The Development of Loratadine
About the Drug:
Loratadine is a long acting second generation antihistamine that is similar in structure to cyproheptadine and azatadine. The pharmacology of loratadine is similar to other antihistamines, but unlike other H1-blockers, loratadine is shown to exhibit competitive, specific, and selective antagonism of H1 receptors.
Loratadine does not penetrate the CNS effectively and has a low affinity for CNS H1-receptors. It is also a piperidine histamine H1-receptor antagonist with anti-allergic properties and without sedative effects. Loratadine blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial smooth muscle, and gastrointestinal smooth muscle, including vasodilatation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscle.
Research and Development
It has been such a time since the discovery of histamine, more than 70 years since the studies spearheaded by Anne Marie Staub and Daniel Bovet led to the discovery of the first antihistamine and more than 60 years since the launch into the clinic of antergan in 1942, followed by diphenhydramine in 1945 and chlorpheniramine, brompheniramine, and promethazine later the same decade.
This drug mainly temporarily relieves the symptoms of hay fever (which is allergy to pollen, dust, or other substances in the air) and other allergies. Some of the common symptoms include sneezing, runny nose, and itchy eyes, nose, or throat. Loratadine is also used to treat itching and redness caused by hives or pruritus. However, loratadine does not prevent hives or other allergic skin reactions. This drug is in a class of medications called antihistamines, which works by blocking the action of histamine, a substance in the body that causes allergic symptoms.
In compound screening, a research entitled “Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine” (Kosoglou et al.,2000) will be used for this component of the development of a drug. In this research, the aim was to evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. In simpler terms, two other drugs were combined with loratadine to check or see if they would affect the drug’s target. The methods used in this research were two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies. In each study, subjects received three 10-day treatments in random sequence, separated by a 14-day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10 (Kosoglou et al.,2000).
In conclusion, Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205–428%) and DCL concentrations (73%; 62–85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70–142%) but not DCL concentrations (6% increase; 1–11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. It is also therefore concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, the effect was not accompanied by a change in the QTc interval in healthy adult volunteers.
Comparing the three most recently developed drugs, desloratadine is the most potent antihistamine followed by levocetirizine and last would be fexofenadine by the mechanism wherein, the lower the concentration, the higher the potency of the drug.
Loratadine has undergone extensive preclinical studies and clinical trials in over 6,000 patients. In the treatment of allergic rhinitis, the drug has efficacy equivalent to four other drugs namely clemastine, terfenadine, astemizole, and mequitazine. Its known duration of action is 18–24 hours making one dose of it every day practical. Loratadine is deprived of sedating or other CNS effects.
In Vitro Studies
For in vitro studies of Loratadine, a research entitled “Onset of action for loratadine tablets for the symptomatic control of seasonal allergic rhinitis in adults challenged with ragweed pollen in the Environmental Exposure Unit: a post hoc analysis of total symptom score” (Tenn, Stacey, Ng, ; Ellis, 2018) wherein previous studies reported that when loratadine was encapsulated, the onset of action for symptom relief was 180 min. However, the unmodified loratadine tablets were not evaluated at that time. This study determines the onset of action of unmodified loratadine tablets by analyzing the total symptom score for the relief of nasal and ocular seasonal allergic rhinitis (SAR) symptoms.
The methods used in this study were a Phase IV, randomized, single-center, double-blind, placebo-controlled, double-dummy, four-way crossover study was conducted in the EEU. Seventy participants were randomized sequentially into one of the four treatments during ragweed pollen exposure. Nasal and ocular symptom scores were self-reported by the participants and recorded. The original study analysis was carried out by evaluating the nasal symptom scores only. For this analysis, both nasal and ocular data from the loratadine and placebo treatment arms were analyzed. The primary endpoint for this analysis was the onset of action of loratadine as measured by the change in total symptom score (TSS) from baseline in comparison to placebo. The onset of ocular symptom relief using the total ocular symptom score (TOSS) was also reported (Tenn, Stacey, Ng, ; Ellis, 2018).
The results were that Loratadine tablets demonstrated a significant and durable improvement in both TSS (P = .005) and TOSS (P = .013) at 75 min post-treatment administration compared to placebo. This therefore concludes that loratadine tablets’ onset of action was 75 min for the relief of nasal and ocular symptoms in adults with SAR. These suggest a faster onset of action for loratadine tablets (75 min) compared to previously reported studies which were conducted with modified loratadine tablets (180 min).
In Vivo Studies