Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence

Abstract

Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5–10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4–64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5–462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β 1 =0.9; P <0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β 1 =2.2, P <0.05, respectively, β 1 =−4.0, P <0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.

Thiazides Attenuate Insulin Secretion Through Inhibition of Mitochondrial Carbonic Anhydrase 5b in β-Islet Cells in Mice

“…HCT significantly attenuated insulin secretion in islets and Min6 cells in vitro at pharmacologically relevant concentrations while not affecting cell viability. 31 We obtained similar findings with other thiazides, including metolazone, chlorthalidone, indapamide, and bendroflumethiazide (Supplemental Figure 6). HCT also significantly lowered sulfonylurea-induced insulin secretion (250 µ M tolbutamide) while it only had a small effect on basal (2 mM glucose) and direct depolarization-induced insulin secretion by high (30 mM) extracellular K + (Figure 2E).…”

“…Hence, the 5 mg/kg HCT dose in mice corresponds to a HCT dose typically employed in humans (12.5–50 mg daily with corresponding steady-state plasma concentrations of 0.02–0.2 µ M). 29–31…”

“…Hence, the 5 mg/kg HCT dose in mice corresponds to a HCT dose typically employed in humans (12.5-50 mg daily with corresponding steady-state plasma concentrations of 0.02-0.2 mM). [29][30][31] Thiazides Attenuate Insulin Secretion In Vivo and In Vitro To further investigate the basis of HCT-induced glucose intolerance, we measured serum insulin levels in mice treated with HCT or vehicle. As depicted in Figure 2, A and B and Supplemental Figure 1, G and H, serum insulin levels were significantly lower 2 minutes after an IPGTT challenge (2 g/kg body weight) in mice pretreated with either 5 or 50 mg/kg body weight HCT, indicating reduced first-phase insulin secretion.…”

Development and Validation of a Dried Blood Spot Assay Using UHPLC-MS/MS to Identify and Quantify 12 Antihypertensive Drugs and 4 Active Metabolites: Clinical Needs and Analytical Limitations

“…In previous research, we already showed that there is a large interpatient variability in AHD concentrations, also at trough concentrations, which makes the LLOD the most important value to assess adherence. 20 This was also confirmed by a meta-analysis by Groenland et al, 21 who warned for the use of pooled trough concentrations when assessing nonadherence. Furthermore, the study by Punt et al 4 did not determine how long after intake they could measure drug concentrations.…”

Nonadherence in Hypertension: How to Develop and Implement Chemical Adherence Testing

“…C min for each drug has been established using literature, although recent evidence has highlighted the large heterogeneity of C min in different studies. 60 To avoid misclassification, some groups have used C min merely as a basis to optimize cutoffs for their local population. 45 Other groups have optimized cutoffs on an individual basis (rather than population), using each patients’ dose alongside scoped pharmacokinetics to estimate a dose-dependent concentration.…”