Pharmacokinetics of calcium antagonists under development

Area of Science:

• Pharmacology
• Drug Development
• Clinical Pharmacology

Background:

• Calcium antagonist drugs are classified into Type I (verapamil-like) and Type II (nifedipine-like) classes.
• Several Type I and Type II calcium antagonists are under clinical development.
• Tiapamil is the only available Type I drug, characterized by high clearance and extensive elimination.

Purpose of the Study:

• To review the pharmacokinetic profiles of Type I and Type II calcium antagonists under clinical development.
• To compare the pharmacokinetic properties of new calcium antagonists with existing drugs.
• To evaluate the influence of disease states and drug interactions on calcium antagonist pharmacokinetics.

Main Methods:

• Review of pharmacokinetic data for developing calcium antagonists.
• Comparison of drug clearance, distribution, and elimination pathways.
• Analysis of studies in patients with hepatic and renal disease.
• Evaluation of drug-drug interactions, including effects on cardiac glycosides and cimetidine.

Main Results:

• Most Type II (dihydropyridine) drugs are pharmacokinetically similar to nifedipine, featuring high clearance and significant presystemic elimination.
• Amlodipine exhibits lower clearance, greater peripheral distribution, and reduced presystemic elimination compared to other dihydropyridines.
• Hepatic disease significantly impacts presystemic clearance of dihydropyridines, while renal failure has minimal influence.
• Tiapamil significantly impairs digoxin clearance, similar to verapamil.
• Drug interactions among dihydropyridines generally have limited clinical significance.

Conclusions:

• A large number of new calcium antagonists are expected in clinical use.
• Amlodipine is unique among the new dihydropyridines due to its distinct pharmacokinetic profile.
• While pharmacokinetic differences exist, potential pharmacodynamic variations among these drugs warrant further investigation.