Improved Chemical Entities: From Bench to Bedside

At a symposium held May 16, 2002, during the ASCP Midyear Conference, two experts discussed isomer technology and other molecular modifications, which can lead to safer, more efficacious therapies. They reviewed therapeutic implications of these agents compared to more conventional therapies.

This program was supported by an unrestricted educational grant from Forest Pharmaceuticals, Inc.

Isomer Technology and Isolated Isomers

Franklin Cerasoli, Jr., PhD, Director, Office of Scientific Affairs and Medical Communications, Sepracor, Inc., Marl-borough, Massachusetts, and Clinical Assistant Professor, Texas Tech University Health Sciences Center, Dallas, Texas discussed advances in drug development related to isomers, isomer technology, and isolated isomers. “Currently there are over 550 drugs on the market that exist with two compounds in them,” he said. One compound is the active agent and the other may be either inert or detrimental.

“These two compounds are identical in every way and exist in equal proportions within the drug, except that they are nonsuperimposable mirror images of each other,” he said. The two identical compounds are the result of rotation around the chiral carbon. Atoms can be oriented in either the right-handed or left-handed direction around the chiral carbon. The atoms of R isomers are oriented in the right-handed direction and those of S isomers are in the left-handed direction.

“Although isomers are symmetric and mirror images of one another, they can have very different pharmacological properties,” said Dr. Cerasoli. For instance, each isomer, in pure solution, bends polarized light in a certain direction. (R)-albuterol, also called levalbuterol, bends light in the left-handed direction. A natural example of isomer differences are the isomers of limonene: (S)-limonene is orange and (R)-limonene is lemon. These isomers interact differently with receptors on the tongue, enabling a person to perceive different tastes. “Isomers can also have very drastically different behaviors,” added Dr. Cerasoli. For instance, the S isomer of thalidomide is a potent teratogen whereas the R isomer is an anti-emetic and a sedative.

In 1992 the FDA restricted the marketing of racemates, drugs that are composed of equal proportions of two isomers. To market racemates, pharmaceutical companies must, in essence, develop and study three drugs: the racemate, the R isomer, and the S isomer. To avoid this, pharmaceutical companies now identify the active isomer and usually market isomerically pure products.

ß2-agonist isomers
Dr. Cerasoli summarized the beta-agonist controversy that occurred in the late 1980s. Following the release of two beta agonists, isoprenaline forte in 1966 and fenoterol in 1977, the mortality rate for asthmatics who were taking these drugs increased by three- and fourfold, respectively. One theory for the mortality increase is that these drugs are racemates and one of the isomers has deleterious pharmacologic properties.

Using current technology, the albuterol isomers were separated and it was determined that (R)-albuterol, or levalbuterol, is the beta agonist. (R)-albuterol binds to the beta2-receptor with high affinity whereas (S)-albuterol cannot bind. Biological receptors are stereospecific. (S)-albuterol has aberrant pharmacological activity that is actually very similar to asthma pathophysiology. (S)-albuterol increases eosinophil activation, histamine release, mucus production, intracellular calcium, and the release of several chemical mediators and cytokines. “(S)-albuterol induces all the stuff that you don’t want to have going on in asthma,” said Dr. Cerasoli.

A clinical study was undertaken to determine the efficacy and tolerability of levalbuterol (J Allergy Clin Immunol 1998;102(6 pt 1):943-52). By measuring FEV1 over a period of several hours, it was found that 1.25 mg of (R)-albuterol improves FEV1 to a greater extent and for a longer period of time than 2.5 mg of racemic albuterol even though the same amount of active bronchodilator was in each drug (1.25 mg (R)-albuterol). “This suggests that (S)-albuterol within the racemic formulation is inhibiting the activity of (R)-albuterol,” Dr. Cerasoli said. In fact, excellent bronchodilation can be attained with just 0.63 mg (R)-albuterol, and for children the dose can be dropped down to 0.31 mg.

“If the (S)-albuterol is removed, the dose of (R)-albuterol required for effective bronchodilation can be lower,” he said. An advantage of decreasing the dose of beta agonist is the corresponding decrease in side effects. For instance, tachycardia is reduced in patients who take levalbuterol versus those who take racemic albuterol. In this study, patients who took levalbuterol three times daily for four weeks had an improvement in their resting FEV1, whereas those taking racemic albuterol showed no improvement. Dr. Cerasoli also summarized a study of asthma patients who were admitted to the emergency department because of an exacerbation of asthma. In the U.S., standard nebulized treatment is 2.5 mg to 5.0 mg of racemic albuterol every 20 minutes three times followed by 2.5 mg to 10 mg every 1 to 4 hours as needed. In general, under this treatment plan, 67% of patients are discharged and 33% are admitted.

Dr. Nowak at Henry Ford Hospital used this regimen to administer various dose levels of levalbuterol or racemic albuterol in patients undergoing acute asthma exacerbation. Racemic albuterol, at dose levels of 2.5 mg or 5.0 mg, improved FEV1 by 20% or 30% after the first dose, 10% after the second dose, 5% after the third dose, followed by no further improvement. Patients treated with 1.25 mg levalbuterol showed a 60% improvement in FEV1 after the first dose and then linear improvements thereafter. Analysis of isomer concentrations in the blood of these patients revealed a correlation between low (S)–albuterol levels and higher levels of bronchodilation.

Another example of a racemic drug is fluoxetine, which takes a long time to become effective, is effective in only about 60% of patients, and takes a long time to wash out. (R)-fluoxetine is the isomer with antidepressant activity. (S)-fluoxetine has antimigraine activity, yet racemic fluoxetine does not have this activity.

Isomeric technology has been applied to drugs in several therapeutic areas. For example, the sleep medication zopiclone is a racemic drug. (R)-zopiclone has little therapeutic benefit, however, it may reduce the effectiveness of the active (S)-zopiclone. “When you pull the (S)-zopiclone isomer out, this sleep medication may be optimized from its current racemic version,” said Dr. Cerasoli. In clinical trials, (S)-zopiclone induces sleep rapidly, lasts a full night, and allows for a refreshed awake feeling in the morning.

Active metabolites
Dr. Cerasoli turned to a discussion of active metabolites and reminded the audience that many of the drugs that are prescribed are not the active agents but must be metabolized into the active agent by the body. “The parent compound from which the active metabolite comes can be inert, have some partial activity, or be deleterious,” said Dr. Cerasoli. If the active metabolite can be identified, isolated, and tested, it may be a more efficacious and safer drug than the parent compound.

By way of example, Dr. Cerasoli focused his discussion of active metabolites on the therapeutic category of antihistamines. The first generation antihistamines, chlorpheniramine and diphenhydramine, are histamine analogs and therefore have the properties of histamine. These antihistamines are effective drugs, but they have some less desirable traits, including short duration of activity, ability to cross the blood brain barrier to induce drowsiness, and anticholinergic affects. The second generation antihistamines, such as terfenadine, astemizole and loratadine, were developed to reduce or eliminate some of these traits. These compounds were more hydrophilic so didn’t cross the blood brain barrier, had longer therapeutic actions, and were nonsedating. Unfortunately, second generation antihistamines could, in some patients, prolong the QT interval, which caused torsade de pointes and even death. For this reason terfenadine and astemizole were removed from the market.

“The next generation of antihistamines is better,” Dr. Cerasoli said. These antihistamines are active metabolites of their respective second generation parent compounds. They afford equal or superior potency, safety profiles, onset of action, and duration of activity. This generation of antihistamines includes fexofenadine (an active metabolite of terfenadine), tecastemizole (an active metabolite of astemizole), and desloratidine (an active metabolite of loratadine). The reason that parent compounds are brought to market with pharmacologies different than originally anticipated often has to do with differences between laboratory animal and human research.

The process of identifying the active metabolite is quite involved. “You have to hunt for the active metabolite in a sea of parent compounds and other metabolites,” explained Dr. Cerasoli. Next, the active metabolite has to be produced in large quantities so that testing can be carried out.

Dr. Cerasoli used astemizole as an example of this process. Astemizole has a very slow onset of action because it is slowly metabolized. One of the four astemizole metabolites, tecastemizole, accounts for only about 7% of the metabolized product. Because tecastemizole has higher affinity for the H1-receptor and is safer than the other metabolites, it was chosen for development into a branded drug. Tecastemizole has a 10-fold higher affinity than the parent compound for the H1-receptor. Because of this high affinity, a 20-fold lower dose of tecastemizole is sufficient to exceed or match the antihistaminic properties of astemizole in laboratory animals.

Clinical studies have compared tecastemizole to placebo in patients with allergic rhinitis. “If one administers the active metabolite to patients that are allergic, you see a very rapid antihistaminic response,” said Dr. Cerasoli. To address the QT interval prolongation concern, several clinical trials were performed, including one with cardiac-compromised patients. In one trial, patients received tecastemizole at 10 times the estimated therapeutic dose for two weeks. Even at very high doses for prolonged periods of time, tecastemizole did not prolong the QT interval, in this trial.

Dr. Cerasoli concluded his discussion by addressing the issue of cost effectiveness of improved chemical entities and again used levalbuterol as an example. In an outpatient setting over a 6-month period, asthma charges per patient for those prescribed albuterol remained constant, whereas the charges for those on levalbuterol decreased by about $350. Although pharmacy costs increased in the levalbuterol group, the costs of medical asthma care (emergency department admissions, hospital visits, and office visits) all declined. Patients who are severe, persistent asthmatics—those who are on two or more controller medications— actually had an increase in asthma care costs when treated with racemic albuterol, but a decline with levalbuterol.

“Improved chemical entities technology can have an important impact in terms of total healthcare costs,” concluded Dr. Cerasoli.

Isomer Technology and SSRIs

Edgar R. Gonzalez, PharmD, FASHP, FASCP, President and Chief Executive Officer, Capital Pharmacy Consultants, Mechanicsville, Virginia and Professor of Clinical Pharmacy, Nevada College of Pharmacy, Henderson, Nevada began by explaining that in terms of isomers, “R” means right and “S” means left. The “S” is for “sinister”.

Dr. Gonzalez discussed another racemic drug, citalopram, which is a serotonin reuptake inhibitor used to treat depression and obsessive-compulsive disorder. In vitro studies of rat brain synaptosomes found that the inhibitory concentration of citalopram was 3.9 nM; (S)-citalopram (escitalopram), 2.1 nM; and (R)-citalopram, 275 nM. Escitalo-pram is more potent than the racemic mixture and the (R) isomer is very weak. “One could argue that the racemic mixture suffers in a detrimental way for being part R compound,” he explained.

Dr. Gonzalez looked at the family of SSRIs and examined their abilities to be highly selective in the inhibition of norepinephrine uptake versus serotonin. Paroxetine and fluoxetine are less selective SSRIs. Although both are highly selective, escitalopram is more selective than citalopram. Whereas these data suggest that use of purified isomers would lead to a lower dose and greater efficacy, clinical relevance is not yet available. “We have seen some of the clinical relevance so far with isomeric albuterol and asthma,” Dr. Gonzalez said.

Because no drug occupies just one receptor, clinical relevance may be inferred by examining the affinity the citalopram compounds have for the histamine H1-receptor. Escitalopram has a low affinity, (R)-citalopram has a high affinity, and racemic citalopram has an intermediate affinity for the histamine H1-receptor. “If you have more selectivity then it is obviously more potent with fewer side effects, such as sedation,” he said.

“In the elderly, biopharmacy is a way of life,” Dr. Gonzalez said. The use of purified isomers may translate into lower doses, more rapid onset of action, and fewer side effects. Some of the limitations of existing SSRIs is their proclivity for drug interactions. One of the benefits of citalopram is its infrequent drug interaction profile. “We have taken something very good (citalopram) and made it even better by distilling out the active moiety and removing the unnecessary part of the mixture (in escitalopram),” said Dr. Gonzalez.

Dr. Gonzalez summarized the pooled analysis of three randomized, double-blind, placebo-controlled trials that were conducted to compare the efficacy and safety of escitalopram and citalopram in the treatment of major depressive disorder. This pooled analysis, by Gorman, measured depression using the MADRS Scale, which is commonly used in Europe and the U.S. (CNS Spectrums 2002; in press). Patients were treated for a period of 8 weeks. At week 1, greater improvement is seen in the escitalopram group than both placebo and racemate groups. The racemate catches up at weeks 2 and 4 and by week 6 shows greater improvement in depression than placebo. Escitalopram is significantly better than citalopram at week 8 also.

“By using the isomer chemistry you can refine the product and get greater efficacy,” Dr. Gonzalez said. When measuring efficacy by improvement in the CGI scale, which is commonly used in depression studies in America, escitalopram starts to outperform the racemate in study week 4. As early as week 1, there is greater improvement in the escitalopram group than the placebo group.

The efficacy of escitalopram and citalopram in treating severe depression was measured using the MADRS depression scale. Escitalopram was more effective than the racemate and placebo as early as 1 week after initiation of treatment. A greater separation of efficacy is seen by 6 weeks. “In the severely depressed patient, this rapidity of onset can have great clinical significance,” Dr. Gonzalez stated.

This rapidity of onset is very important for depressed patients. “When treating depressed patients we used to have to wait six weeks to see if there was a 60% chance that they were one of the responders,” said Dr. Gonzalez. With escitalopram, a response to therapy can be identified within 1 week and can be confirmed in 4 weeks. In terms of productivity, getting to a successful endpoint sooner and managing depression more rapidly would be cost effective. “So there is something to be gained with this racemate isomer separation,” he said.

These studies also addressed the safety of the (S)-isomer of citalopram. About half as many patients in the escitalopram group discontinued the study due to adverse events than in the citalopram group. The percent of patients in the escitalopram group who dropped out of the study because of adverse events was equivalent to that of the placebo group. “Citalopram is a highly safe and effective compound, made even safer by distilling away the unnecessary isomer,” said Dr. Gonzalez.

Dr. Gonzalez concluded his presentation by cautioning the audience to look at the dose and understand that differences in bioavailability might exist between the racemate and the isomer. The summarized studies were all “real comparisons of placebo versus effective doses of citalopram and escitalopram,” he said. In two of the studies, citalopram was flexibly dosed at 20 to 40 mg and the third used a fixed dose arm of 40 mg. Escitalopram was dosed at 10 to 20 mg. Dr. Gonzalez referred to a study of omeprazole in which the racemate was used at 10 mg and the purified isomer was used at 40 mg. “Is that a valid comparison?” he asked. The citalopram studies were valid comparisons with respect to dosage and bioavailability.

All contents Copyright © 1999 - 2002 Medical Association Communications