Pharmacokinetic Variability of Amlodipine Serum Concentration and Effect on Blood Pressure in Patients Treated for Hypertension

We investigated the effects of age, sex, BMI, total number of prescribed daily pills, common biomarkers, and CYP3A4/5 polymorphisms on dose-adjusted amlodipine concentration (CDR) in hypertensive patients. We also examined associations between the same covariates, dose, and serum amlodipine concentrations with uncontrolled hypertension. Amlodipine concentrations were measured in 471 patients treated with ≥ 2 antihypertensive drugs, with 50% having uncontrolled hypertension (daytime ambulatory blood pressure ≥ 135 mmHg). CYP analyses were performed in a subgroup of 258 patients, 82% of these uncontrolled. Women used lower daily doses (p < 0.001) and had higher CDR (p < 0.001) than men. CDR increased with age (p < 0.001), reduced kidney function (p < 0.001) and CYP3A4*22 allele (p = 0.006). Patients with uncontrolled hypertension had lower CDR (p = 0.014). Women were half as likely as men to have uncontrolled hypertension (p = 0.002). At the group level, a 20 nmol/L increase in concentration, corresponding to adjustment from 5 to 10 mg, was associated with a 16.5% decreased probability of uncontrolled hypertension. Female sex, increasing age, reduced kidney function, and reduced CYP3A4 activity increased amlodipine CDR. The included covariates explained 41% of the amlodipine concentration variability. Females had a reduced probability of uncontrolled hypertension, and increased amlodipine concentration was associated with decreased probability of uncontrolled hypertension. We suggest using TDM of amlodipine as an aid for clinical decision-making in cases of unsatisfactory treatment response, to identify possible non-adherence or pharmacokinetic deviations. Trial Registration: ClinicalTrials.gov identifier: NCT03209154.