Pharmacokinetic evaluation of SQV-SBE7?CD complex:Plasma concentration-time profiles of SQV and SQV complex for all subjects are shown in Fig 1 and 2. The comparative mean plasma concentration-time profiles for both treatments are shown in Fig 3.Cmax and the time to reach Cmax(Tmax) were read directly from the observed plasma concentration vs. time data. The plasma elimination half-life was estimated from the log-linear regression of the terminal plasma concentrations as a function of time after dosing. The area under the plasma concentration vs. time curve was calculated by using the linear trapezoidal rule over a single hour dosing interval. All the calculated pharmacokinetic parameters such as Cmax, Tmax, AUC0-12hr, AUC0-?, AUMC0-?, MRT, Ke, t½, Vd/F and Cl/F for each subject following single oral administration of SQV and its complex and mean, s.d.,% CV values of pharmacokinetic parameters for each subject are given in Table 1. The Cmaxof SQV from SQV and SQV complex with SBE7?CD was found to be 254±18.81 and 515.25±28.65 ng/mL respectively. The Tmax values were unchanged and found to be 4 hr for both groups. The elimination rate constant and t½were found to be in the range of 0.163 to 0.175 hr-1 and 3.99 to 4.26 hr respectively for both groups. The obtained t½ of SQV was found to be in the range of earlier reported values (3.5-4.5 hr). 18AUC0-12hr and AUC0-? values for SQV were found to be 1867.5±42.07 and 2293.04±82.13 ng.hr/mL respectively. For SQV complex, the respective values were found to be 3116.99±116.46 and 3860.93±138.50 ng.hr/mL.Two fold increment in Cmaxvalue and 1.66 fold increment in AUC0-12hr were obtained for SQV complex than SQV alone. The relative percent bioavailability (Frel) of SQV complex was 168% indicating enhanced oral bioavailability of SQV complex. Plasma concentration-time profile of SQV showed low and double peak phenomenon whereas SQV-SBE77?CD showed smooth elevation of plasma levels with one Cmax value i.e. single peak.The Vd/F and Cl/F were found to be 26.83±1.69 L and 4.36±0.15 L/hr respectively for SQV, 14.92±1.56 L and 2.59±0.09 L/hr respectively for SQV complex.The variability in oral pharmacokinetics of SQV could also be explained by its limited solubility. Because the water solubility of SQV is negligible, its dissolution in GIT is dependent on the pH and the inherent solubilization capacity of the intestine. In rats receiving SQV suspension, a small variation of these factors could lead to a significant difference in dissolution properties and subsequently in the plasma drug concentration. However, in rats receiving SQV-SBE7?CD, as SBE7?CD could solubilize SQV, the impact of such factors became non-determinative and thus, the oral kinetics in rats receiving SQV-SBE7?CD showed less variability than that in rats receiving SQV suspension. It was noticed that there was a primary peak at 0.5 hr and a secondary peak at about 4 hr (Tmax) after dosing in the concentration vs. time graph for rats given the SQV suspension where as such a phenomenon was not observed for the rats receiving SQV-SBE7?CD. Several possible mechanisms have been proposed to explain double peak phenomenon of orally administered protease inhibitors such as enterohepatic recycling, regional distribution differences of active absorption/efflux proteins in the gut, and variable gastric emptying. Earlier literature on SQV also reported similar type of double peak absorption phenomenon as observed in the present investigation.12(Shilpi S, MushirA, Sanjula B, Alka A, Anil and Javed A. Solid dispersion as an approach for bioavailability enhancement of poorly water soluble drug, ritonavir. AAPS Pharm Sci Tech 2010; 2: 518-527.)Pharmacokinetic evaluation of RTV-RM?CD complex:The comparative mean plasma concentration-time profiles for both treatments are shown in Fig. 4. All the calculated pharmacokinetic parameters such as Cmax, Tmax, AUC0-12hr, AUC0-?, AUMC0-?, MRT, Ke, t½, Vd/F and Cl/F for each subject following single oral administration of RTV and its CD complex and mean, s.d., % CV values of pharmacokinetic parameters for each subject are given in Table 2. The peak plasma concentration (Cmax) RTV in the pure drug and its complex were 109.17±9.6 and 264.74±16.52 ng/mL, while AUC0-12hr and AUC0-? were found to be 951.20±28.54, 1636.07±162.51 ng.hr/mL, 1585.16±56.22 and 2300.19±118.21 ng.hr/mL respectively. These values indicated maximum plasma concentration and area under the curve were achieved by RTV complex formulation. Cmaxvalue was 2.4 times and AUC0-12hr was 1.66 times higher for RTV complex than RTV. The relative percent bioavailability (Frel) of RTV complex observed was 140.58% indicated enhanced oral bioavailability of RTV complex. Pure RTV also exhibited slightly variable bioavailability, which is commonly observed with protease inhibitors.20 However, with RTV-RM?CD complex, such phenomenon was not observed. The Tmax values were unchanged and found to be 2 hr for both groups. The elimination rate constant was found to be in the range of 0.011 to 0.144 hr-1 andt½ for RTV was found to be 9.37±1.59 hr and for RTV complex it was 6.07±0.69 hr respectively for RTV complex and is nearer to the reported values (6.07-7.35 hr).BoffitoM, Jackson A, Amara A, Back D, Khoo S, Higgs S, et al,Pharmacokinetics of darunavir/ritonavir and atazanavir/ritonavir once daily over 72 hrs following drug cessation, Antimicrob Agents Chemother 2011;55: 4218-23For pure drug, the Vd/F and Cl/F were found to be 82.35±6.45 L and 6.15±0.56 L/hr respectively and for its complex, 38.06±3.1 L and 4.35±0.22 L/hr respectively.