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 CmaxSS, CminSS, tmaxSS, 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 (K0 = 4 mg/h) and first‐order (K1 = 0.05 h−1) release constants were optimal for the formulation of sustained‐release d4T tablets, plasma concentrations within the therapeutic range being achieved. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3260–3267, 2011