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. Keywords: Tipranavir; Ritonavir; Intracellular; Pharmacokinetics.

Articolo presente in – HAART and correlated pathologies n. 3

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Gammaglutamyltranspeptidase (gamma-GT) Levels before Treatment are Predictive of Tipranavir Interruption in ART Multiexperienced HIV-1-Infected Patients

The Italian Tipranavir EUP/EAP study was an observational study involving nine Italian centres that enrolled three class drug-experienced patients who consecutively entered the EUP/EAP TPV programs. The Cox model performed to assess the risk correlates of interrupting TPV included sex, age, HIV risk factors, HBV/HCV status, use of T20,CD4, HIV-RNA, ALT, γ-GT, cholesterol, triglycerides, glucose levels determination before starting TPV.
The study enrolled 175 patients followed up for a median time of 30 weeks (range 3-68). TPV was interrupted by 46 patients (16 for intolerance, 14 for immuno-virological failure, four for disease progression – including two deceased – 12 for patient decision).
The factors independently associated with treatment interruption for any cause were previous ART duration (OR 1.18, 95%CI 1.03-1.35, p=0.016 per each additional year) and γ-GT BL (grade 2 vs 0: OR 6.31, 95%CI 2.49-16.4, p< 0.0001). The γ-GT BL median level in the 16 patients who interrupted TPV for intolerance was 122 IU/L (range: 11-352). Both γ-GT and ALT were significantly increased at interruption compared to BL (p=0.041 and p=0.016 respectively, Wilcoxon test). A transient protective effect against γ-GT and TG increase was observed in patients receiving T20 with TPV (p=0.034 and p=0.027 respectively at week 12 in a Cox model assessing the risk of increasing one toxicity grade). γ-GT level seems to be relevant and more sensitive than ALT/AST level or HBV/HCV status in predicting the risk of TPV interruption. Unreported alcohol abuse could be considered a potential cofactor limiting the effectiveness and safety of TPV/RTV treatment.
Keywords: HIV-1; Tipranavir; Gamma-GT; Treatment Interruption.

Articolo presente in – HAART and correlated pathologies n. 1

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