Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

Abstract

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption.

Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model

“…A PBPK/PD modeling strategy was used to investigate dose adjustment recommendations for amlodipine during and after co-administration of RTV containing 2- or 3-DAA regimens. Unlike previously published PBPK models for amlodipine [ 20 , 21 ], which did not confirm the extent and contribution of CYP3A4-mediated clearance, the model developed here is compared against dedicated clinical DDI studies with ritonavir. A PBPK model to be used to predict DDI pertaining to a particular metabolic pathway needs to be adequately qualified and verified for that intended purpose and verification of the fractional contribution of the particular pathway is a critical aspect [ 14 ].…”

“…Blei [ 20 ] developed a PBPK model for amlodipine, but the model did not include CYP3A4-mediated clearance, which is essential in order to model mechanistic DDI with perpetrator drugs. Dennison et al [ 21 ], developed a PBPK model for amlodipine which included CYP3A4-mediated clearance, however their focus was on dissolution and oral absorption of amlodipine. Dennison et al also assigned the entire oral clearance to be due to CYP3A4 and there was no effort to confirm the contribution of the particular enzyme through DDI with CYP3A4 inhibitors.…”

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

“…The relative difference between two curves ƒ 1 values up to 15% indicates little difference between two dissolution curves, while drug products are considered similar when the calculated ƒ 2 is between 50 to 100 [4]. In one study, ƒ 1 and ƒ 2 and PBPK simulations for atorvastatin formulations proved to be bioequivalent, supporting the argument for class II inclusion in biowaiver applications, ideally in silico modeling in conjunction with in vitro dissolution [37]. However, for class II drug products, the probability of BE after a similar dissolution profile was 61% with false positive results (similar dissolution but not bioequivalent (NBE)) was up to 90% [38,39].…”

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

“…[1,2] However, such complex drug therapy regimes may result in poor adherence. A combination product, which includes two or more active pharmaceutical ingredients (APIs) combined in a single dosage form, a socalled a fixed-dose combination (FDC), [3][4][5][6][7][8][9] will improve patient adherence [10,11] and thus maximize the benefits of antihypertensive therapy.…”