Essay: Lyrica (pregabalin)

Background/Introduction

Lyrica also known as pregabalin is an anti-epileptic drug also known as an anticonvulsant. It is also used to treat nerve pain and fibromyalgia (1). Epilepsy is a neurological disorder characterized by having recurrent seizures (2). Epilepsy can be treated with a select group of drugs; one other treatment is neurotonin (gabapentin) which is actually a precursor of Lyrica (pregabalin) (2). Nerve pain, which is typically a symptom of nerve damage, is often associated with various diseases, illnesses, and injuries such as “diabetes, shingles, and spinal cord injuries” (1). Fibromyalgia is a chronic pain disorder that is associated with many symptoms but is specifically characterized by “pain in the muscles, ligaments, and tendons” (3). Fibromyalgia is often treated with various types of therapies, but regarding pain management, medication is typically used. In addition to Lyrica, Cymbalta (duloxetine), and Savella (milnacipran) are also used; Lyrica was the first FDA approved drug to treat fibromyalgia, followed by approval of Cymbalta, and then Savella (3). Lyrica, Cymbalta, and Savella are currently the only FDA approved drugs to treat fibromyalgia. Lyrica was approved by the FDA in 2004, and then again in 2007 for the treatment of fibromyalgia (3,4). Overall, Lyrica’s main use is as an anticonvulsant, and it was this idea for a new anticonvulsant that ultimately led to its initial discovery (5, 6).

Discovery and Preparation

Lyrica (S-3-aminomethyl-5-methylhexanoic acid) is a 3-substituent GABA (-aminobutyric acid) (5,6). Lyrica’s discovery was through rational design and optimization, by Dr. Richard B. Silverman and one of his colleagues, Dr. Ryszard Andruskiewicz in 1988 (6). He wanted to find inhibitors that inhibited GABA-AT (-aminobutyric acid aminotransferase), as inhibitors of GABA-AT have anticonvulsant activity (6). GABA-AT degrades GABA and converts it to L-glutamate; and when there is an imbalance between the two, seizures result (6). The goal was to find inhibitors that were selective towards GABA-AT “(to raise GABA levels) without inhibiting L-glutamic acid decarboxylase (GAD), the PLC enzyme that converts L-glutamate to GABA” (6). He asked his colleague to come up with a series of 3-alkyl-GABA and 3-alkylglutamate analogs, it was from this, 14 3-alkyl-GABA analogs were created “(including four stereoisomers)” through the synthesis described in figure 2 (6). To determine which analogs to make they first started by adding lipophilic groups to GABA to improve inhibition potency, then they added lipophilic compounds to already known inhibitors to make up the 14 analogs (8). From there, their inhibition of GABA-AT and GAD was measured to find the best and most lipophilic inhibitor of GABA-AT (6). It was found that none of them were inhibitors of GAD, instead they activated it, which therefore increased the rate that GABA was formed and that led to their testing as possible anticonvulsant compounds with a new anticonvulsant mechanism (6,8). Of the 14 compounds, 3-isobutyl-GABA proved to be the best anticonvulsant agent (figure 3) and the (S)-(+)- isomer of this is now marketed as Lyrica (6,8,9). The R isomer was actually more potent, but S was the better anticonvulsant agent (6).

On a large-scale, Lyrica is synthesized through the mechanism as shown in figure 4. This mechanism is called the “malonate route,” this route proved to be the most cost-effective way of mass producing Lyrica and is the one that is most commonly used today (11).

Biological Activity and Lead Optimization

Pregabalin “interacts with the 2- δ subunit of calcium channels and is a substrate for the system L transporter (blood-brain-barrier crossing)” and when it comes to these two targets they have different SAR’s (summarized in figures 3 and 5) (6,9,11). In vitro, substituent size and orientation affected the interactions and affinities for the 2- δ and system L (11). When a methyl group was added – to amine, modifying the side chain at the C3 led to a drop in affinity in 2- δ and complete loss of affinity to system L proving the original isobutyl group was the “ideal” side chain at C3, and therefore it increased 2- δ affinity (11). Substitution at C2/C3 led to lowered 2- δ affinity (11). In all, it showed that in order for in vivo pharmacological activity “both 2- δ binding affinity and system L transporter activity are required” (11).

The in vivo and in vitro evaluation looked “for the ability to promote analgesic, anticonvulsant, and anxiolytic-like effects in rodents,” which is essentially their efficacy in anxiety, epilepsy, and pain (11). In vitro, compounds were assessed with their ability to “inhibit binding of [3H] gabapentin to pig brain membranes, and potency to inhibit[3H] leucine in CHO cells” (11). In vivo, compounds were measured by their ability to prevent induced seizures, “reverse shock-induced suppression of drinking in the Vogel water lick conflict assay,” and “by the ability to increase paw withdrawal latency in the carrageenan-induced thermal hyperalgesia model” in mice (11). With the correlation of in vivo and in vitro not being perfectly linear (figure 6), due to factors such as “differences in oral absorption or clearance rates” but in all, system L transporter is required to access the CNS and interaction of the drug with the 2- δ accounts for its pharmacological activity (11).

Mechanism of Action and Drug Resistance

Lyrica’s mechanism of action is the same as another GABA analog called gabapentin. While Lyrica activates GAD, its activation actually has nothing to do with its mechanism of action and its anticonvulsant activity (6). Its mechanism of action is that it “selectively binds to the 2-δ subunit of voltage-gated calcium channels” (6). When this occurs the Ca2+ going into the neuron is reduced and the release of L-glutamate is blocked. This blockage essentially has the same effect as raising GABA, which is a reduction of seizures (6). In addition to the blockage of L-glutamate, other excitatory neurotransmitters (noradrenaline and substance P) release is blocked/reduced (6,13). Any pharmacological activity is due to the binding to the 2-δ subunit, and the affinity for the L system transporter is required to cross the BBB. (11). This affinity for the L system transporter can be attributed to the fact that Lyrica acts as a mimic of L-leucine, which is what system L transports into the brain (6). Since Lyrica has the same mechanism of action as gabapentin, but it is “better” at it, is how they were able to test it by measuring the inhibition of [3H] gabapentin binding to pig brain membranes as previously mentioned (11). While Lyrica is a GABA analog, “it is inactive at all GABA receptors, and it does not have any effect on its uptake or degradation resulting in GABA levels being unchanged” (6). Although GABA levels remain unchanged it provides the same effect as if they were raised (6). While there is no real evidence for any resistance to Lyrica it does have very appealing pharmacokinetic properties (6).

Applications and Market Analysis

One of the things that makes Lyrica so appealing is its great pharmacokinetic properties (6). “In its first full year of sales in 2006, Lyrica had $1.2 billion in global sales,” these sales were primarily for its use in “epilepsy, neuropathic pain, and generalized anxiety disorder” (6). Since its 2006, sales have increased to ~$4.96 billion in 2016, up 3% from 2015, but down 4% from 2014 (figure 8) (15). Lyrica’s pharmacokinetics are “linear and highly predictable” with a half-life of ~6 hours independent of dose and frequency, with an onset of as early as 2 days (6). When dose is increased, efficacy is increased (figure 9) (6,16). Even though Lyrica has had success and has seen an increase in sales in the US; in Europe, generics became available in 2014 resulting in the decrease (15). This exclusivity will be lost in 2018 in the US, which will result in another decrease (15). Lyrica is currently competing with many drugs such as generics, gabapentin, Cymbalta, and Savella (2,3,4,15). In the future, Lyrica will be used in an extended release form (FDA approved – 2017), and it is currently being evaluated for its use in children (17,18). With these, Lyrica has potential to remain one of the best-selling drugs in the market, with generics as a threat (15,17,18). While Lyrica has had a huge impact since its discovery and approval (2004) it does not seem that its impact will remain steady as a brand name drug in the future, but overall, as a generic and brand name it seems its impact will remain strong until something better is discovered.

References

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2. Epilepsy Foundation. What is Epilepsy? https://www.epilepsy.com/learn/about-epilepsy-basics/what-epilepsy (accessed Oct 25, 2017).
3. National Fibromyalgia & Chronic Pain Association. What is Fibromyalgia? https://www.fmcpaware.org/aboutfibromyalgia.html (accessed Oct 25, 2017).
4. Drugs.com. Lyrica Approval History. https://www.drugs.com/history/lyrica.html (accessed Oct 25, 2017).
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9. Silverman, R.B.; Andruszkiewicz, R.; Nanavati, S.M.; Taylor, C.P.; Vartanian, M.G. 3-Alkyl-4-aminobutyric acids: the first class of anticonvulsant agents that activates L-glutamic acid decarboxylase. J. Med. Chem. 1991. 34(7): 2295 – 2298.
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12. Taylor, C.P.; Angelotti, T.; Fauman, E.; Pharmacology and mechanism of action of pregabalin: The calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Research. 2007. 73(2): 137 – 150.
13. Dworkin, R.H; Kirkpatrick, P. Fresh from the Pipeline: Pregabalin. Nature Reviews Drug Discovery. 2005. 4(6): 455 – 456.
14. Shim, J.H. Clinical Application of α2-δ Ligand. Hanyang Med. Rev. 2011. 31(2): 55 – 62.
15. Pfizer. Appendix A: 2016 Financial Report. https://s21.q4cdn.com/317678438/files/doc_financials/Annual/2016/2016-financial-report.pdf (accessed Nov 28, 2017).
16. Freynhagen, R.; Strojek, K.; Griesing, T.; Whalen, E.; Balkenohl, M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005. 115(3): 254 – 263.
17. Pfizer. U.S. FDA Approves Lyrica® CR (Pregabalin) Extended-Release Tablets CV. https://investors.pfizer.com/investor-news/press-release-details/2017/US-FDA-Approves-LYRICA-CR-pregabalin-Extended-Release-Tablets-CV/default.aspx (accessed Dec 5, 2017).
18. Zamani, G.; Tavasoli, A.; Zare-Shahabadi, A.; Rezaei, N.; Ahmadvand, A. Efficacy of Pregabalin in Childhood Refractory Partial Seizure. Iran. J. Pediatr. 2014. 24(1): 100 – 104.

Originally published 15.10.2019