Pharmacokinetics Study Of Ritonavir In Chinese Healthy Volunteers

Ritonavir is a member of a class of anti-HIV-1 drugs called the viral protease inhibitors.It blocks the HIV protease,thereby reducing the viral load in the infected individual. It is one of the effective anti-HIV new drugs,and it is recommended as part of combination of HAART. The pharmacokinetics study of ritonavir has been reported abroad, but no report has been found about ritonavir in china up to now. The study of ritonavir (both imported and domestic) pharmacokinetics in Chinese healthy volunteers is reported in this thesis and it will provide academic foundation for the development and clinical use of ritonavir.Objective To study the pharmacokinetics of ritonavir in Chinese healthy volunteers. Methods A single oral dose 600mg of two ritonavir oral solutions was given to 18 healthy volunteers in a randomized cross-over study.The interval was one week.None of the subjects had a history of significant medical illness or hypersensitivity to any drugs.They were not alcohol—addicted and were non—smokers.None of them had taken any other drugs for at least 2weeks before the study and did not take any other drugs during the study.Their normal health status were judged on the basis of a physical examination with screening blood chemistries,including a complete blood count and liver function test, urinalysis and electrocardiogram performed before the study.After an overnight fast ,each of them took a-600mg oral dose of ritonavir oral solution with 200ml water. A standardized meal was served separately at 4 hours and 10 hours after the drug ingestion.Venous blood samples (4ml each)were collected into heparinized tubes,immediately before the drug administration and at 0.5,1,1.5,2,3,4,5,6,8,12,24,36hours after dosing.the samples were spun immediately after the collection,and the plasma samples were stored at -20°Cuntil assayed.Then 0.5mL plasma was taken to a clean tube,3mL acetonitrile was added to each tube for extraction,tubes were vortexed vigorously for 1 min,centrifuged for 10 min at 3500 r/min,and the organic layer was evaporated at 40°C under conditions of a mild nitrogen.When the tubes were dry,0.1ml acetonitrile:0.05M Monobasic ammonium phosphate buffer(50:50),pH5.6,was added for reconstitution.Tubes were vortexed vigorously for 1 min,and 20 u 1 was injected via Agillent Corp.The sample was delivered using a mobile phase composed of 50% acetonitrile and 50% 0.05M monobasic ammonium phosphate at pH 5.6.The flow rate was 1.0 ml/L.Detection was monitored at a wavelength of 210 nm. The plasma concentration—time data were disposed with 3p97 program. The peak concentration (Cmax) and the peak time (Tmax) of ritonavir were determined from the respective observed concentration-time data. The area under the curve (AUC) were calculated by the linear trapezoidal method. The data are expressed as mean values±SD throughout the paper. Difference in pharmacokinetic data between domestic formulation and imported formulation were evaluated statistically by use of a two-sample t test./* value of <0.05 was considered to be statistically significant.Results It has been studied that the ritonavir pharmacokinetics in Chinese healthy volunteers by using reversed high-performance liquid chromatography (RP-HPLC) with UV detector as determination of ritonavir concentration in plasma . The results show that this method was specific and selective for ritonavir in plasma and impurity substance in plasma didn't interfere with determination of ritonavir. Obtained linear regression equation was C=0.0074 X A -0.0367 (r=0.9999). The method was validated for a linear range of 0.078~40-00 mg/L for ritonavir. The relative recoveries of ritonavir in plasma were in the range of 87.50%—104.00%. Determined RSDs of within-day and day-to-day were less than 15%(n=5). The lower limit of quantitation was 0.02mg/L for ritonavir under this condition and could cdntent the requirement of biological determination.The study results showed that the data of.the two formulations were fitted to a one-compartment open model in healthy volunteers.The main pharmacokinetics parameters of imported and domestic ritonavir were as follows: Cmax were (19.61 ± 5.19) mg/Land (20.63 + 5.60) mg/L; rmflJwere (2.58 + 0.73) h and (2.75+0.90) h; T,/?c. were (6.19±0.77) hand (5.88 + 0.91) h;Tl/2tu, were (0.36 + 0.18)hand (0.40+ 0.0.21) h ;AUC0-t were(194.9+47.94)mg-h/Land (200.6 + 74.92) mg-h/L;were (198.87 ±48.46) mg-h /L and (204.4 + 76.70) mg-h /L; respectively.The relativebioavailability ofF°'and ^^"were (101.36 + 21.23)% and (101.14±21.11)%, V/F were 31.37 + 6.75L and 31.24 + 8.56L; Cl/F were 3.55 + O.86L/h and 3.81 + 1.38L/hrespectively.The results of ANOVA and two one-sided t test statical analysis showed that domestic ritonavir and imported ritonavir were bioequivalent.Conclusion 1. The pharmacokinetic process of imported ritonavir and domestic ritonavir were fitted to one-compartment open model.2. The domestic ritonavir and imported ritonavir had the similar pharmacokinetic parameters and they were bioequivalent.