Advanced Formulations of Pilo: Understanding the Old and the New

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9 min read

Drs. Gupta and Radcliffe discuss the history of pilocarpine and how to use upcoming reformulations with lower concentrations to treat presbyopia.

In this video from Interventional Mindset, Drs. Preeya K. Gupta and Nathan Radcliffe discuss advances in pilocarpine formulation and application and how ophthalmologists can use new, lower-concentration formulas to treat presbyopia.

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The evolution of the pilocarpine molecule

As pilocarpine takes on novel applications, the molecule continues to be reformulated, recycled, repurposed, and reimagined with new indications for different conditions.
Initially, pilocarpine was one of the first fixed combination medications, commonly called E2-P2 (epinephrine 2% and pilocarpine 2%), which dates back to the 1960s. This formula was refined in the 1980s as a standalone treatment (pilocarpine only) for glaucoma, normally dosed four times a day in concentrations ranging from 0.5%, 1%, 2%, 4%, and 6%.
Over time, pilocarpine fell out of favor for treating glaucoma and ocular hypertension with the advent of latanoprost joining the glaucoma medication market in the early 2000s.

How does pilocarpine work?

Pilocarpine is a muscarinic M3 receptor agonist that acts on the iris sphincter muscle and ciliary body muscle, causing pupillary constriction (miosis) coupled with improving the facility of trabecular meshwork outflow, which in turn, decreases intraocular pressure (IOP).
It’s important to note when prescribing pilocarpine that the higher the concentration, the higher the intensity of those properties (and potential amplification of adverse events) you will see. Generally, pilocarpine has a 3- to 4-hour half-life that can cover symptoms for around 6-hour intervals with a single drop.
The original formulation of pilocarpine used benzalkonium chloride (BAK), which is known to be associated with ocular surface disease. In order for pilocarpine to remain stable in the bottle, it has to rest in an acidic pH, and as patients will know, acidic pH solutions can cause significant discomfort when they hit the eye. When pilocarpine was used more commonly in yesteryear to treat glaucoma, patients reported issues such as burning/stinging and hyperemia related to the acidity of the formula.

Patient communication and selection for pilocarpine

When Dr. Radcliffe speaks with patients about starting pilocarpine, he makes sure to bring up risks, such as the dimming of vision and the induction of a myopic accommodative shift. Techniques eyecare practitioners (ECPs) can use to decrease the risk of these events include a slow on- and offset of the medication to cut down on the movement of the vitreous base, and more frequent dosing could help patients to stay in the constricted accommodative state rather than fluctuating back and forth.

The age dependency of accommodation is a significant variable when prescribing pilocarpine.

Dr. Radcliffe leans towards prescribing pilocarpine to treat glaucoma in pseudophakic patients because they won’t experience the myopic shift. Instead, these patients might have more consistent pupillary constriction allowing them to pick up a few lines of reading.
Pseudophakic patients are also less likely to experience brow aches as a side effect because they no longer have a natural lens bowing forward from accommodation, which potentially can crowd the angle.

Clarifying the risk for retinal tears or detachments from Vuity drops

Dr. Radcliffe outlined how pilocarpine has been blamed for causing retinal tears and detachments, but the connection between these two isn’t as definitively causative as it might seem. Before Vuity (AbbVie) 1.25% pilocarpine hit the market, pilocarpine and retinal detachments were primarily connected in the literature via case reports.
Dr. Radcliffe believes that the connection between pilocarpine and retinal tears or detachment correlates more with the predisposition many glaucoma patients have to these conditions. For example, pigmentary glaucoma patients treated with pilocarpine already have a higher baseline rate (7 to 15% likelihood) of retinal tears.
While there are reports of patients going on Vuity who had subsequent retinal detachments, when taken in the context of the number of reports, the prevalence still fits within the baseline likelihood of retinal detachment.
Ultimately, it makes sense that giving a patient who already has a predisposition to retinal tears a medication that causes vitreous movement could increase the risk of retinal detachment. The added tension of the iris-lens diaphragm moving forward alongside the release of the vitreous adds even more strain to an already stressed system.

At this point in time, it is unclear whether pilocarpine increases the overall likelihood that someone with a predisposition for retinal tear will have a retinal detachment or if it simply moves the timeline forward for people with a higher risk for the condition.

Communicating with patients about the risk of retinal tear or detachment

Dr. Radcliffe highlighted that deciding how and when to discuss this depends on the patient’s case presentation. Examining the patient and ensuring to check their peripheral retina along with preferentially ultra-widefield (UWF) imaging found in fundus cameras such as Optos, Spectralis, Eidon, and others is key for stratifying risk and choosing how to approach the conversation.
It’s important that ECPs mention retinal tear and detachment as a low-risk potential adverse event from using pilocarpine. The risk can be described similarly to how you would discuss the possibility of retinal detachment following cataract surgery, YAG capsulotomy, or laser peripheral iridotomy.

Comparing the formulation histories of pilocarpine and brimonidine

As mentioned earlier, when prescribing medications, a higher dose often equates to a higher risk of complications or side effects. To explore this deeper, Dr. Gupta compared the industry-wide shift to using lower concentration formulations of well-known molecules (seen with pilocarpine) to brimonidine.
Brimonidine was introduced to the market by Allergan as Alphagan with a 0.2% brimonidine concentration and now has a generic brimonidine formulation of 0.1%. More recently, Lumify (Bausch + Lomb) joined the market with a 0.025% concentration. At this concentration, brimonidine has a vasoconstrictive or “eye whitening” effect, which is interesting since, at higher doses, the most common side effect is red eye.

When Alphagan 0.2% was originally with BAK, the formula was quite acidic.

Allergan reformulated the drops to lower concentrations of 0.15% and then 0.1% with a new preservative called Purite, which is a stable oxychloro complex (SOC) to replace BAK, which could tolerate a higher pH and reduce the side effect profile.
At a higher pH, the ophthalmic formula was less charged, allowing more neutral molecules to penetrate the eye which led to higher absorption rates of brimonidine. With less of the drug residence time on the surface of the eye, there were lower rates of allergies in patients. As a result of the pH change, Alphagan P 0.1% had a slightly higher efficacy than the original Alphagan formula.

To reformulate pilocarpine to target presbyopia, similar to Alphagan P, Allergan changed the pH of the 1.25% pilocarpine concentration by combining it with pHast technology, a novel buffering solution. This innovation allows pilocarpine to be stored in an acidic environment in the bottle and then rapidly adjust to the physiologic pH of the ocular surface.

Takeaways for prescribing pilocarpine

With these new formulations, ECPs have the ability to customize pilocarpine-based treatments more closely to the needs of the patient while decreasing the likelihood of adverse events. As new pilocarpine-based medications for presbyopia roll out into the market, Dr. Radcliffe expressed that he’s excited to go back and reassess patients who didn’t have success with Vuity or pilocarpine 1.25%.
Since it’s rare to measure accommodative amplitude in presbyopic patients, it’s difficult to know their residual accommodative abilities. A patient with a thicker lens with less inherent ability to accommodate will have a poorer pharmacological response to pilocarpine than a younger patient with broader accommodative ability.
Now with lower concentrations, these pilocarpine-based medications could be a good match for patients in their late 30s or 40s experiencing latent hyperopia and those who tried Vuity but experienced unwanted side effects.

Conclusion

Treating presbyopia nonsurgically is new to many ophthalmologists and requires having a strong understanding of the pharmacokinetics of legacy molecules such as pilocarpine.
Some practitioners may feel uneasy using pilocarpine, but much of that stems from a lack of understanding of how the molecule impacts the ocular physiology and identifying which patients it works the best for.
It’s important that eyecare practitioners stay up-to-date on the most recent research on these reformulations of legacy molecules and keep in mind that formulation and pH can both greatly impact patient outcomes.
Preeya K. Gupta, MD
About Preeya K. Gupta, MD

Dr. Gupta earned her medical degree at Northwestern University’s Feinberg School of Medicine in Chicago, and graduated with Alpha Omega Alpha honors. She fulfilled her residency in ophthalmology at Duke University Eye Center in Durham, North Carolina, where she earned the K. Alexander Dastgheib Surgical Excellence Award, and then completed a fellowship in Cornea and Refractive Surgery at Minnesota Eye Consultants in Minneapolis. She served on the faculty at Duke University Eye Center in Durham, North Carolina as a Tenured Associate Professor of Ophthalmology from 2011-2021.

Dr. Gupta has authored many articles in the peer-reviewed literature and serves as an invited reviewer to journals such as Ophthalmology, American Journal of Ophthalmology, and Journal of Refractive Surgery. She has also written several book chapters about corneal disease and ophthalmic surgery, as well as served as an editor of the well-known series, Curbside Consultation in Cataract Surgery. She also holds several editorial board positions.

Dr. Gupta serves as an elected member of the American Society of Cataract and Refractive Surgery (ASCRS) Refractive Surgery clinical committee, and is also is the Past-President of the Vanguard Ophthalmology Society. She gives presentations both nationally and internationally, and has been awarded the National Millennial Eye Outstanding Female in Ophthalmology Award, American Academy of Ophthalmology (AAO) Achievement Award, and selected to the Ophthalmologist Power List.

Preeya K. Gupta, MD
Nathan Radcliffe, MD
About Nathan Radcliffe, MD

Nathan M. Radcliffe, M.D. is a highly-experienced glaucoma and cataract surgeon.

Dr. Radcliffe graduated Alpha Omega Alpha from the Temple University School of Medicine and was named transitional resident of the year at the University of Hawaii in Honolulu. He was Chief Resident at New York University for his ophthalmology residency and Chief Glaucoma Fellow at the New York Eye and Ear Infirmary.

He was the Director of the Glaucoma Services at NYU and Bellevue hospital and currently, is part of the advanced Microincisional Glaucoma Surgery Center at New York Eye and Ear Infirmary. Dr. Radcliffe is unique because he is active in both academic and private practice settings. He is a microincisional glaucoma surgery (MIGS) innovator and instructor and has given lectures all over the United States.

Dr. Radcliffe was the first surgeon in New York to offer patients the CyPass Supraciliary Microstent, the Kahook Dual Blade Goniotomy, Visco 360 and Trab 360, the G6 micropulse laser, and Allergan’s Xen subconjunctival implant.

Dr. Radcliffe has managed some of the most difficult glaucoma and cataract cases from all over the world and is truly able to offer a tailored glaucoma and cataract surgery to his patients, being able to perform all of the available glaucoma surgeries that are currently FDA approved, and knowing the procedures and the efficacy and safety data well enough to correlate the optimal procedure with the patient’s disease.

Nathan Radcliffe, MD
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