Why Do Medical Professionals Low Dose PPIs In Infants

Using proton pump inhibitors for treating acid reflux disease in infants and young children is fairly simple and straightforward.  In general, it is not too different from the way that other medicines are used in infants and young children. It is supported by data that was gathered from a study done by the University of Missouri by Dr. Jeffrey Phillips (Dr. P) and Dr. Marcella Bothwell (Marci). That study was called MarciKids. Another acronym for Midwest Acid Reflux Children’s Institute. Some of you may have heard of it especially if you are a Mom or Dad of a baby with acid reflux. One study looked at the half-life of a typical PPI medicine (lansoprazole).  The half-life was much shorter in infants that were over a month of age when compared to adults. A second study looked at the dose required to control acid reflux symptoms in infants and young children and found that two doses to three doses per day was effective in those who had failed a single daily dose. The basic principle of MarciKids and the dosing regimen is, because an infant metabolizes a PPI medicine at a faster rate, the PPIs (proton pump inhibitors) need to be dosed accordingly.  It has also been shown that the Volume of Distribution (a pharmacokinetic term) is larger in infants and young children and as such the dose should be larger.

A few basic concepts:  A drug regimen (whether a PPI drug regimen or other drug regimen) consists of a dose and a dosing interval (that is how often to give it - such as two times per day or three times per day) and then how long to give the drug (e.g. weeks, months, etc.)

Low Dosing PPI's Principle #1

Use the lowest dose possible to control symptoms of acid reflux.  This is pretty straightforward because you only want to give as much drug as needed to treat the problem. Not too much and not too little. It’s important that when working with PPI medicines you should increase the DOSE and the DOSING INTERVAL gradually (waiting about 14 days before changing the dosage regimen).  The need to wait 14 days is time is needed to determine if the dosage regimen you’re using will have a desired effect (control acid reflux-related symptoms.  Some medical care practitioners (your physicians and nurses) will add a second dose of PPI and/or increase each of the doses. Then ask you to report back or to come in after 2 weeks for a visit to see how acid reflux-related symptoms are responding.  This is a normal occurrence when administering, what is considered a generally safe drug class, such as PPI’s. Sometimes there are situations where your health care provider is reluctant to increase the dosing regimen and instead may suggest that there is nothing else that can be done, they may add another type of medicine or suggest that your baby will outgrow the symptoms of reflux (although it is not known exactly when an infant may outgrow reflux symptoms – it typically happens by 1 year of age or so). Obviously, if an infant is suffering from significant symptoms of acid reflux (infant GERD), it can be hard to imagine waiting that long. There are options for your baby. You can see below the reason this might happen[1].

Low Dosing PPI's Principle #2

A reasonable dosing strategy was one that developed as a result of the MarciKids studies and observations. It is to use 0.5 to 0.65 mg per pound of bodyweight of the infant per dose AND to use two or three of these doses per day.  The reason for the range is because there is variability and it is useful to allow some flexibility in matching doses with available PPI dosage forms (for example, Prevacid® SoluTabs are available in 15 mg and can be broken in half – thus giving a 7.5mg dose).  Let’s say your physician wants to use a dose for your infant who is 14 pounds. 
So Step 1: is 0.5 mg/lb x 14 lbs = 7mg 
AND 
0.65 mg/lb x 14 lbs = 9.1 mg. 
So a reasonable dose is found at 7.5mg (because this is ½ of a SoluTab) and it falls between 7mg and 9.1mg.

Why do doctors under dose PPI’s and why do some of them use H2 blockers instead of PPIs? A word from Dr. P. (Dr. Jeffrey Phillps)

I’ve received this question a number of times. The issue with PPIs (as with most drugs) is they were developed and initially used in adults. The use of PPIs in infants began soon after Losec® (now Prilosec®, omeprazole) was released on the market. However, the dosage form was enteric-coated granules/pellets in a capsule, which can be difficult to administer to an infant. Many of the Moms I’ve worked with have commented over the years, and I have witnessed, that the little pellets ended up on the infant’s lips. The pellets are present because PPIs were developed for use in adults and they needed to be protected from stomach acid (so the PPIs were first available as capsules containing the pellets – which are enteric coated and thus protected from stomach acid). Most PPI’s are of this form and are delayed in their release until they get past the stomach (thus called delayed release). This is because the medicine has to get past the stomach acid to be absorbed into the bloodstream in the duodenum and thereby reach the site of action, which is the parietal cell (proton pumps). The proton pumps are what make stomach acid. If the PPI doesn’t get past the stomach acid the drug gets destroyed by the stomach acid and becomes ineffective.

I began work on a liquid version of omeprazole that contained sodium bicarbonate and no pellets. The sodium bicarbonate neutralized the stomach acid long enough to allow the PPI medicine to be absorbed into the bloodstream and then move to the site of action in the parietal cell. This type off PPI is termed an immediate release PPI. That formulation became Zegerid® that I invented and later was distributed on the market. Zegerid does come as a packet of pure powder (which contains no granules) in a 40mg and 20mg size and because of the lack of pellets, which make other PPI’s delayed release; Zegerid is the only immediate release PPI on the market today.

Sometime after I made my publications in the medical literature about using sodium bicarbonate, pharmacists started making up "compounded" suspensions using sodium bicarbonate. Since I was involved in treating infants with reflux with Dr. Marcella Bothwell, ENT (i.e. Marci); we measured the half-life of the PPIs (omeprazole and lansoprazole) in the bloodstream of infants where there was some difficulty in achieving control of GERD symptoms. The half-life tells you how fast a medicine is eliminated from the body (the bloodstream). So a half-life of 1.5 hours means that half of the medicine is gone from the body in 1.5 hrs. For ~20 year old and older adults the half-life for most PPIs is about 1.2 to 1.5 hrs. (it gets longer the older you get). What we found was that for infants after 4 weeks, the half-life for PPIs was ~0.4 hrs to 0.5hrs. This meant that infants were metabolizing the PPIs about 2 to 3 times faster than adults.

Here is some of that data.

At the same time, Dr. Bothwell and I had found that many infants did not respond to single daily doses and many only partially responded to twice daily doses, so we were finding that three doses per day was working in a number of infants. They were tolerating the dosage regimen well.  This was reasonable because adults typically take a PPI once a day (with some taking twice a day) and infants were metabolizing the PPI two to three times faster. Then we did a study in infants who were only partially responding to their PPI dosing regimen.  It was a three-center study to see what doses were needed to make symptoms of reflux improve significantly.

Here is that study.

Now fast forward to about 5 years ago. The pharmaceutical companies did studies with their PPIs (esomeprazole, omeprazole, pantoprazole, lansoprazole) that used a small dose of PPI once a day and compared it to placebo in infants in a prospective, randomized double-blind fashion to treat infant GERD.
The findings: PPIs were found to be no different than placebo at controlling infant acid reflux symptoms (infant GERD).

Summary
So, you might be led to think that a physician prescribing a PPI for an infant (which many still do) would look at these pharmaceutical company studies with the low dose once a day and say to themselves, "Well the small dose once a day does not work any better than a placebo, so I wonder about using a larger dose or more times a day" (in fairness some physicians and nurses have done that) - but others may not be aware that other studies and medical literature suggested that higher doses are needed for infants with GERD. Therefore, they give the low dose once a day – or they prescribe a different type of acid blocker (H2 blocker, such as Zantac®).
Zantac is proven to be less effective than PPIs and Zantac (also Pepcid®, Tagamet®, Axid®) is prone to losing efficacy after a period of treatment (this is known as tolerance, also called tachyphylaxis). As I have discussed elsewhere, “all medicines have risks but the risk of untreated acid reflux in an infant should also be considered in the risk: benefit equation."
That is a reasonable explanation as to why, when you go to your physician or nurse and comment that the dose of PPI does not seem to be working (or you may just comment that symptoms are not improving) they may be reluctant to increase the dose of PPI.

If you’d like to connect with other parents of babies that are having huge successes with MarciKids PPI treatments you can join the Infant Acid Reflux Solutions Facebook Group. You are not alone and there are answers.

Foot Note [1]: Within the past few years a number of PPI drug studies were performed in infant and in some cases young children.  These studies were performed by the pharmaceutical manufacturers of various PPI medicines.  For example, studies were done with omeprazole (Prilosec®), esomeprazole (Nexium®), pantoprazole (Protonix®) and lansoprazole (Prevacid).  The studies were generally very well done studies and interestingly they all essentially showed the same thing – namely that none of the PPIs made a difference when compared to placebo in the acid reflux symptoms that were followed.  The studies all used a single dose of the PPI and generally the doses were small.  To some this may suggest that PPIs don’t work in infants for acid reflux; however an equally reasonable explanation is that a small dose given once a day is not a sufficient amount to control symptoms.  None of the studies used dose-ranging techniques to see if once a day or twice a day or three times per day were different from each other in symptom control.
Other research has suggested that infants (over 1 month to 1 year) need higher doses of PPIs.  But this literature was not included in the discussion of dosing rationale.  Certainly, it is well known that infants over 1 month of age metabolize drugs faster than say a 40-year-old generally healthy adult. But again this was not discussed in the rationale for determining a dosage regimen in the PPI trials mentioned above.  The studies are available at the FDA’s website and discussion from a meeting held by the FDA in regard to these studies is there for you to read.  I encourage you to read the information available and discuss with your physician or nurse or pharmacist to see what makes sense for your individual situation. 

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