acidity; a much better effect on gastric acidity correlated with higher plasma concentrations. When you start to change formulations, there are a number of things that can change the absorption properties of a drug, not the least of which is the solution, which is what we're affecting here with bicarbonate. But also the size of the particlesthemselves can change the manner in which a drug is absorbed.

One of the questions that immediately comes to mind when you talk about putting a buffer in with a drug like PPIs is what effect does the buffer have on the pH, because isn't that going to do something? Of course it will. We know that bicarbonate is a pretty decent buffer and studies were designed to look at that and what they did, typically, was give the dose an hour before a meal and then start measuring pH after the meal. And if you drink some bicarbonate, it will buffer your stomach, but after about an hour, that effect is pretty well gone. So this avoids having to look at much of the effect of the bicarbonate. On the left, we have omeprazole powder by itself following the meal and the placebo control, and there's a very small effect on pH; while on the right, we have the powder plus 30 mEq of antacid suppressing acid secretion markedly compared with the control group. So not only does the bicarbonate have an effect, but after that effect is gone, you now are seeing an effectof the omeprazole, which is essentially absent in the formulation not containing the bicarbonate.

Zegerid (omeprazole powder for oral suspension) is the tradename of this new product and this was a study done with one of the prototype suspensions. It's a fairly small study, 10 subjects here being compared against Prilosec (omeprazole), but I think it's a useful picture to give you a clearer idea of what's going on with the absorption. The buffered immediate-release product is exactly that; it is an immediate-release product with a very rapid time to maximum plasma concentration (T_max) and a very high maximum plasma concentration (C_max) compared with the delayed-release product, which has to empty out of the stomach before anything happens; and depending on particle size, that's going to take a little while. Then you get a delayed increase with a fairly modest C_max. It turns out that the AUC comes out to be about the same, and one of the interests in formulating a product was to make a product that was essentially bioequivalent, atleast from the standpoint of AUC, which is the typical way that it is measured. But as you're going to see with some of the pH data, some of us are now starting to think that this increase in C_max might be a very useful feature.

How does this change or difference in pharmacokinetics translate into a change in pharmacodynamics? Here we have omeprazole in the delayed-release formulation and the immediate-release formulation and the pH effect for the 4 to 6 hour period after the first dose, so we're looking at early onset of response. And omeprazole does not have a rapid onset of response, particularly in a delayed-release formulation (in the 4- to 6-hour period, there is about a 27% reduction in mean acid concentration in the stomach); with the immediate-release product, a halving of the concentration within the first 4 to6 hours, which is a 2-fold better response with the same dose of drug, and the only difference being the formulation that is being administered.

We all made up these simplified omeprazole suspensions (SOS), which some of you may still be using. Everybody makes them up, gives them to the patient, and assumes they're going to work. There have actually been very little data to see whether they really do work, and most of the data are simply pharmacokinetic data, as Song did in this trial, which was published in the American Journal of Health-System Pharmacy some years ago. This is the AUC of the capsule or the SOS, day 1, day 7, and the T_max data. On day 1, the intact capsule is twice as bioavailable as the stuff you make in your pharmacy, and on day 7, while you've got accumulation of drug with both formulations, you still have about a 2-fold better bioavailability. I think a lot of us figured that suspension was just as good as gold, but in fact it's about half as good as gold! It doesn't quite come up to the same level of pharmacokinetic response.

Here's another study looking at both C_max and AUC, day 1 and day 5, comparing the capsule and the SOS solution made with the bicarbonate.

Once again, the peak concentration markedly increased and the AUC, particularly at steady state, markedly increased using the intact capsule compared with the simple solution that we make in pharmacies.

It's not exactly the most desirable thing in the world to have something that's got half the bioavailability, and it's probably fairly variable depending on who you are and how you make it. So it really was useful to have a formulation come along that is being prepared and designed for good release characteristics.

As I said, the idea was to try and make a formulation that was bioequivalent, and this was a study that was set up to do that; it's a crossover trial. It's a steady-state trial, using 20- and 40-mg doses of the delayed- and immediate-release compounds given an hour before breakfast, with a washout period between administrations.

These are the results of some of those data; the plasma concentrations of the immediate-release vs delayed-release product. You see the increase in C_max with AUCs being nearly identical, essentially equivalent. And the endpoint, if you will, of trying to produce a formulation that was bioequivalent was obviously being accomplished. Well, you have similar bioequivalence, but do we care?

What we're really interested in is what's going on with pH. These are the 24-hour pH data on day 7, steady state for omeprazole with the immediate- or the delayed-release formulation. It's a 24-hour clock and the drug's being given in the morning and this shows your 3 meals during the day. There's pretty good pH control with the 20 mg; the 40 mg is a little better, as we would expect. But there is a dip, as we see with most PPIs, during the early evening hours, where we do get acidification of the stomach in spite of the fact that we're taking PPIs. That's been one of the problems that will be addressed later in some of the clinical talks.

It would be nice if we could eliminate this dip and what's been done with some of the PPIs is to give a nighttime dose. When you give a bedtime dose of a PPI, the patient isn't fed and the drug does not work very well. When you give a nighttime dose of a PPI, why doesn't it work? The reason is because there's nothing to turn the pumps on. And one of the interesting things about this compound is that the presence of the bicarbonate turns the pumps on. Because you get that neutralization of the stomach acid, that produces a nice response, pumps come on, and the drug acts.

This was a study that was done looking at the 20- and 40-mg doses once a day, and then on the last day of this regimen, on day 8, they gave an AM and a bedtime dose, again given fasting. With the 40 mg and the 20 mg, again you see the drops during the early evening, but when the dose was given right before bedtime, there is no drop. So now we see omeprazole being effective at a nighttime administration, which has never been achieved before. It has never been achieved with any of the PPIs, but we have a compound, sodium bicarbonate, which is turning on the pumps, enabling the drug to bind to the receptors exactly when the drug is present, which is very key for the activity of these compounds.

Pantoprazole, a lot of people talk about this as being a great nighttime drug. It's actually no different at all than any of the other PPIs. This study was done comparing the omeprazole immediate-release formulation with pantoprazole, 40 mg of each, and we have a steady state set of data here. It was given once daily for the first 6 days, and you're looking at percent pH greater than 4 during the nighttime hours (8 hours). There is twice as good a response with the immediate-release product compared with pantoprazole, and then they did the twice-daily dosing (before dinner and at bedtime) and noticed again a nice increase in response. So if you have people who have nocturnal heartburn problems, this is an ideal formulation to be using in those patients.

So we've got a new formulation, and maybe some potential advantages and disadvantages, and I've tried to summarize those. There are a number of advantages; first of all, we get higher plasma concentrations, not the AUC, but C_max. And I think that's going to lead to some very interesting studies to see if that may not be playing a crucial role in the response for these compounds. And up until now, we've never had any way to manipulate C_max with the PPIs; it's always been a fairly low and nonadjustable quantity, but now we can do that. We've got a compound that stimulates the production of acid, turns the pumps on when the drug is present in the canalicular space, which is precisely what you need to do to make these drug maximally effective. So that's a great idea; it's the absolutely perfect physiologic response that you want for these compounds. You get a fast antacid response; let us not forget that sodium bicarbonate does have antacid properties. If apatient is having an acute episode of heartburn and you give them sodium bicarbonate, you'll cure their heartburn episode. So there may be some advantages for patients from that standpoint in producing fairly rapid symptom relief, which you simply cannot get with the other PPIs. You can put it in NG tubes; it doesn't plug them up, it doesn't have any gums or anything in there to mess up your NG tubes.

It's certainly less expensive to purchase something than it is to make this in your pharmacy, and you have a product with known stability, with known bioequivalence, and a much more elegant pharmaceutical preparation. And it can be taken without regard to meals. You can't feed people with gastroesophageal reflux disease (GERD) at night to get their PPIs to work better because then they're going to have reflux all night. In this formulation, it doesn't matter whether they eat or not; they're going to have a stimulus to their pumps without regard to meals.

There are some potential disadvantages. First of all, there's some sodium bicarbonate in the immediate release product. It's about 20 mEq. That's not a lot, but it may be important for some patients who are on a heavy sodium restriction. When mixing up those SOS suspensions, remember there is 1 mEq of sodium in every mL of that 8.4% solution, so you were often giving 20 to 50 mEq of sodium with those doses that you were extemporaneously comparing. This is actually a lower dose and you're using this once a day in most of these patients. So it's something to keep in mind. You do have to reconstitute the formulation that's currently available, and it's a little harder to store a packet than it is a tablet. For you who have storage problems, maybe that's an issue, maybe not.

In summary, I think this does represent a unique formulation. It certainly has avoided some of the problems and limitations of the delayed-release formulations. The kinetics and the pharmacodynamics are very interesting, and we now need to talk about the clinical applications of this formulation.