- In vitro-in vivo correlation of the drug-drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat. [Journal Article]Expert Opin Drug Metab Toxicol 2019EO
- CONCLUSIONS: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.
- High dietary fat modulates neurobehavioural but not oxidative and neurochemical effects of lopinavir/ritonavir in mice. [Journal Article]Curr Pharm Biotechnol 2019CP
- CONCLUSIONS: In conclusion, the study shows that while dietary composition may alter the neurobehavioural responses to lopinavir/ritonavir in healthy mice, its effects on oxidative status, L-glutamate and acetylcholinesterase activity remains relatively unaffected.
- High rate of acute kidney injury in patients with chronic kidney disease and hepatitis C virus genotype 4 treated with direct-acting antiviral agents. [Journal Article]Int Urol Nephrol 2019IU
- CONCLUSIONS: Treatment of HCV among stage 2, 3a, and 3b patients was achieved safely with a sofosbuvir-based regimen. We recommend that stage-4 patients wait until starting hemodialysis or transplantation.
- Efficacy, Safety, and Predictors of Direct-acting antivirals in Hepatitis C Virus Patients with Heterogeneous Liver Diseases. [Journal Article]New Microbiol 2019; 42(4)NM
- Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new directacting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofos…
Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new directacting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir±Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or nonresponse (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver-Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virologicalresponse.
- Efficacy and Safety of 12-week Interferon-based Danoprevir Regimen in Patients with Genotype 1 Chronic Hepatitis C. [Journal Article]J Clin Transl Hepatol 2019; 7(3):221-225JC
- CONCLUSIONS: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated. Trial Registration Clinical-Trials.gov Identifier: NCT03020082.
- Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China. [Journal Article]J Clin Transl Hepatol 2019; 7(3):213-220JC
- CONCLUSIONS: In treatment-naïve, noncirrhotic HCV Chinese patients infected with HCV genotype 1, all-oral regimen of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks was highly efficacious, safe, and well tolerated.
- Implementation of an intensive adherence intervention in patients with second-line antiretroviral therapy failure in four west African countries with little access to genotypic resistance testing: a prospective cohort study. [Journal Article]Lancet HIV 2019LH
- CONCLUSIONS: Poor adherence is the first problem to tackle in patients for whom second-line ART is failing when resistance tests are not routinely available and is effectively a manageable problem. Lack of access to genotypic resistance testing should not be an obstacle to the prescription of third-line ART in patients who do not achieve viral resuppression after adherence reinforcement.
- Effect of comedication on ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin therapy in chronic hepatitis C - a real-world study. [Journal Article]Clin Exp Hepatol 2019; 5(3):215-223CE
- CONCLUSIONS: Although most HCV-infected patients received concomitant medications, only some required treatment modification. OBV/PTV/r ± DSV ± RBV was effective in all subgroups, irrespective of the number of comedications taken. Multimorbidity and polypharmacy in patients with chronic hepatitis C should not discourage the decision to initiate antiviral therapy, although caution should be exercised for potential drug-drug interactions.
- A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development. [Journal Article]J Clin Pharmacol 2019JC
- Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this co…
Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12-fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.
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- Cyclodextrin solubilization and complexation of antiretroviral drug lopinavir: In silico prediction; Effects of derivatization, molar ratio and preparation method. [Journal Article]Carbohydr Polym 2020; 227:115287CP
- Lopinavir (LPV) is currently used in combination with ritonavir for the clinical management of HIV infections due to its limited oral bioavailability. Herein, we report the application of an in silico method to study cyclodextrin (CyD) host-guest molecular interaction with LPV for the rational selection of the best CyD for developing a CyD based LPV delivery system. The predicted CyD, a (2-hydrox…
Lopinavir (LPV) is currently used in combination with ritonavir for the clinical management of HIV infections due to its limited oral bioavailability. Herein, we report the application of an in silico method to study cyclodextrin (CyD) host-guest molecular interaction with LPV for the rational selection of the best CyD for developing a CyD based LPV delivery system. The predicted CyD, a (2-hydroxy)propyl-gamma derivative with high degree of substitution (HP17-γ-CyD) was synthesized and comparatively evaluated with γ-CyD and the commercially available HP-γ-CyD. All complexes were prepared by supercritical assisted spray drying (SASD) and co-evaporation (CoEva) at molar ratios (1:1 and 1:2); and afterwards fully characterized. Results indicate a higher LPV amorphization and solubilization ability of HP17-γ-CyD. The SASD processing technology also enhanced LPV solubilization and release from complexes. The application of in silico methodologies is a feasible approach for the rational and/or deductive development of CyD drug delivery systems.