title: Optimization of release kinetics from sustained-release formulations using model-independent pharmacokinetic simulation.
abstract: In the present work, a single model-independent approach was developed to optimize the release kinetics of drugs from sustained-release formulations, using stavudine (d4T) as a model drug. This approach is based on the pharmacokinetic simulation of drug plasma levels through a semiparametric approach of the input function and on convolution with an empirical polyexponential unit impulse response function. Input functions were evaluated using different zero-order and first-order release constants. Optimum drug release to obtain a specific pharmacokinetic profile was approached using target model-independent pharmacokinetic parameters such as C(max)(SS), C(min)(SS), t(max)(SS), and peak-trough fluctuations. A Monte Carlo simulation was performed to estimate the fractional attainment of d4T plasma concentrations over therapeutic d4T levels. Zero-order (K(0) = 4 mg/h) and first-order (K(1) = 0.05 h(-1)) release constants were optimal for the formulation of sustained-release d4T tablets, plasma concentrations within the therapeutic range being achieved.
authors.affiliation: Usala Laboratories, C/ Licenciado Méndez Nieto s/n 37007, Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maderuelo
authors.affiliation: Usala Laboratories, C/ Licenciado Méndez Nieto s/n 37007, Salamanca, Spain; Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Salamanca, C/ Licenciado Méndez Nieto s/n 37007, Salamanca, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Zarzuelo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Salamanca, C/ Licenciado Méndez Nieto s/n 37007, Salamanca, Spain. Electronic address: jmlanao@usal.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Lanao
mesh_terms: D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D009010:Monte Carlo Method; D012995:Solubility; D018119:Stavudine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D013607:Tablets; D018119:Stavudine