Intracellular Accumulation of Tipranavir/Ritonavir

Measurement of plasma concentrations of PIs is a reliable tool but only the fraction reaching the intracellular compartment is expected to exert action. Aim of our study was to evaluate intracellular penetration of TPV/RTV in multiexperienced patients administered with 2 NRTIs + TPV/RTV 500/200 mg BID. Plasma and PBMCs TPV and RTV concentrations were measured at the end of dose interval (Ctrough) in 14 pts; five pts. underwent also to complete 12-h PK sampling (1.5, 3.5, 7 and 12 hours after dose intake). Plasma TPV and RTV concentrations were measured by validate HPLC methods while intracellular ones in PBMCs by RP-HPLC coupled with an ESI-MS detector. Values were given as mean ± SD. TPV Ctrough in PBMCs and plasma were 7176 ± 6465 and 43080 ± 30319 ng/ml, (ratio 0.15 ± 0.036). RTV Ctrough in PBMCs and plasma were 1319 ± 1101 and 345 ± 386 ng/ml, (ratio 4.86 ± 1.68). Correlations between plasma TPV Ctrough and PBMCs TPV Ctrough (R=0.969, p<0.0001), plasma RTV Ctrough (R=0.776, p=0.001), PBMCs RTV Ctrough (R=0.837, p=0.837, p<0.0001) were observed. This is the first report on intracellular penetration of TPV/RTV: tipranavir showed to have a poor intracellular accumulation (near 15%) while RTV showed a concentration within the cells up to four-fold higher than in the plasma. Further studies are warranted to investigate such differential accumulation and the clinical impact of these findings.Correlation between intracellular and plasmatic concentrations of TPV support the use of the latter as a tool for TDM in the clinical setting.