Improvement in Bioavailability and Pharmacokinetic Characteristics of Efavirenz with Booster Dose of Ritonavir in PEGylated PAMAM G4 Dendrimers

Efavirenz (EFV) with a booster dose of ritonavir (RTV) (EFV-RTV) inhibits the metabolism of EFV and improves its bioavailability. However, inadequate organ perfusion with surface permeability glycoprotein (P-gp) efflux sustains the viable HIV. Hence, the present investigations were aimed to evaluate the pharmacokinetics and tissue distribution efficiency of EFV by encapsulating it into PEGyalated PAMAM (polyamidoamine) G4 dendrimers with a booster dose of RTV (PPG4ER). The entrapment efficiency of PEGylated PAMAM G4 dendrimers was found to be 94% and 92.12% for EFV and RTV respectively with a zeta potential of 0.277 mV. The pharmacokinetics and tissue distribution behavior of EFV within PPG4ER was determined by developing and validating a simple, sensitive, and reliable bioanalytical method of RP-HPLC. The developed bioanalytical method was very sensitive with a quantification limit of 18.5 ng/ml and 139.2 ng/ml for EFV and RTV, respectively. The comparative noncompartmental pharmacokinetic parameters of EFV were determined by administrating a single intraperitoneal dose of EFV, EFV-RTV, and PPG4ER to Wistar rats. The PPG4ER produced prolonged release of EFV with a mean residential time (MRT) of 24 h with C-max 7.68 mu g/ml in plasma against EFV-RTV with MRT 11 h and C-max 3.633 mu g/ml. The PPG4ER was also detected in viral reservoir tissues (lymph node and spleen) for 3-4 days, whereas free EFV and EFV-RTV were cleared within 72 h. The pharmacokinetic data including C-max, t(1/2), AUC(tot), and MRT were significantly improved in PPG4ER as compared with single EFV and EFV-RTV. This reveals that the PPG4ER has great potential to target the virus harbors tissues and improve bioavailability.