Plasma trough concentrations of antihypertensive drugs for the assessment of treatment adherence: a meta-analysis
Authors: Groenland E.H , Van Kleef M.E.A.M , Bots M.L , Visseren F.L.J , Van Maarseveen E.M , Spiering W 
Published: November 2020

Abstract

Background
Non-adherence to antihypertensive drugs is an important behavioral contributor to poor blood pressure control and is associated with increased risk of cardiovascular disease, hospitalization and increased healthcare costs. Biochemical drug screening in plasma is an accurate method for the detection of non-adherence. When performed qualitatively (present/not present) this method may lead to overestimation of adherence to drugs with long half-lives. Detection of non-adherence may be improved by performing it quantitatively (measurement of exact concentrations) making use of reliable, drug-specific cut-off values based on exposure parameters in plasma.

Purpose
To perform a literature review and meta-analysis of pharmacokinetic studies to determine plasma population trough concentrations of three frequently prescribed antihypertensive drugs with different pharmacological properties; amlodipine, hydrochlorothiazide and valsartan. These population trough concentrations could possibly be used as drug-specific cut-off values for the diagnosis of (non-)adherence.

Methods
PubMed was searched for pharmacokinetic studies regarding amlodipine, hydrochlorothiazide and valsartan up to December 2019. Eligible studies reported steady-state mean trough concentration estimates and their variance measured in healthy subjects or in patients with hypertension without hepatic or renal failure. Pooled trough concentrations were estimated using a DerSimonian and Laird random-effect approach. To take dependency between mean trough concentrations into account a multilevel meta-analysis was performed. Meta-regression was used to explore sources of heterogeneity identified by the I2 statistic.

Results
The literature search identified 1154 potentially relevant articles of which 44 were eligible for inclusion; 23 for amlodipine, 10 for hydrochlorothiazide and 11 for valsartan. The overall pooled mean trough concentration estimate was 9.3 ng/ml (95% confidence interval: 8.4–10.2) for amlodipine, 29.4 ng/ml (24.4–43.3) for hydrochlorothiazide and 355.4 ng/ml (294.1–416.6) for valsartan (figure 1A-C). Substantial heterogeneity was present for all three pooled estimates (I2 &gt;90%). Based on meta-regression 33.3%, 20.3% and 8.2% of the heterogeneity between the studies can be explained by differences in dose for amlodipine, hydrochlorothiazide and valsartan, respectively.

Conclusions
Plasma trough concentrations of amlodipine, hydrochlorothiazide and valsartan are highly heterogeneous over the different study populations. This heterogeneity is caused, at least in part, by differences in drug dose. Use of the pooled trough concentration mean estimate as a cut-off in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence and should therefore be implemented with caution. Future research might focus on combining drug specific pharmacokinetics with individual patient characteristics to predict personalized trough concentrations.
Figure 1

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): UMC Utrecht