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31.
Efficacy of etravirine combined with darunavir or other ritonavir‐boosted protease inhibitors in HIV‐1‐infected patients: an observational study using pooled European cohort data 下载免费PDF全文
J Vingerhoets V Calvez P Flandre A‐G Marcelin F Ceccherini‐Silberstein C‐F Perno M Mercedes Santoro R Bateson M Nelson A Cozzi‐Lepri J Grarup J Lundgren F Incardona R Kaiser A Sonnerborg B Clotet R Paredes HF Günthard B Ledergerber A Hoogstoel S Nijs L Tambuyzer L Lavreys M Opsomer Etravirine Cohort Study Group 《HIV medicine》2015,16(5):297-306
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OBJECTIVES: Ritonavir (RTV) at doses of 400 mg twice a day (bid) or higher adversely affects serum lipids. However, the effect of RTV 100 mg bid on serum lipids is unknown. We conducted a study to evaluate the effect of RTV 100 mg bid on fasting serum lipid profiles in HIV-negative healthy volunteers. METHODS: Ritonavir 100 mg bid was administered for 14 days to 20 healthy HIV-seronegative adults with normal serum lipids. After a 7-day washout, lopinavir/ritonavir (LPV/RTV) 400/100 mg bid was administered for 14 days. Fasting serum lipid parameters were measured twice at baseline, after 14 days of RTV, and after 14 days of LPV/RTV, and comparisons were made at each time-point for levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the total/HDL cholesterol ratio and triglycerides. RESULTS: After 14 days of RTV 100 mg bid, total cholesterol level increased by 10.2% (P<0.001), LDL cholesterol level increased by 16.2% (P<0.001), triglyceride levels increased by 26.5% (P<0.001), HDL cholesterol level decreased by 5.4% (P<0.01) and the total/HDL cholesterol ratio increased by 17.3% (P<0.001). The addition of LPV 400 mg bid to RTV 100 mg bid resulted in no significant further changes in LDL cholesterol or triglyceride level or total/HDL cholesterol ratio, but there were significant increases in both total cholesterol (8.0% increase; P=0.007) and HDL cholesterol levels (6.7% increase; P=0.008). CONCLUSIONS: Ritonavir dosed at 100 mg bid significantly increased the concentration of total cholesterol, LDL cholesterol, total/HDL cholesterol ratio and triglycerides and reduced HDL cholesterol concentration. The addition of LPV 400 mg bid to RTV 100 mg bid further increased both total and HDL cholesterol levels without affecting the total/HDL ratio. 相似文献
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Objective
To evaluate the pharmacokinetics and safety of a boosted saquinavir (SQV)/ritonavir (RTV) combination, administered as either the hard gelatin capsule (HGC) or soft gelatin capsule (SGC) formulation of SQV, in 24 healthy volunteers.Methods
This was a single‐centre, open‐label, randomized, 2 × 2 crossover study. Twelve subjects were randomized to receive SQV/RTV 1000 mg/100 mg twice daily (BID) orally for 10 days, as either the HGC or SGC formulation. The pharmacokinetic profile of SQV was determined on day 10. Subjects then crossed over to the opposite SQV formulation, and the pharmacokinetic profile was determined again on day 20. The primary analysis was the assessment of bioequivalence based on logarithmically transformed values for AUC(0?24 h) and Cmax for the two formulations.Results
There was a statistically significant increase in the geometric means of all the pharmacokinetic variables evaluated for SQV‐HGC/RTV compared with SQV‐SGC/RTV. A mean AUC0?24 h‐value of 15.798 µg/mL/h was reported for the HGC formulation compared with 11.655 µg/mL/h for the SGC formulation (P = 0.0043). The SQV‐HGC/RTV combination was better tolerated in terms of gastrointestinal system disorders. Furthermore, no elevations in triglycerides or total cholesterol were reported with SQV/RTV during the entire study period.Conclusion
In healthy volunteers, RTV boosting of SQV‐HGC produces plasma exposures at least comparable to SQV‐SGC, which is accompanied by an improvement in gastrointestinal system disorders.37.
Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients 下载免费PDF全文
Kappelhoff BS Huitema AD Crommentuyn KM Mulder JW Meenhorst PL van Gorp EC Mairuhu AT Beijnen JH 《British journal of clinical pharmacology》2005,59(2):174-182
AIMS: The aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics. METHODS: Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir-containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero-order and first-order absorption, with and without absorption lag-time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored. RESULTS: From 186 patients 505 ritonavir plasma concentrations at a single time-point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one-compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h(-1) (95% prediction interval (95% PI) 9.38-11.7), 96.6 l (95% PI 67.2-121) and 0.871 h(-1) (95% PI 0.429-1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7-fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir. CONCLUSIONS: The pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors. 相似文献
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Mattia C.F. Prosperi Maurizio Zazzi Grazia Punzi Laura Monno Grazia Colao Paola Corsi Simona Di Giambenedetto Genny Meini Valeria Ghisetti Stefano Bonora Monica Pecorari Maria Rita Gismondo Patrizia Bagnarelli Tiziana Carli Andrea De Luca for the ARCA Collaborative Group 《Journal of medical virology》2010,82(12):1996-2003
Protease inhibitor (PI)‐resistant HIV‐1 has hardly ever been detected at failed boosted PI‐based first‐line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first‐line lopinavir/ritonavir (LPV/rtv)‐based therapy with available baseline HIV‐1 RNA load, a viral genotype and follow‐up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV‐1 RNA >500 and >50 copies/ml, respectively, after 6 months of treatment. Cox proportional hazard models detected baseline HIV‐1 RNA (RH 1.79, 95%CI 1.10–2.92 per 1 ? log10 increase, P = 0.02) and resistance to the nucleoside backbone (RH 1.04, 95%CI 1.02–1.06 per 10‐point increase using the Stanford HIVdb algorithm, P < 0.001) as independent predictors of HIV‐1 RNA at >500 copies/ml, but not at the >50 copies/ml cutoff criteria. Higher baseline viral load, older patient age, heterosexual route of infection and use of tenofovir/emtricitabine were predictors of failure at month 3 using the 50‐copy and/or 500‐copy threshold. Resistance to LPV/rtv did not occur or increase in any of the available 36 follow‐up HIV‐1 genotypes. Resistance to the nucleoside backbone (M184V) developed in four cases. Despite the likely differences in patient population and adherence, both the low rate of virological failure and the lack of development of LPV/rtv resistance documented in clinical trials are thus confirmed in clinical practice. J. Med. Virol. 82:1996–2003, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Elena López Aspiroz Salvador Enrique Cabrera Figueroa Alfonso Domínguez-Gil Hurlé María José García Sánchez 《Enfermedades infecciosas y microbiología clínica》2013
Lopinavir/ritonavir (LPV/r) has demonstrated virological and immunological efficacy in the combined antiretroviral treatment (cART), in both naïve and experienced patients. Furthermore, LPV/r showed a high barrier to the development of resistance. Although generally well tolerated, adverse gastrointestinal side effects and metabolic disorders are frequent. 相似文献
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