FIP treatment with oral forms GS-441524

Niels C. Pedersen, Nicole Jacque,
3.10.2021
Original article: FIP treatment with oral formulations of GS-441524

Introduction

Initial field testing of GS-441524 for FIP treatment involved subcutaneous administration. This route of administration was based on previous pharmacokinetic (PK) studies performed in laboratory cats. The intravenous and subcutaneous routes of injection yielded similarly high blood levels, which were maintained at virus-inhibiting concentrations for more than 24 hours. Oral administration has been found to lead to blood levels that peak after 2 hours, but reach only about 40 % peak levels of subcutaneous and intravenous administration (Pedersen NC, unpublished data, 2018). However, dogs that have a longer intestinal tract developed for omnivores can absorb up to 85 % GS441524 orally. ^{[1, 5]}. Dogs are often used as a surrogate for humans in oral absorption studies, so oral absorption in humans is also likely to be higher than in cats. 

Chinese suppliers of GS-441524 copied the diluent, drug concentration, and subcutaneous route used in the original published field study. Mutian was the first company to offer GS441524 on an unapproved market. Mutian was also the first company to investigate and offer an oral formulation. Mutian researchers found that effective blood levels of GS-441524 could only be achieved by increasing the concentration of the drug in their oral preparations. Other companies (eg Aura, Lucky) subsequently offered their own versions of the orally administered drug GS-441524. However, as of September 2021, Mutian no longer lists GS oral preparations (in any form) on its website. Aura, Lucky and Capella are currently the most widely used oral forms of GS441524 in the United States.

Current brands of capsules / tablets are sold as nutritional supplements and their labels list several common harmless chemical compounds and medicinal herbs, with GS-441524 not being listed at all. This is probably so that manufacturers avoid customs controls. Regardless of the list of ingredients, GS-441524 is the active ingredient in all oral products. The exact concentration of GS-441524 in the various oral preparations is kept secret by the vendors, but it is clearly higher (1.5-2-fold?) Than would be required if the drug was administered subcutaneously. 

Initially, we were critical of the oral route for two reasons. First, oral forms were more wasted by what was initially a rare and expensive resource. Second, published research on oral absorption of nucleosides (GS-441524 is a nucleoside) documents a concentration limit or ceiling for oral absorption ^[2-5]. Results with nucleoside-related EIDD-1931 showed a decrease in bioavailability from 56 to 36 % with increasing oral dose ^[6]. This limitation would theoretically make it difficult to achieve the extremely high blood levels needed to treat some forms of FIP (e.g., neurological) and / or to overcome the problem of acquired drug resistance. Oral bioavailability can also be significantly reduced by certain substances in the diet, and cat owners are known to use a large number of dietary supplements, some of which could adversely affect treatment. 

More and more owners and veterinarians appear to be using GS-441524 oral therapy for some or all of their treatment. The cost of GS-441524 oral products has been steadily declining and improving over the last two years. The problem of injection site reactions together with the more effective oral preparations GS-441524 have stimulated oral treatment and more and more cats are being treated with oral drugs either partially or completely. 

Composition and labeling

Most established oral preparations are small tablets that are easier to administer than larger capsules. Newer formulations, such as Sweeper, offer a soluble film form of GS-441524 to avoid "pill" difficulties in some cats. 

The actual amount of GS-441524 in the tablet / capsule and the recommended dosage of the oral medication will vary considerably depending on the form of the FIP, the vendor and the experience of the owner and the FIP treatment groups. Therefore, the actual amount (mg) of GS-441524 in a tablet or capsule is usually not reported. Instead of the actual amount of GS-441524 in a tablet or capsule, the seller's dosage is often based on the number of tablets needed per kg of weight, e.g. 1 tablet / kg orally (P0) every (q) 24 hours (h) for cats with wet or dry FIP and without ocular or neurological impairment. The amount of GS-41524 in one such tablet administered after 24 hours corresponds to a dose of 4-6 mg / kg SC after 24 hours, but the actual amount of GS in one tablet can be doubled as in 1 ml of injectable GS to compensate for the reduced bioavailability when administered oral route. 

In addition, one supplier (Aura / Spark) has tablets labeled for q12h administration and another for q24h dosing. 1 tablet / kg after 12 hours contains half the amount of GS-441524 (probably 4-6 mg) as 1 tablet / kg after 24 hours (probably 10 mg) - the reason is that dosing after 12 hours prevents a decrease in blood concentration 24 hours ago . However, effective blood levels after a single dose of PO or SC are maintained for 24 hours or longer in both cases. At doses corresponding to 10-15 mg / kg SC q24h, a further advantage of q8h or q12h may be over q24h, as it may help to circumvent the absorption ceiling. Therefore, in cats with doses corresponding to 10-15 mg / kg SC q24h or higher, a dose division of q8h or q12h is often used.

Dosage

The recommended starting dose of GS-441524 for cats with wet or dry FIP and without neurological or ocular symptoms is 4-6 mg / kg SC q24h. The injection dose for cats with ocular disease is 8 mg / kg SC q24h and for cats with neurological disease 10 mg / kg SC q24h. If a cat is started on wet FIP and then develops eye disease, the dose is immediately increased to 8 mg / kg SC q24h and if neurological symptoms develop, it is increased to 10 mg / kg SC q24h. Failure to treat FIP at doses higher than 15 mg / kg SC q24h indicates drug resistance. Doses of PO corresponding to 4-6, 8 and 10 mg / kg SC q24h are 10, 16 and 20 mg / kg PO q24h. (Note: some oral preparations are designated as SC equivalents, but in fact contain up to twice the reported mg GS) The recommended duration of treatment is 12 weeks, with dose increases if considered necessary. However, it is known that some cats can be cured in 6 weeks with any form of GS-441524, several in 8-10 weeks and almost all in 12 weeks. Young cats with abdominal wet FIP tend to respond the fastest, cats with dry FIP slower and cats with neurological FIP the slowest. Therefore, it is a "universal" recommendation to treat any cat with FIP, regardless of form, for at least 12 weeks. The daily dose in the form of PO can be divided into q12h, which may be advantageous in higher dose treatment to avoid an absorption ceiling. SC and PO treatment can be alternated q12h to avoid large injection volumes.

Oral GS dosing is less accurate than for injections. Tablets are difficult to separate because they tend to break, so halving is often the best thing to do. If the calculated dose after use falls within the indicated doses in the tablets, it is always recommended to round up to the nearest half of the tablet. 

Serving

All oral brands have similar instructions for the administration of capsules or tablets. Half an hour of fasting before and after administration is generally recommended. A small amount of treats can encourage cats to take the tablets, and many cats consume them when they are placed on a plate wrapped in treats (e.g., Churu). 

Costs

The price of oral GS has dropped significantly over the last year. Nevertheless, the relative price of the oral GS-441524 is 20-40 % higher (depending on the supplier) than its injectable version.  

Factors affecting oral and injectable administration 

Cats currently experiencing vomiting / regurgitation and diarrhea are generally considered unsuitable candidates for oral treatment with GS-441524. Therefore, cats with severe gastrointestinal disease are often injected at least until these problems are resolved. Most people, especially in the past, have started injecting GS-441524. The injection form is cheaper and the dosage is more precisely controlled. Absorption of GS-441524 is also more reliable by the subcutaneous route than by the oral route, which is often a critical factor in the initial treatment of cats that are initially seriously ill and unstable. Whether a cat will continue to inject GS-441524 is often conditioned by the owner's ability to inject as efficiently as possible, the cat's willingness to adapt to the pain of the injection, and the occurrence of injection wounds (lesions) at the injection site. Oral medications are often a welcome relief for both the owner and the feline patient in such situations. Some substances administered orally may interfere with the absorption of GS-441524. Therefore, you should avoid the inclusion of other medications and nutritional supplements unless they are necessary for the treatment of FIP. 

Comparison of the success of treatment with injection and oral GS-441524  

Assuming that the dosage is accurately calculated and properly adjusted, the success rate of the oral drug GS-441524 currently reflects the success rate of the injectable drugs. Nevertheless, differences in responses between oral and injectable GS-441524 have been reported. A small number of cats did not respond well to oral GS-441524 as initial treatment or led to relapses during injection replacement. Alternatively, switching cats to oral GS-441524 at the equivalent dose resulted in resolution of the disease, which did not respond well to injections. It is difficult to attribute these dramatic differences in formulation response as GS-441524 administered subcutaneously or orally enters the bloodstream and eventually the tissues. This is more likely to be due to the fact that the brands of GS-441524 injectable or oral medicine used prior to such a change were not good or that there were problems with absorption or administration. Indeed, there have been many cases where switching to another oral or injectable brand immediately resulted in improved response. 

It was originally thought that only the injectable form of GS-441524 could achieve the extremely high levels of blood and cerebrospinal fluid needed to effectively treat neurological disease, especially in situations where the virus developed varying degrees of drug resistance. However, oral markers such as Aura / Lucky have been effective in many cats with neurological FIP. This also applied to some cats that did not respond to the extremely high doses of GS441524 injection. More and more cats with neurological FIP are being treated exclusively with the oral form of GS. This is due either to greater experience with oral treatment in severe cases of FIP, or probably to higher quality oral products. 

An overview of currently available oral form brands GS-441524 

Note: The GS label and content reflect information provided by suppliers and have not been independently verified. 

Mutian - This is the original and most famous brand of the oral form GS-441524. It has been sold in several different forms, including several tablets and capsules. At the beginning of 2021, Mutian switched to the form of tablets, designated as 200 mg or 50 mg "Mutian" or "Xraphconn" - these deliver an equivalent SC dose of 10, respectively. 2.5 mg GS-441524. The tablets are significantly larger (8.5 mm diameter) than tablets from other suppliers. Recently, a new capsule formulation is rarely available. As of September 2021, Mutian's website no longer offers the option of PO. For all oral forms of Mutian, the supplier states the dosage: 100 mg / kg “Mutian” for wet / dry FIP, 150 mg / kg Mutian for ocular FIP and 200 mg / kg for neurological FIP. 

Aura / Spark - Aura is a long-established brand and is sold in tablets that are given every 12 or 24 hours. They are sold in versions q12h and q24h, but there is no difference in composition (ie extended release, etc.) between the two versions. The actual amount of GS-441524 in each tablet is not reported, but the label and effective dose are as follows:

The equivalent oral dose for> 10 mg / kg daily GS injection is increased proportionately. The tablets can be combined regardless of the 12 / 24h label using an effective injection dose - for example, a 2.5 kg cat with a wet FIP could take one tablet 24h - 2 kg and one tablet 12h - 1 kg per day.

Lucky - Lucky tablets are designated 24h - 1 kg (equivalent dose 5-6 mg / kg SC) or 24h - 2 kg (equivalent dose approximately 10-12 mg / kg SC) and are said to have the same composition as comparable Aura tablets, although they have a different Face. For FIP without ocular or neurological symptoms, you should give one 1 kg tablet daily per kg cat weight or one 2 kg tablet for every 2 kg, rounded to the nearest half tablet. Multiply the number of tablets per day by 1.5 for ocular or 2 for neurological forms. 

Capella - Capella produces two tablet sizes, 1 kg (dose 5-6 mg SC equivalent) and 2 kg (dose 10-12 mg SC equivalent). For FIP without ocular or neurological symptoms, you should give one 1 kg tablet daily per kg cat weight or one 2 kg tablet for every 2 kg and round up to the nearest half tablet. Multiply the number of tablets per day by 1.5 for ocular or 2 for neurological forms. 

Kitty Care - This is another low-cost brand that now offers both injectable and oral GS-441524. Each tablet is assumed to contain the equivalent of a 6 mg SC dose of GS-441524. 

Hero 16 -It is a well-known brand, which is supplied in easy-to-apply and divisible tablets intended for administration in a dose of one tablet per 2 kg body weight, such as Capella 2 kg tablets. Each tablet probably contains 16 mg of GS-441524. 

Rainman - This brand is popular in China and seems to have a good reputation in the countries where it is used. It is sold in 1 kg and 2 kg tablets, which are believed to contain the equivalent of 5-6 mg and 10-12 mg SC GS-441524. 

Mary - Mary is sold in capsules that probably contain the equivalent of 6 mg SC GS-441524

Additional brands- Panda, Pany, Sweeper, Sweeper movie

Reference studies on GI uptake of nucleosides similar to GS-441524 and GS-441524

1. Thomas L. A precursor to remdesivir shows therapeutic potential for COVID-19. https://www.news-medical.net/news/20210209/A-precursor-to-remdesivir-showstherapeuticpotential-for-COVID-19.aspx.
2. Painter GR, Bowen RA, Bluemling GR, et al. The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 2019; 171: 104597. doi: 10.1016 / j.antiviral.2019.104597
   After oral administration EIDD-1931 is quickly absorbed as evidenced by plasma T-max-values ranging between 0.5 and 1.0 h.Exposures are high (C-ma-xvalues range between 30 and 40μM) and are dose dependent, but significantly less than dose proportional. The observation of decreasing bioavailability with increasing dose may indicate capacity limited absorption, a phenomenon that has been reported for other nucleosides (de Miranda et al., 1981). EIDD-1931, like most endogenous nucleosides and xenobiotic nucleoside analogs, is a highly polar, hydrophilic molecule (cLog P = −2.2) and therefore likely to require functional transporters to cross cell membranes. This dependence would explain the capacity limited uptake seen in the pharmacokinetic studies done using the CD-1 mice. Earlier reports also indicated that nucleoside uptake into mouse intestinal epithelial cells is primarily mediated by sodium dependent concentrative nucleoside transporters (Cass et al., 1999; Vijayalakshmi and Belt, 1988).
3. Cass, CE, Young, JD, Baldwin, SA, Cabrita, MA, Graham, KA, Griffiths, M., Jennings, LL, Mackey, JR, Ng, AM, Ritzel, MW, Vickers, MF, Yao, SY, 1999 .Nucleoside transporters of mammalian cells. Pharm. Biotechnol. 12313–12352
4. de Miranda, P., Krasny, HC, Page, DA, Elion, GB, 1981. The disposition of acyclovir indifferent species. J. Pharmacol. Exp. Ther. 219 (2), 309–315
5. Vijayalakshmi, D., Belt, JA, 1988. Sodium-dependent nucleoside transport in mouse intestinal epithelial cells. Two transport systems with differing substrate specificities. Biol. Chem. 263 (36), 19419–19423.
6. Yan VC, Khadka S, Arthur K, Ackroyd JJ, Georgiou DK, Muller FL. Pharmacokinetics of Orally Administered GS-441524 in Dogs. bioRxiv, doi: https://doi.org/10.1101/2021.02.04.429674
7. FIP Warriors CZ / SK, https://www.fipwarriors.eu/, https://www.facebook.com/groups/fipczsk