Population analyses of sustained-release verapamil in patients: effects of sex, race, and smoking.
OBJECTIVE
Our objective was to determine the effects of age, sex, and sustained-release formulation on apparent oral clearance of sustained-release racemic verapamil in patient populations.


METHODS
Population pharmacokinetic analyses were performed on data from 186 patients with hypertension, coronary artery disease, or supraventricular arrhythmias who were receiving long-term sustained-release oral racemic verapamil (Covera SR in 105 patients, Calan SR in 67 patients, and other formulations in 14 patients; mean +/- SD dose, 280 +/- 139 mg) for clinical care or as a part of phase III efficacy studies. Of those 186 patients, 135 were men (age, 63 +/- 12 years; ideal body weight, 70.7 +/- 6.6 kg) and 51 were women (age, 60 +/- 17 years; ideal body weight, 53.7 +/- 7.2 kg). Verapamil was measured by HPLC, and population analyses were performed by use of NONMEM software. Sex, age, and formulation were the covariates considered in the population model building. Subgroup analyses of race, smoking, and alcohol consumption were also performed. Significance of covariates was determined by likelihood ratio tests.


RESULTS
Sex significantly affected steady-state clearance of oral sustained-release racemic verapamil. Apparent oral clearance of sustained-release verapamil was 23.8 +/- 2.3 mL/min per kilogram in women compared with 18.6 +/- 3.4 mL/min per kilogram in men. Clearance estimates were faster in black subjects compared with white subjects, as well as in smokers compared with nonsmokers. Effects of age, formulation, and alcohol consumption were not detected.


CONCLUSIONS
In middle-aged and older patients, apparent oral clearance of sustained-release racemic verapamil was affected by sex (faster in women compared with men), race (faster in black subjects compared with white subjects), and smoking (faster in smokers compared with nonsmokers) but not by age, alcohol, or formulation.
Kang
Dongwoo
D
Division of Clinical Pharmacology, Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, USA.
Verotta
Davide
D
Krecic-Shepard
Mary Ellen
ME
Modi
Nishit B
NB
Gupta
Suneel K
SK
Schwartz
Janice B
JB
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003327:Coronary Disease / Q000188:drug therapy / Q000378:metabolism; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D019998:Racemases and Epimerases; D044469:Racial Groups; D012737:Sex Factors; D012907:Smoking / Q000097:blood / Q000378:metabolism*; D013617:Tachycardia, Supraventricular / Q000188:drug therapy / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014700:Verapamil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D014665:Vasodilator Agents; D014700:Verapamil; D019998:Racemases and Epimerases