PHARMACOKINETIC VARIABILITY OF AMLODIPINE SERUM CONCENTRATION AND EFFECT ON BLOOD PRESSURE IN PATIENTS TREATED FOR HYPERTENSION

Objective: The calcium channel blocker amlodipine is frequently used to treat hypertension. We examined the impact of age, sex, body mass index, number of daily pills, time since intake, biomarkers, and CYP 3A4/5 polymorphisms on serum amlodipine concentration in patients from a national hypertension study. We also investigated whether the same covariates, amlodipine doses and serum concentrations changed the odds of having uncontrolled hypertension. Design and method: Serum amlodipine concentrations were measured in 471 patients treated with 2 or more antihypertensive drugs, of whom 50% had uncontrolled hypertension (systolic ambulatory daytime BP >= 135 mmHg). Patients gave information about amlodipine doses, time since last intake, and other current medications. CYP analyses were performed in a subgroup of n=258, most with uncontrolled hypertension (83%). Results: Mean age was 62 ± 11 years, 32% were female, most patients were Caucasian (94%) and 88% were overweight (BMI>= 25). Women used lower total daily doses (p<0.001), had higher median serum amlodipine concentrations (p<0.022) and higher median CDRs (concentration-dose-ratio) (p<0.001) than men. CDR increased with age (p<0.001) and with reduced kidney function (p<0.001). The multivariable regression analysis confirmed that the CYP3A4 ∗22 allele was associated with an increase in amlodipine CDR (p=0.006), while CYP3A5 with one and two functional alleles showed no clear association. The 10 covariates explained 41% of the pharmacokinetic variation of amlodipine concentration in this linear model. Median CDR was 5.6 nmol/L/mg in uncontrolled and 6.3 nmol/L/mg in controlled hypertension, p=0.014. The multiple logistic regression analysis showed that female sex was associated with a 50% reduction in the odds of uncontrolled hypertension (p=0.003). A 20 nmol/L increase in amlodipine concentration was weakly associated with a 16.3% decrease in the odds for uncontrolled hypertension, p=0.069 (Figure).Conclusions: Female sex, old age, reduced kidney function and reduced CYP3A4 activity were associated with higher amlodipine serum concentrations. The 10 covariates explained 41% of the serum amlodipine concentration variability. Female sex and increased amlodipine concentrations were associated with less uncontrolled hypertension. Thus, serum amlodipine measurements can be used in addition to blood pressure to guide amlodipine dosing in subgroups of patients.