Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir Mini-Tabs Plus Ribavirin for Children Aged 3–11 Years with Hepatitis C Genotype 1a

Introduction To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C virus (HCV) genotype (GT) 1. Methods This is an ongoing, open-label, Phase 2/3 study in children 3–11 years old infected with HCV GT1 who were HCV treatment-naïve and non-cirrhotic. Pediatric mini-tablet formulations of OBV, PTV, ritonavir, and DSV plus ribavirin oral solution were administered for 12 weeks based on body weight. Endpoints included SVR12, adverse events (AEs), and pharmacokinetic parameters. Results Overall, 26 children received OBV, PTV, ritonavir, and DSV plus ribavirin; 14 were 3–8 years old and 12 were 9–11 years old; 35% were male; and all had chronic HCV GT1a infection. The SVR12 rate was 96% (25/26; 95% CI 81.1–99.3), with 1 child failing to achieve SVR12 due to non-adherence and treatment discontinuation. Treatment-emergent AEs of Grade ≥ 3 occurred in 3 children; 2 events in 1 child were considered serious; and none were considered treatment-related. No AEs led to discontinuation of study treatment. The most common AEs were headache (27%), fatigue (23%), pyrexia (19%), and vomiting (19%). Pharmacokinetic results showed mini-tablet formulations of OBV, PTV, DSV, and ritonavir drug exposures were comparable to the adult formulation. Conclusion The mini-tablet combination of OBV, PTV, ritonavir, and DSV plus ribavirin to treat HCV GT1a infection for 12 weeks was highly effective and suitable in children 3–11 years of age

Effect of VX-770 in Persons with Cystic Fibrosis and the G551D- CFTR Mutation

A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro

Metrics evaluating bioavailability and bioequivalence, principles, and applications in the steady state

grantor: University of Toronto'Bioavailability' is defined by the rate and extent to which a drug substance reaches the systemic circulation. Two pharmaceutical products are considered to be 'bioequivalent' when their bioavailabilities from the same molar dose are so similar that they are unlikely to produce clinically relevant differences in therapeutic and/or adverse effects. The 'purposes of the present study' were to develop principles for evaluating quantitative properties of metrics for the determination of bioavailability and bioequivalence, to assess these properties for the maximum plasma concentration (Cmax) in single- and multiple-dose studies, and to develop and evaluate properties of secondary, steady-state metrics for assessing' the equivalence of absorption rates, clearances and volumes of distribution. Favourable properties of metrics were defined both qualitatively and quantitatively. A good metric should be specific, show high kinetic sensitivity with respect to the underlying kinetic quantity, be linear to it, and exhibit low statistical responsiveness to variations in both observations and parameters which are not of primary interest. The properties of metrics were illustrated on the example of Cmax by both algebraic calculations and computer simulations. It was found that the steady-state Cmax has a much lower kinetic sensitivity to the absorption rate constant (ka) than the single-dose C max, especially at high accumulation and slow absorption. The variation of Cmax is smaller at steady state than after a single dosing when the dominant source of variation is ka, Overall, Cmax should not be applied for assessing bioavailability and bioequivalence in the steady state. Properties of various secondary metrics were evaluated for assessing the 'equivalence of absorption rates in the steady state' by simulations. At fast absorption and low accumulation, the intercept metric has the most favourable combined kinetic and statistical features. At the unfavourable condition of slow absorption and high accumulation, AAUC is preferred. At intermediate conditions, AUCF, Swing and especially PTF are moderately favourable. Properties of the secondary metrics were assessed also for the evaluation of the 'equivalence of clearances and volumes of distribution in the steady state'. At high accumulation and slow absorption, Cmax , is the most favourable metric for assessing the equivalence of clearances, but least favoured for the equivalence of volumes of distribution.Ph.D

Time-dependent Inhibitory Effects of FK1706, a Novel Non-immunosuppressive Immunophilin Ligand, on CYP3A4/5 Activity in Humans in Vivo and in Vitro

Abstract We investigated the inhibitory effects of FK1706, a novel non-immunosuppressive immunophilin ligand, on CYP3A4/5 in in vitro and in vivo settings. First, the inhibitory effects of FK1706 (preincubation dependency, inactivation rate estimation, and reversibility) were tested using human liver microsomes. Second, the effect of repeated oral dose of FK1706 (60 mg q.d. for 14 days) on the pharmacokinetics of midazolam (single oral 2 mg dose) was tested in healthy volunteers. Finally, pharmacokinetic modeling and simulation were performed. In vitro experiments showed that FK1706 inhibited CYP3A4/5 in time-dependent and irreversible manner. In vitro maximum inactivation rate constant (k inact ) and concentration of inhibitor that gave half-maximal k inact (K I ) were estimated to be 10.1 h -1 and 2,050 ng/mL, respectively. In the clinical study, FK1706 produced a two-fold increase in area under the time-concentration curve (AUC) of midazolam. A pharmacokinetic model developed for this study which described the time course of concentrations of both FK1706 and midazolam and incorporated CYP3A4/5 inactivation in the liver and intestine successfully predicted the change in the pharmacokinetics of midazolam using in vitro k inact and K I values (1.66-to 2.81-fold increase in AUC predicted), and estimated the in vivo inactivation rate to be 0.00404 to 0.0318 h -1 ·mL/ng. In conclusion, FK1706 weakly or moderately inhibited the activity of CYP3A4/5 in vitro and vivo at the tested dose. The model developed here would be helpful in predicting drug-drug interactions and in the design of dose regimens which avoided drug-drug interactions

Exposure–Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s12325-016-0320-y">https://link.springer.com/article/10.1007/s12325-016-0320-y</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens

<div><p>Background</p><p>Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections.</p><p>Aim</p><p>To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens</p><p>Methods</p><p>In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV.</p><p>Results</p><p>Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels.</p><p>Conclusions</p><p>Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.</p></div

Low ITPase activity and the rs12979860 CC genotype protect against RBV-induced anemia.

<p>Hemoglobin (Hb) change from baseline (BL) to end of treatment (EOT) was calculated and regression modeling was done to illustrate the association of Hb changes with ITPAse functional activity and rs12979860 Genotype. The 2 arms are indicated, and are categorized by rs12979860 genotype. Line color indicates the fit for regression analysis: Blue- IFNL4 CC in placebo arm; Red- rs12979860 CT in placebo arm; Green- rs12979860 TT in placebo arm; Black- rs12979860 CC in RBV arm; Purple rs12979860 CT in RBV arm; Light Green- rs12979860 TT in RBV arm.</p

RBV log2(Ctrough) is dependent on ITPase activity and age.

<p>The contour fit plot for RBV log2(Ctrough) was generated using ITPase functional activity, RBV log2(Ctrough), and age of the individual.</p

GLM analysis of plasma RBV concentration in Arm A (DAA+RBV) shows the model is useful (p = 0.0269, R2 = 15.3%).

<p>GLM analysis of plasma RBV concentration in Arm A (DAA+RBV) shows the model is useful (p = 0.0269, R2 = 15.3%).</p