Abstract
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course of ATS, and (ii) to evaluate the major highlights and limitations of the PBPK models of ATS published so far. The PBPK models incorporate common elements related to the physicochemical aspects of ATS. However, there are important differences in relation to the analyte evaluated, the type and effect of transporters and metabolic enzymes, and the permeability value used. Additionally, this review identifies major processes (lactonization, P-gp contribution, ATS-Ca solubility, simultaneous management of multiple analytes, and experimental evidence in the target population), which would enhance the PBPK model prediction to serve as a valid tool for ATS dose optimization.
Highlights
Statins are the first-line treatment of choice/gold-standard in the pharmacological management of hypercholesterolemia [1], and they have been positioned as the most effective oral drugs for the treatment and prevention of cardiovascular diseases associated with dyslipidemia [2,3]
Statins can be administered in the active form or as inactive drugs, which require activation within the organism
Another example comes from a fixed-order crossover study in 660 Finnish healthy volunteers [35], which concluded that individuals carrying the ABCG2 c.421C > A single-nucleotide polymorphism (SNP) had a 72% higher
Summary
Statins are the first-line treatment of choice/gold-standard in the pharmacological management of hypercholesterolemia [1], and they have been positioned as the most effective oral drugs for the treatment and prevention of cardiovascular diseases associated with dyslipidemia [2,3]. Statins can be administered in the active form (atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin) or as inactive drugs (simvastatin and lovastatin), which require activation within the organism. In general, safe and well tolerated [4,5]. Atorvastatin (ATS) is one of the most prescribed [8] statin worldwide for the treatment of hypercholesterolemia in order to diminish the cardiovascular risk [9]. ATS is a second-generation synthetic statin that is administered as the calcium
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