Pharmacokinetic interactions between simeprevir and ledipasvir in treatment naive hepatitis C virus genotype 1-Infected patients without cirrhosis treated with a simeprevir-sofosbuvir-ledipasvir regimen

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n = 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n = 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended

Методичні вказівки для проведення практичних занять і організації самостійної роботи з навчальної дисципліни «Управління нерухомим майном» (для студентів 4 курсу денної і заочної форм навчання напряму підготовки 6.080101 – Геодезія, картографія та землеустрій).

Table S2. Week-4 simeprevir pharmacokinetic parameters after administration in (a) Panels 1–3 and (b) Panel 4. (DOCX 15 kb

Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Abstract Background In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. Methods HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. Results The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. Conclusions Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. Trial registration number NCT01724086 (date of registration: September 26, 2012

Dog model with implanted pump to test boosters for antiretroviral medication

A dog model was developed to test the capacity of boosters for antiretroviral medication. Two dogs were implanted with a modified constant-flow Codman 3000 infusion pump, adapted to release viscous solutions of darunavir (TMC114) at a constant rate of 25mg/dog/day in the venous blood stream. Booster candidates were given by oral gavage for at least 4 days up to maximum 7 days in cross-over fashion, separated by a wash-out period of minimum 1 week. The booster candidates were tested at doses of 20 and/or 40mg/kg/day: blood sampling for determination of the boosting effect was performed on the last day of booster administration. The model allowed to (1) compare the boosting ratio of these booster candidates based on the exposure (determination of the area under the curve (AUC) of darunavir in presence versus absence of the booster candidate), (2) detect delay in boosting activity by evaluation of the shift of Cmax of darunavir following booster administration versus the Cmax of the booster candidate) and (3) calculate the intrinsic booster capacity, by correcting for the systemic exposure of booster candidate by normalizing the booster ratio for the booster's AUC. The latter parameter (intrinsic booster capacity) allows to determine the booster's metabolic contribution in inhibiting the metabolism of antiretroviral medication (most likely via inhibition of CYP3A4), minimizing the impact of potential effects of the booster at the level of the gastro-intestinal tract.status: publishe

Additional file 1: of Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Study design. HCV NS3/4A, NS5B and NS5A sequence analysis. (DOCX 32 kb

Co-administration of darunavir and a new pharmacokinetic booster: formulation strategies and evaluation in dogs

Various formulations for combination of the anti-HIV protease inhibitor darunavir (DRV) and TMC41629, a pharmacokinetic booster for DRV, were studied. TMC41629 (a BCS-IV compound) was formulated in capsules, as polyethylene glycol 400 (PEG400) solution, binary or ternary self-microemulsifying drug delivery system (SMEDDS), inclusion complex with hydroxypropyl-beta-cyclodextrin (HPbetaCD) or polyvinylpyrrolidone-co-vinylacetate 64 (PVP/VA64) extrudate. In addition, tablets were prepared using unmilled or micronized powder and a disintegrant. On co-administration with DRV tablets in dogs, DRV plasma concentration levels were boosted by TMC41629, the PVP/VA64 extrudate achieving the highest DRV levels (2-fold increase). Yet, with extrudate prepared with both compounds, no boosting effect was observed, likely due to transition of DRV from crystalline solvate to amorphous state. Therefore, a co-formulation, combining DRV as crystalline solvate with amorphous TMC41629, was developed. DRV/kappa-carrageenan 80/20% (w/w) beads coated with TMC41629 released at least 80% within 1h in 0.01M HCl with 0.5% sodium lauryl sulphate, TMC41629 dissolving faster than DRV. In dogs, the DRV exposure increased 2.7-fold with the TMC41629-coated beads relative to DRV alone, yet remained lower, but less variable, than following co-administration as separate formulations. Coating of TMC41629 on DRV/kappa-carrageenan beads is a suitable technique for co-formulation, whereby TMC41629 can function as a booster of DRV.status: publishe

Development of an implantable infusion pump for sustained anti-HIV drug administration

Factors such as insufficient drug potency, non-compliance and restricted tissue penetration contribute to incomplete suppression of Human Immunodeficiency Virus (HIV) and the difficulty to control this infection. Infusion via standard catheters can be a source of infection, which is potentially life threatening in these patients. We developed an implantable infusion pump, allowing to accommodate large volumes (16-50mL) of high viscous solutions (up to 23.96mPas at 39 degrees C) of anti-HIV agents and providing sustained release of medication: a standard Codman 3000 pump, which was initially developed to release aqueous solutions ( approximately 0.7mPas) into the spinal cord such as for pain medication, was transformed for release of viscous solutions up to 40mPas by adapting the diameter of the capillary flow restrictor, the capillary length and way of catheterisation--by placing the indwelling catheter in the vena cava. A pilot study of the pump implanted in 2 dogs showed continuous steady-state release of the protease inhibitor darunavir (25mg/dog/day administered for 25 days), thereby achieving plasma concentration levels of approximately 40ng/mL. Steady-state plasma levels were reproducible after monthly refill of the pumps. In conclusion, the implantable adapted Codman 3000 constant-flow infusion pump customized to anti-HIV therapy allows sustained release of anti-HIV medication and may represent an opportunity to reduce the pill burden and complexity of dosing schemes associated with common anti-HIV therapy.status: publishe

Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-naïve Hepatitis C virus Genotype 1-infected Patients without Cirrhosis Treated with a Simeprevir/Sofosbuvir/Ledipasvir Regimen

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naïve HCV genotype 1-infected patients without cirrhosis, treated with simeprevir/sofosbuvir/ledipasvir in a two-panel, Phase 2, open-label study (NCT02421211). Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In Panel 1 (N=20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from Days 1--14; steady-state pharmacokinetics (PK) of simeprevir were assessed (Day 14). On Day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (Day 28). In Panel 2 (N=20), the effect of simeprevir on ledipasvir was investigated. From Days 1--14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (Day 14). On Day 15, simeprevir was added and a full PK profile was obtained (Day 28). The least squares mean maximum plasma concentration and area under the concentration--time curve (90% confidence interval) increased 2.3- (2.0-2.8) and 3.1- (2.4-3.8) fold for simeprevir, respectively, (Panel 1); and 1.6- (1.4-1.9) and 1.7- (1.6-2.0) fold for ledipasvir, respectively (Panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic response 12 weeks after treatment end. Adverse events, mainly Grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended.status: publishe

Pharmacokinetics-Pharmacodynamics of a Respiratory Syncytial Virus Fusion Inhibitor in the Cotton Rat Model▿

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple Emax model with a maximal viral titer reduction (Emax) of 1.5 log10. The plasma drug level required to achieve 50% of the Emax (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors

Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection

A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of aonce-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin andof the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virusgenotype (GT)1-infected treatment-naïve and prior-relapse patients.Methods:The study comprised four 12-week treatment panels: Panel 1 (n= 10; GT1a) and Panel 2-Arm 1 (n= 12; GT1b):simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000–1200 mg/day;Panel 2-Arm 2 (n= 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a;n= 7) or without (Arm 2: GT1b;n= 8) ribavirin; Panel 4:simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1:n=22;GT1a/GT1b)or60 mg once daily (Arm 2:n= 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end oftreatment (12 weeks of combination treatment; SVR12).Results:In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9(33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirinand 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1apatients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. Nodeaths,seriousadverseevents(AEs),Grade4AEsorAEs leading to treatment discontinuation occurred.Conclusions:The 2- and 3-DAA combinations were well tolerated.HighSVRratesof93%and100%inGT1a-andGT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg andTMC647055/ritonavir