Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects

Abstract

PurposeA new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance.MethodsThe pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography–tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period.ResultsForty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration–time curve from time 0 to the last measurement (AUC0–t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0–t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0–t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353–0.9846) and 0.9431 (0.8698–1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0–t (FDC/concomitant administration) were 0.9829 (0.9143–1.0567) and 0.9632 (0.8798–1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study.ConclusionCKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

“…Highest variability was observed for telmisartan and ezetimibe clearance with CV values of 59 and 66%, respectively. It has been demonstrated previously in the literature that telmisartan shows high variability in PK parameters (Chen et al 2013 ; Deppe et al 2010 ; Kang et al 2018 ; Stangier et al 2000b ). Overall, UGT1A3-related UFs were below the default TK UF of 3.16 (Table 4 ).…”

A new strategy for taste masking on bitter drug by other combined drug in fixed-dose combination: bitterness of Amlodipine besylate could be masked efficiently by Valsartan

“…[20] ARB/ACEi + CCB combination therapy is a particularly useful option, as the addition of ARB/ACEi to CCBs has been found to reduce the incidence of peripheral oedema, the most common CCB-related adverse effect. [21][22][23] Further, the AML/VAL FDC has been reported to result in a safe and effective reduction of BP across all hypertension grades with a majority of patients attaining their BP goals. [24,25] Our finding that VAL also suppresses the bitterness of AML suggests that the combination AML/VAL will not have any problems with non-adherence due to bitterness.…”

<p>Contribution of Trough Concentration Data in the Evaluation of Multiple-Dose Pharmacokinetics for Drugs with Delayed Distributional Equilibrium and Long Half-Life</p>

“…In the case of non-nested models, the Akaike information criteria (AIC) value was used to select the Based on the literatures on amlodipine PK, a two-compartment model with first-order absorption was adopted initially. 8,9 Various absorption (e.g., zero-order absorption, lag time, Weibull-type absorption, and dual absorption) and disposition structures (e.g., one-compartment model and threecompartment model) were tried as needed. Each PK parameter was assumed to follow a log-normal distribution and is described as…”