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Next-Generation Antihistamines: New Highways

FDA Roadmap for What’s Next and What’s New in Allergic Rhinitis Therapy

“The objective of clinical research is to discover knowledge that increases the understanding of human biology and that may be used to develop measures to improve health,” said Eli Meltzer, MD, clinical professor of pediatrics, University of California, San Diego; co-director, Allergy and Asthma Medical Group and Research Center, San Diego. 

Research must conform to a set of rules and regulations as well as ethical considerations. The first of these is that a project have social and/or scientific value. Secondly, projects must have appropriate design and include enough patients to reach meaningful conclusions. Additional requirements are unbiased subject selection, a favorable risk-benefit ratio, and independent review. Informed consent must be obtained such that the patient’s participation is voluntary throughout. “Without these ethical and clinical considerations, clinical research cannot be done appropriately,” said Dr. Meltzer. 

The pharmaceutical industry conducts drug development research in concert with the Food and Drug Administration (FDA), which has specific requirements and involvement. Average yearly expenditure for drug development research is currently about $6 billion worldwide, over half of which is spent in the United States. The average cost of developing one drug is $500 million. Of 5,000 compounds investigated, one makes it to market, and of those that go into the clinical phase of research, only one of five makes it to market. 

The system for evaluation of safety and efficacy of a drug is a stepwise process that has been developed over the last 50 years. The process begins with a new chemical entity (NCE). At the time of synthesis of the NCE, a patent is filed, and the drug company has 20 years to develop and market the drug. During the next or preclinical phase, pharmacology studies evaluate bioavailability, potency, dose response, efficacy, and drug interactions in vitro and in animal models. This phase takes approximately 2 years, and only one of 1,000 compounds will make it into the next phase. 

After the preclinical work is done, the pharmaceutical company submits an Investigational New Drug application that then allows a drug to be used in human trials. The first of the clinical trial phases, or Phase I, involves pharmacokinetic and pharmacodynamic studies of small numbers of healthy people; the primary objective is evaluation of safety. Typically these are open-label, single-dose studies. Thirty percent or more of drugs that reach Phase I do not pass to Phase II. 

Phase II involves studies of small numbers of patients who are generally healthy with the exception of the targeted disease. These are generally short-term, double-blind, placebo-controlled studies. Another one-third of drugs that reach this phase will be discarded. 

Phase III studies are performed in populations of up to 5,000 patients with the targeted disease. Studies are almost always placebo controlled and double blind in design, are often multicenter, and often have multiple endpoints. An additional 5% to 10% of drugs that reach Phase III are eliminated due to adverse events or insufficient efficacy.

Following Phase III, a new drug application is submitted to the FDA for review, at which time the drug is evaluated for safety and efficacy. Following approval, additional studies may be requested; these are known as Phase IV studies and may include studies of long-term safety, drug interactions, and pharmacoeconomics. Post-marketing surveillance is also required on an ongoing basis. 

There are a team of participants in this clinical drug development process. The FDA is key, as is the pharmaceutical industry and the clinical investigators. Contract research organizations or site management organizations can facilitate the process of designing and implementing the study, analyzing the data, and preparing the reports. Patients are extremely important and must be treated with respect. Institutional review boards also are important in ensuring that the study is carried out within the guidelines of good clinical practice. 
 
 

Why Choose this Road? Rationale for Next-Generation Antihistamines

“H-1 antihistamines are one of the largest classes of drugs in use in the world,” said Estelle Simons, MD, professor and head, Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. This drug class is extremely well studied, with 400-500 papers published on this subject yearly. 

First-generation antihistamines, which were introduced before the 1980’s, are modestly effective, but would probably not have been approved for use if introduced today because of their sedative and psychomotor side effects. The second-generation antihistamines terfenadine and astemizole were the first non-sedating antihistamines, but are no longer in common use in most countries due to potential cardiac effects. The second-generation drugs have less propensity to cross the blood-brain barrier than first-generation antihistamines, are thus much less likely to cause sedation, and do not cause dry mouth and urinary dysfunction.

There are currently several next-generation antihistamines approved or in development (Table 1). These drugs are either active metabolites or an enantiomer (mirror image) of a second-generation antihistamine. Levocetirizine is currently in use in Europe and the United Kingdom. Fexofenadine is in use worldwide.

“Histamine has been described as the quintessential mediator of inflammation,” said Dr. Simons. Its effects on the acute allergic response include increased vasodilation resulting in vascular permeability, extravasation resulting in edema, and increased gland secretion resulting in sneezing and itching. 

In addition, antihistamines have a role beyond the acute response in preventing up-regulation of cells and mediators involved in the delayed hypersensitivity response; these anti-inflammatory effects are not mediated directly by the H-1 blocking effects. For example, doubling of cytokine release by lung macrophages in vitro in response to histamine is down-regulated in the presence of fexofenadine. “Hundreds of papers have been published that confirm that H-1 blockers down-regulate the late-phase inflammatory response,” said Dr. Simons.

“For each new generation of antihistamines, requirements for regulatory approval are becoming more stringent,” said Dr. Simons. New antihistamines must have rapid absorption, lack of accumulation or tachyphylaxis with multiple doses, and must not interact with other drugs. Lack of special dosing requirements in any population and 24-hour duration of action are expected. These properties must be demonstrated in Phase I and Phase II studies. For example, studies presented in poster sessions at the current meeting demonstrate that concentrations of tecastemizole are not affected by renal or hepatic impairment, co-administration of erythromycin, or age, and there is no evidence of development of tachyphylaxis following months of administration. In addition, clinical onset of action was been demonstrated to be faster than that of the second-generation agent loratadine. 

Many Phase III clinical trials have compared the efficacy of antihistamines. Efficacy is frequently similar between treatment groups; a significant difference may not be clinically relevant or may be present in only some of several studies. “The important issue in comparative studies of antihistamines is the difference in side-effect profiles,” said Dr. Simons. Some patient populations, for example those with low body mass, may be particularly at risk for side effects.

A very large post-marketing study of fexofenadine, loratadine, acrivastine, and ceterizine was performed in the 1990s in the United Kingdom as part of their pharmacovigilanace system. Adverse events were reported by family physicians. The incidence of CNS or other adverse events was very low, although significantly more drowsiness was reported in patients taking acrivastine and ceterizine than loratadine and fexofenadine. “All of these antihistamines are very non-sedating compared to the first-generation antihistamines,” said Dr. Simons. This difference has also been demonstrated in controlled comparative clinical trials using sleep latency and psychomotor performance tests. 

Another important safety issue of antihistamines is cardiotoxicity. This is not a class effect. Prolongation of the QTc interval is rare, occurring in less than 200 patients worldwide. This effect of astemizole and terfenadine did not become apparent until several years after FDA approval. Risk factors include female gender, pre-existing cardiac or EKG abnormalities, use of drugs such as imidazole antifungals or macrolide antibiotics, renal disease, and concomitant use of other medications that may also prolong the QTc interval. New antihistamines must be thoroughly tested to exclude this effect prior to regulatory approval. Studies include doses up to 10 times the usual dose for up to one year with intense EKG monitoring. 

Additional next-generation antihistamines under investigation include additional active metabolites and enantiomers and combined antagonists with not just H-1 blocking but H-2 blocking and/or leukotriene modifier effects. “I think it’s not at all outside the realm of possibility that we will some time in this century have designer antihistamines that will be tailored to specific patients,” said Dr. Simons. 

Table 1 Selected Next-Generation Antihistamines and Their Relationship to Second-Generation Drugs

Next-generation antihistamine
- Fexofenadine
- Desloratadine
- Levocetirizine
- Tecastemizole

Chemical relationship to second-generation antihistamine
-Metabolite of terfenadine
-Metabolite of loratadine
-Enantiomer of cetirizine
-Metabolite of astemizole

 

How Do We Safely and Effectively Navigate the Road of Next-Generation Antihistamines?

“While the goal of treatment of allergic rhinitis with antihistamines is to control symptoms, the last thing we want to do is to impair activities of daily living with side effects,” said Lawrence DuBuske, MD, consultant in allergy, Brigham and Women’s Hospital; and clinical instructor in medicine, Harvard Medical School, Boston, Massachusetts. First-generation antihistamines can have a significant effect on cognition and motor skills, impairing driving as much as alcohol intoxication.

The newer-generation antihistamines have been developed with the goal of improving or eliminating side effects rather than improving efficacy, as first-generation antihistamines are very effective in controlling symptoms. First-generation antihistamines are nonselective, binding not only to histamine receptors but also to muscarinic, serotoninergic, dopaminergic, and alpha-adrenergic receptors. They also readily cross the blood-brain barrier, saturating 70% to 90% of H-1 receptors in the central nervous system, inducing not only sedation, but also anticholinergic effects such as constipation and urinary retention, which are particularly important in the elderly.

“Newer-generation antihistamines are highly selective for H-1 receptors and have much less penetrance of the blood-brain barrier than first-generation antihistamines,” said Dr. DuBuske. Recent studies indicate that there is approximately 5% to 15% of H-1 receptor blockade in the brain with newer-generation H-1 receptor antagonists. There are, however, some differences between these agents, with cetirizine, acrivastine, and azelastine associated with sedation twice that of placebo in clinical trials, whereas fexofenadine, loratadine and desloratadine are associated with an incidence of sedation not different from placebo. While terfenadine and astemizole were associated with high receptor selectivity and little central nervous system side effects, these drugs were limited by their rare potential cardiotoxicity and have been withdrawn from the American market. 

Oral antihistamines have little effect on nasal congestion; the second-generation agents such as fexofenadine and ceterizine may reduce congestion by approximately 5%. For this reason, antihistamines are often combined with decongestants such as pseudoephedrine. These two agents are more globally effective when used in combination than either agent alone. The stimulant effect of pseudoephedrine does not counteract the central nervous system adverse effects of antihistamines when used in combination; however, insomnia can occur in some patients using combination antihistamine/decongestant products, causing patients to eliminate the bedtime dose and decreasing the overall efficacy of the antihistamine component of these drugs. 

One way to overcome this drawback of combination antihistamine/decongestant therapy is to combine an antihistamine and decongestant in a once-daily formulation taken in the morning, such that most of the pseudoephedrine is released during the daytime. Another approach is to combine an antihistamine with a leukotriene antagonist. Studies of combination therapy with loratadine and montelukast have demonstrated greater daytime nasal and ocular symptom reduction than is achieved with either agent alone. 

Several third-generation antihistamines are now in development or in use in Europe. These agents are metabolites or isomers of second-generation agents (Table 1). There is no published literature comparing the clinical efficacy of these third-generation agents with their second-generation related compounds, although studies of histamine-blocking effect have been published, along with studies of safety and pharmacodynamics.

Terfenadine, the second-generation agent, is metabolized in part to terfenadine carboxylate, or fexofenadine, the third-generation agent. Fexofenadine has less oral bioavailability than terfenadine. The dose-response curve of fexofenadine is flat, such that increasing the dose beyond 60 mg yields little difference in efficacy. Efficacy is compromised at doses of 40 mg or less. Reduction in bioavialability of fexofenadine of greater than 40% can occur due to interference with absorption by magnesium-containing antacids or a high-fat meal (Allegra-D® Product Insert). The adverse cardiac effects of terfenadine have not been demonstrated with fexofenadine.

Desloratadine is more potent than loratadine with respect to blocking the H-1 receptor. It also has more linear pharmacology, minimal drug interactions, and no interactions with food. In addition, 9 studies of desloratadine have demonstrated clinical improvement in nasal congestion with this agent; efficacy in relieving nasal obstruction has been reported as equivalent to 120 to 240 mg of pseudoephedrine twice daily or 240 mg once daily. In addition, studies suggest that the clinical benefit in the treatment of seasonal asthma associated with allergic rhinitis may be comparable to that of montelukast. The high potency of this drug allows it to be used effectively in lower doses than are required with some of the other agents. The potency of desloratadine may afford unique efficacy for seasonal allergic rhinitis/asthma patients, especially those who have concomitant significant nasal congestion. Like loratadine, desloratadine is non-sedating, non-impairing, and does not add to the adverse effects of ethanol.

While cetirizine is a recemic mixture of active and inactive isomers, levocetirizine contains only the active form. Comparative efficacy data suggests comparable efficacy between the two agents. There is no data to suggest that the newer agent levoceterizine is safer than the older agent ceterizine with respect to sedation and psychomotor impairment.

Tecastemizole, previously known as norastemizole, is a metabolite of astemizole. “Tecastemizole has the major advantage over astemizole of having no cardiac toxicity at normal doses and not inducing weight gain in animal studies,” said Dr. Dubuske. Animal studies have demonstrated alteration of QTc intervals only at extremely high concentrations. The inhibition of wheal and flair response to histamine is comparable to or greater than with astemizole. Tecastemizole also has a higher H-1 receptor affinity than currently available antihistamines, and up to 20-fold greater potency than astemizole in vivo than the parent compound. “Preclinical studies of tecastemizole are very promising,” said Dr. DuBuske.  


 

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