Pharmacokinetic and Safety Profiles of a Fixed‐Dose Combination of Amlodipine, Valsartan, and Atorvastatin: A 3‐Period Replicate Crossover Study

Abstract

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed‐dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160‐mg amlodipine/valsartan tablet and a 20‐mg atorvastatin tablet. This was a randomized, open‐label, single‐dose, 3‐sequence, 3‐period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference‐scaled average BE approach was used if applicable, as well as the conventional limit of 0.80‐1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUCt) between the FDC and separate formulations were within the 0.80‐1.25 limit for all analytes but atorvastatin. The estimated within‐subject standard deviation of the log‐transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489‐1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80‐1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3‐period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment‐emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects

“…This difference might be mainly due to multiple doses of atorvastatin for 7 days, reducing the within-subject variability. The high variability in the plasma concentrations of atorvastatin, especially in the absorption phase, was also observed in other studies with similar standard deviations ( Hwang et al, 2020 ; Kim et al, 2020 ).…”

“…Therefore, this study was designed as a partial replicated crossover study where subjects received intervention R twice and received intervention T and V once. In this study, the within-subject CV of C ss,max and AUC τ of atorvastatin were 33.6 and 11% (data not shown), slightly smaller than those of previous studies (38–44.1% for C max and 16.7–15.5% for AUC) ( Hwang et al, 2020 ; Kim et al, 2020 ). This difference might be mainly due to multiple doses of atorvastatin for 7 days, reducing the within-subject variability.…”

“…In this study, when atorvastatin was co-administered with tegoprazan, the C ss,max and AUC τ of atorvastatin increased by 9 and 3%, respectively. These increases were not clinically significant since none of them were statistically significant and the within-subject CVs of the C ss,max and AUC τ of atorvastatin are known to be high ( Hwang et al, 2020 ; Kim et al, 2020 ). Thus tegoprazan would not have any effect on OATP1B1 at clinical dose.…”

“…Atorvastatin was known as a highly variable drug with a within-subject CV of more than 30%. Based on the previous replicate crossover studies of atorvastatin, the within-subject CV of C max and AUC were 39-45% and 17-23%, respectively (Hwang et al, 2020;Kim et al, 2020). In the case of highly variable drugs such as atorvastatin, some regulatory agencies recommend a full or partial replicated crossover design (US Food and Drug Administration, 2001).…”

Quality Attributes and In Vitro Bioequivalence of Amlodipine (5 mg) Tablets in Ica, Peru

“…Although in vitro bioequivalence studies are performed for class 1 (high solubility and high membrane permeability) and class 3 (high solubility and low membrane permeability) drugs, according to BCS, the same is carried out in three dissolution media at pH 1.2, pH 4.5, and pH 6.8, comparing the dissolution profiles of T the generic with the reference (3,5). Amlodipine (3-ethyl-5-methyl-2-[(2aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5dicarboxylate) is a class 1 dihydropyridine according to BCS, a calcium channel blocker, and due to its lateral amino group, it presents a pKa of 9.4; therefore, it is absorbed from the intestinal mucosa, obtaining bioavailability of 60-65%, indicating good solubility and permeability and low intestinal metabolism due to the action of cytochrome P450 3A4 (CYP3A4) despite the fact that said enzyme is expressed in intestinal epithelial cells (7)(8)(9)(10)(11). The maximum plasma concentration (Cmax) is 5.87 ng/mL, reached in a maximum time (tmax) of 5-8 hours (9,12).…”