Search

For survival analysis applications we propose a novel procedure for identifying subgroups with large treatment effects, with focus on subgroups where treatment is potentially detrimental. The approach, termed forest search, is relatively simple and flexible. All‐possible subgroups are screened and selected based on hazard ratio thresholds indicative of harm with assessment according to the standard Cox model. By reversing the role of treatment one can seek to identify substantial benefit. We apply a splitting consistency criteria to identify a subgroup considered "maximally consistent with harm." The type‐1 error and power for subgroup identification can be quickly approximated by numerical integration. To aid inference we describe a bootstrap bias‐corrected Cox model estimator with variance estimated by a Jacknife approximation. We provide a detailed evaluation of operating characteristics in simulations and compare to virtual twins and generalized random forests where we find the proposal to have favorable performance. In particular, in our simulation setting, we find the proposed approach favorably controls the type‐1 error for falsely identifying heterogeneity with higher power and classification accuracy for substantial heterogeneous effects. Two real data applications are provided for publicly available datasets from a clinical trial in oncology, and HIV. [ABSTRACT FROM AUTHOR]

Group sequential design (GSD) is widely used in clinical trials in which correlated tests of multiple hypotheses are used. Multiple primary objectives resulting in tests with known correlations include evaluating (1) multiple experimental treatment arms, (2) multiple populations, (3) the combination of multiple arms and multiple populations, or (4) any asymptotically multivariate normal tests. In this paper, we focus on the first three of these and extend the framework of the weighted parametric multiple test procedure from fixed designs with a single analysis per objective to a GSD setting where different objectives may be assessed at the same or different times, each in a group sequential fashion. Pragmatic methods for design and analysis of weighted parametric group sequential design under closed testing procedures are proposed to maintain the strong control of the family‐wise Type I error rate when correlations between tests are incorporated. This results in the ability to relax testing bounds compared to designs not fully adjusting for known correlations, increasing power, or allowing decreased sample size. We illustrate the proposed methods using clinical trial examples and conduct a simulation study to evaluate the operating characteristics. [ABSTRACT FROM AUTHOR]

Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug‐drug interactions. The pharmacokinetic interaction of the HCV fixed‐dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed‐dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration‐time curve from time 0 to 24 hours (AUC0‐24) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0‐24 of elbasvir was ∼2 times higher and the AUC0‐24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0‐24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV. [ABSTRACT FROM AUTHOR]

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug‐drug interactions. We evaluated the pharmacokinetic interaction of the direct‐acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open‐label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration‐time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV‐coinfected people. [ABSTRACT FROM AUTHOR]

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV‐seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate‐glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration‐time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.18 (95% confidence interval [CI], 1.06–1.30) for carriers of 1 copy and 1.42 (1.10–1.84) for carriers of 2 copies of the risk allele C compared with noncarriers. The SLCO1B1 variant rs4149032 T allele was associated with a decrease in letermovir AUC with GMR (95%CI) of 0.93 (0.85–1.02) and 0.82 (0.73–0.92) for carriers of 1 and 2 copies of the risk allele T, respectively, compared with noncarriers. The UGT1A1*6 variant rs4148323 A allele was present predominantly in Asian participants and was associated with an increase in letermovir AUC compared with noncarriers (GMR, 1.36; 95%CI, 1. 1.07–1.74). SLCO1B1 variant rs2306283, UGT1A1*28 TA promoter repeat, and BCRP variant rs2231142 had no effect on letermovir PK. Together, these data suggest that variants of enzymes and transporters that are involved in the disposition of letermovir in vitro may account for some variability in letermovir PK, but do not affect exposure to a clinically relevant extent. [ABSTRACT FROM AUTHOR]

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single‐dose trial in healthy participants. Trial 2 was a multiple‐dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0‐∞ were 0.98 (0.89–1.08), 0.97 (0.86–1.09), and 0.88 (0.78–1.00) in the presence/absence of EBR; 0.98 (0.81–1.19), 1.13 (0.97–1.32), and 1.10 (0.82–1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0‐∞ in the absence/presence of BUP/NAL were 1.22 (0.98–1.52) and 0.86 (0.63–1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy. [ABSTRACT FROM AUTHOR]

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK‐8742‐P010 and MK‐5172‐P030) in non‐hepatitis C virus (HCV)‐infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R‐ and S‐methadone AUC0‐24 were 1.03 (90% confidence interval (CI), 0.92–1.15) and 1.09 (90% CI, 0.94–1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02–1.17) and 1.23 (90% CI, 1.12–1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0‐24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94–1.53) and 1.03 (90% CI, 0.76–1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed‐dose regimen. [ABSTRACT FROM AUTHOR]

Abstract: A broadband circularly polarized antenna based on the crossed‐dipole structure is designed. The antenna consists of a pair of dual‐side printed crossed dipoles, a loop phase delay line, and a parasitic patch. By modifying the configuration of the dipoles and introducing a parasitic patch, a wide axial ratio (AR) bandwidth is obtained. A defected ground plane is designed, which has a significant improvement in extending the 3‐dB AR bandwidth and enhances the gain. The proposed prototype is manufactured and measured for validation. Measured results show that the antenna achieves both −10 dB impedance bandwidth and 3‐dB AR bandwidth of 68.6% (2.3–4.7 GHz). Moreover, the average gain of the antenna is about 8 dBi within the operating band, with a floating less than 2 dB. [ABSTRACT FROM AUTHOR]

Abstract: Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4‐part, open‐label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once‐daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24‐hour area under the concentration‐time curve of GZR was increased by approximately 15‐fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2‐fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations. [ABSTRACT FROM AUTHOR]

Synthesis of triacylglycerol requires the glucose-derived glycerol component, and glucose uptake has been viewed as the rate-limiting step in glucose metabolism in adipocytes. Furthermore, adipose tissue contains all three isoforms of the glycolytic enzyme phosphofructokinase (PFK). We here report that mice deficient in the muscle isoform PFK-M have greatly reduced fat stores. Mice with disrupted activity of the PFK-M distal promoter were obtained from Lexicon Pharmaceuticals, developed from OmniBank OST#56064. Intra-abdominal fat was measured by magnetic resonance imaging of the methylene proton signal. Lipogenesis from labeled glucose was measured in isolated adipocytes. Lipolysis (glycerol and free fatty acid release) was measured in perifused adipocytes. Intra-abdominal fat in PFK-M–deficient female mice (5–10 months old) was 17 ± 3% of that of wild-type littermates (n = 4; P < 0.02). Epididymal fat weight in 15 animals (7–9.5 months) was 34 ± 4% of control littermate (P < 0.002), with 10–30% lower body weight. Basal and insulin-stimulated lipogenesis in PFK-M–deficient epididymal adipocytes was 40% of the rates in cells from heterozygous littermates (n = 3; P < 0.05). The rate of isoproterenol-stimulated lipolysis in wild-type adipocytes declined ~10% after 1 h and 50% after 2 h; in PFK-M–deficient cells it declined much more rapidly, 50% in 1 h and 90% in 2 h, and lipolytic oscillations appeared to be damped (n = 4). These results indicate an important role for PFK-M in adipose metabolism. This may be related to the ability of this isoform to generate glycolytic oscillations, because such oscillations may enhance the production of the triacylglycerol precursor α-glycerophosphate. [ABSTRACT FROM AUTHOR]