Prediction of pharmacokinetic parameters and dose of pregabalin gastroretentive formulation in healthy adults, healthy pediatrics and renal-impaired geriatrics

Abstract

IntroductionThe study aimed to predict pregabalin individualized doses in healthy adults, pediatrics and renal impaired geriatric patients by using physiological based pharmacokinetic (PBPK) model for gastroretentive formulation producing comparable pharmacokinetics to that of the immediate release (IR) formulation to obtain doses on basis of their physiological needs. MethodologyThe PBPK model of pregabalin was developed for a healthy adult, healthy pediatrics, healthy and renal impaired geriatric (with creatinine clearance, CLcr = 90, 60, 30, 15 ml/min) at different once daily doses of the IR and GR formulations. In PBPK adult model, PK parameters were also predicted in fasting and fed condition after administration of pregabalin 300 mg of IR and 330 mg of sustained release (SR) formulations. The doses in the renal impaired geriatrics and healthy pediatric population were computed by a dose decremental method and were selected at which the comparable pharmacokinetics parameters to that of the reported values in healthy adults were obtained. ResultsIn healthy adults, comparable PK parameters were obtained after administration of pregabalin 300 mg of IR and 330 mg of SR formulation in fasting and fed state and there was no effect of food on the bioavailability of pregabalin. In neonates to infants and toddlers, the same AUC0-48 to that of the adults was obtained with a 40–82 mg dose of GR formulation of pregabalin. For pre-schooled and schooled virtual populations, a dose of 40–170 mg and for adolescents, 40–330 mg produced the comparable AUC0-48 as that of the normal adults, 42.20 ± 32 μg h/ml. The predicted doses of gastroretentive formulation in renal impaired geriatric with CLcr, 60, 30, and 15 ml/min were 220–330, 110 to 220 and 55–85 mg, respectively to achieve the same level of PK parameters as elder individual with normal CLcr (90 ml/min) after administration of 330 mg of gastroretentive formulation. ConclusionPBPK models effectively predicted dose for the modified GR pregabalin formulations in special populations such as pediatrics and elder renal impaired individuals.