St John's wort (SJW; Hypericum perforatum) induces CYP3A4 that is involved in the metabolism of the hepatitis C virus (HCV) protease inhibitor boceprevir. Reduced boceprevir exposure and efficacy ...would contribute to therapeutic failure and increase the risk for resistance development. Boceprevir is co-administered with interferon/ribavirin, and depression has been described frequently in patients undergoing HCV treatment. Patients may purchase over-the-counter herbals to manage depression, and knowing the interaction between SJW and boceprevir is desirable.
This Phase I, open-label, three-period, cross-over pharmacokinetic study enrolled healthy males and females who, following consent and screening procedures, were randomized to receive SJW on days 1-14, SJW plus boceprevir (SJW on days 22-35 and together on days 31-35) and boceprevir on days 52-56, separated by 7 day washout periods, or the same treatment in the opposite order. Pharmacokinetic sampling was performed at the end of each phase.
Seventeen (11 female) subjects completed the study and no serious adverse events were reported. Geometric mean ratios (GMRs) and 90% CIs for boceprevir (with SJW versus alone) AUC(0-8), C(max) and C8 were 0.91 (0.87-0.96), 0.94 (0.82-1.07) and 1.00 (0.79-1.27), respectively. GMRs and 90% CIs for hypericin, the active component of SJW, (with boceprevir versus alone) AUC(0-8), C(max) and C(8) were 1.23 (1.10-1.38), 1.32 (1.16-1.52) and 1.37 (1.19-1.58), respectively.
SJW did not have a clinically significant effect on boceprevir plasma concentrations (or those of its metabolite), suggesting that SJW and boceprevir can be safely co-administered.
A high-performance liquid chromatography method with UV detection was developed and validated for the simultaneous quantification of linezolid (LZD), rifampicin (RFP), levofloxacin (LEVO), and ...moxifloxacin (MOXI) in human plasma. The method is based on a simple organic protein precipitation that guarantees rapid sample preparation and a direct injection into the high-performance liquid chromatography system. The use of quinoxaline as internal standard improved accuracy (relative standard deviation, RSD% <14.9%) and precision (RSD% <14.3%). The recovery was 75.9% (RSD% = 5.8). The limits of quantification were 0.234 microg/mL for LEVO, 0.312 microg/mL for LZD, 0.156 microg/mL for MOXI, and 0.622 microg/mL for RFP. This method allows the simultaneous measurement of LEVO, LZD, MOXI, and RFP in human plasma and may be used for both routine clinical applications and pharmacokinetic studies.
the darunavir genotypic inhibitory quotient (gIQ) has been suggested as one of the predictors of virological response to darunavir-containing salvage regimens. Nevertheless, which resistance ...algorithm should be used to optimize the calculation of gIQ is still debated. The aim of our study was to compare seven different free-access resistance algorithms and their derived gIQs as predictors of 48 week virological response to darunavir-based salvage therapy in the clinical setting.
patients placed on two nucleoside reverse transcriptase inhibitors + 600/100 mg of darunavir/ritonavir twice daily ± enfuvirtide were prospectively evaluated. Virological response was assessed at 48 weeks. Darunavir resistance interpretation was performed according to seven different algorithms, of which two were weighted algorithms. Analysis of other factors potentially associated with virological response at 48 weeks was performed.
fifty-six treatment-experienced patients were included. Overall, 35 patients (62.5%) had a virological response at 48 weeks. Receiver operator characteristic curve analysis showed that De Meyer's weighted score (WS) and its derived gIQ (gIQ WS) were the most accurate parameters defining virological response, and related cut-offs showed the best sensitivity/specificity pattern. In univariate logistic regression analysis, baseline log viral load (P = 0.028), optimized background score ≥ 2 (P = 0.048), WS >5 (P = 0.001) and WS gIQ ≥ 600 (P < 0.0001) were independently associated with virological response. In multivariate analysis, only baseline log viral load (P = 0.008) and WS gIQ ≥ 600 (P < 0.0001) remained in the model.
in our study, although different resistance interpretation algorithms and derived gIQs were associated with virological response, gIQ WS was the most accurate predictive model for achieving a successful virological response.
To assess the pharmacokinetics (PK) of raltegravir and ezetimibe when co-administered to healthy volunteers.
This was a prospective, open-label, crossover study, with subjects randomly assigned to ...group 1 (raltegravir 400 mg twice daily, raltegravir plus ezetimibe 10 mg once daily, wash-out period, ezetimibe) or group 2 (ezetimibe, raltegravir plus ezetimibe, wash-out period, raltegravir); all phases lasted for 10 days. Steady-state full PK sampling was performed at days 10, 20 and 40. Raltegravir and ezetimibe PK parameters were determined by non-compartmental methods and comparisons in the presence of the potentially interactive drug measured by geometric mean ratio (GMR) and 95% confidence intervals (CIs).
Twenty subjects (10 females) completed the study. Raltegravir PK parameters did not change significantly in the presence of ezetimibe: GMRs (95% CI) were 1.16 (0.89-1.51) for AUC(0-12), 1.13 (0.81-1.58) for maximum plasma concentration (Cmax) and 1.12 (0.72-1.74) for trough concentration (Ctrough). Ezetimibe AUC0-24 and Ctrough were lower in the presence of raltegravir GMRs (95% CI) were 0.79 (0.68-0.91) for AUC0-24 and 0.78 (0.60-0.99) for Ctrough, while ezetimibe glucuronide Cmax was 40% higher (90% CI 1.17-1.66). There was marked inter-individual variability in the PK of the two drugs, especially during co-administration.
There were no significant changes in raltegravir PK parameters with or without ezetimibe. However, in the presence of raltegravir, ezetimibe AUC0-24 and Ctrough were significantly lower (>20%) and ezetimibe glucuronide Cmax was higher. Clinical data to assess the importance of the change in ezetimibe concentrations are warranted.
Objectives Antiretroviral combinations including atazanavir are currently not recommended in HIV-infected patients with end-stage liver disease (ESLD). The objective of our study was to evaluate ...efficacy, pharmacokinetics and safety of unboosted atazanavir in HIV-infected patients with ESLD screened for orthotopic liver transplantation (OLTx). Patients and methods Single-arm, 24 week pilot study. Atazanavir-naive patients undergoing highly active antiretroviral therapy were switched to atazanavir 400 mg/day plus two non-thymidine nucleoside reverse transcriptase inhibitors. Results Fifteen patients (10 males and 5 females) were included. In the study period, 2 patients were transplanted and 10 completed 24 weeks of atazanavir treatment. Median area under the concentration–time curve at week 4 was 19 211 ng·h/mL (IQR = 8959–27 500). At week 24, median atazanavir trough concentrations (Ctrough) per patient calculated across the study were above the minimum effective concentration (MEC = 100 ng/mL) in 8 of 10 subjects. Atazanavir Ctrough time-point values were always above the MEC in five patients. The other three subjects experienced only one determination below the MEC, with median atazanavir Ctrough levels across the study being above the MEC in two of them. At 8 of 11 time-points when atazanavir and proton pump inhibitors (PPIs) were co-administered and at 16 of 19 time-points in which patients had a concomitant tenofovir association, atazanavir Ctrough was above the MEC. Conclusions Unboosted atazanavir showed a favourable pharmacokinetic profile and was able to maintain or gain immuno-virological eligibility for OLTx in all patients. Limited biochemical toxicities (including unconjugated hyperbilirubinaemia) and allowance of concomitant administration of tenofovir and PPIs were observed.
Background Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide ...plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting. Methods Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide Ctrough were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12. Results Optimized background score (OBS) and enfuvirtide Ctrough concentrations were associated with VL decrease at week 12. An OBS ≥2 and enfuvirtide Ctrough >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure–response relationship both in the total population and in different groups according to OBS <2 or ≥2. Higher estimates of IC50 were calculated for the OBS <2 group when compared with the OBS ≥2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I0 (0.31 versus 0.21 log) and Imax (−2.64 versus −3.33 log). Conclusions Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.
A high-performance liquid chromatography method for the determination of ertapenem in human plasma using ultraviolet detection (300 nm) was developed and validated. The method involved a simple ...organic protein precipitation that guarantees rapid sample preparation. By using meropenem as internal standard, it also guarantees improved precision (relative standard deviation <3.70) and accuracy (deviation from true value <6.58%). The method was linear from 0.59 to 150 microg/mL and reproducible. In conclusion, this method allows the measurement of ertapenem in human plasma and may be used for both clinical routine applications and pharmacokinetic studies.
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