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Family members and friends play an important supportive role in the management of chronic illnesses like diabetes, which often require substantial lifestyle changes. Some studies suggest that there may be racial differences in the kinds of support people receive, though little research has examined this idea within a chronic illness context. The current research takes a qualitative approach to examining similarities and differences between Black and White individuals with type 2 diabetes in the dimensions of support received from their family members, with a particular focus on better understanding more intrusive forms of support, such as unsolicited and overprotective support. Semi-structured interviews were conducted (N = 32) to characterize differences in support received by Black and White individuals with type 2 diabetes. The results of the thematic analysis suggested that unsolicited and overprotective support were not universally perceived to be negative, as previous work on White populations seemed to suggest. Rather, if the support provided was perceived as inhibiting autonomy, it was generally undesired by participants from both racial groups—however, for Black participants, knowing that the support was provided out of love could make it more acceptable. The analysis also revealed several underexplored dimensions of received support, including the directiveness of support and the tone used to deliver support. The current study provides an initial step towards grounding social support theory in the experiences of marginalized populations and will inform further development of a culturally sensitive measure of social support for individuals with chronic illness.

In a large randomized trial that compares regimens in which brentuximab vedotin replaced bleomycin, the group receiving the brentuximab had a 4.9 percentage-point improvement in modified progression-free survival, less pulmonary toxicity, and more myelotoxicity and neurotoxicity.

Solvency II requires that firms with Internal Models derive the Solvency Capital Requirement directly from the probability distribution forecast generated by the Internal Model. A number of UK insurance undertakings do this via an aggregation model consisting of proxy models and a copula. Since 2016 there have been a number of industry surveys on the application of these models, with the 2019 Prudential Regulation Authority (“PRA”) led industry wide thematic review identifying a number of areas of enhancement. This concluded that there was currently no uniform best practice. While there have been many competing priorities for insurers since 2019, the Working Party expects that firms will have either already made changes to their proxy modelling approach in light of the PRA survey, or will have plans to do so in the coming years. This paper takes the PRA feedback into account and explores potential approaches to calibration and validation, taking into consideration the different heavy models used within the industry and relative materiality of business lines.

Introduction Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. Methods Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23–42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations. Results The steady-state concentration 24 h post-dose (C 24 ) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration–time curve from dosing to 24 h post-dose (AUC 0–24 ), maximum concentration ( C max ), and C 24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC 0–24 , C 24 , and C max , respectively). Both drugs were generally well tolerated. Conclusion The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.

Background and Objective Doravirine is a novel non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1. In two open-label, single-dose, randomized, two-period, crossover trials, the bioavailability of doravirine administered alone or in a fixed-dose combination (FDC) was determined under fed and fasted conditions. Methods Doravirine 100 mg alone or with lamivudine and tenofovir disoproxil fumarate (each 300 mg) were administered to healthy subjects fasted or 30 min after a high-fat, high-calorie breakfast. Twenty-eight subjects, aged 26–55 years, enrolled (doravirine, n  = 14; FDC, n  = 14). The sequence of fed/fasted treatment was randomized (1:1). Pharmacokinetic data were analyzed as geometric mean ratios (GMRs) with 90% confidence intervals. Results Doravirine area under the plasma concentration–time curve (AUC) from time zero to infinity (fed/fasted GMRs: alone 1.16 [1.06–1.26]; FDC 1.10 [1.02–1.20]), AUC from time zero to the last measurement (GMRs: alone 1.18 [1.08–1.29]; FDC 1.10 [1.01–1.20]), and plasma concentration 24 h after administration (GMRs: alone 1.36 [1.19–1.55]; FDC 1.26 [1.13–1.41]) values increased in the fed versus fasted state when administered alone or as the FDC; the magnitude was not clinically meaningful. Doravirine maximum achieved concentration was similar after fed or fasted administration for both doravirine alone and FDC (GMRs: alone 1.03 [0.89–1.19]; FDC 0.95 [0.80–1.12]). The pharmacokinetics of tenofovir and lamivudine in the FDC were also slightly altered by administration with food; the changes were not clinically meaningful. Conclusions All treatments were generally well tolerated. Food had no clinically meaningful effect on doravirine 100 mg alone or as part of an FDC.

Background and Objective Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics. Methods In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4–18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements. Results Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78–1.06) and 0.90 (0.80–1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21–1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10–0.15), plasma concentration at 24 h post-dose: 0.03 (0.02–0.04), maximum plasma concentration: 0.43 (0.35–0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion. Conclusions Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma, N Engl J Med 2018;378:331-344. In the Abstract (page 331), the first sentence under Results should have begun, “At a median follow-up of 24.6 months,” rather than “. . . 24.9 months,” the lower limit of the first confidence interval should have been 78.8, rather than 78.7, and the final P value should have been 0.04, rather than 0.03. In the second sentence, the parenthetical should have read, “(hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20),” rather than “(hazard ratio . . . , 0.72 [95% CI, 0.44 to 1.17]; P=0.19).” In the Patients subsection of Results (page 334), the second sentence should have said that 59% . . .

Background The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. Objective The objective of this study was to quantitatively characterize the benefit–risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. Methods We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. Results Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. Conclusions These analyses support a favorable benefit–risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. Trial Registration Numbers ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537

Introduction Doravirine is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor exhibiting a robust safety and efficacy profile in combination with other antiretrovirals. While existing data do not suggest that doravirine delays cardiac repolarization, the aim of this trial was to evaluate the effects of a supratherapeutic dose of doravirine on the heart-rate corrected QT (QTc) interval in healthy adults. Methods A randomized, three-period, crossover, placebo-controlled trial was conducted in healthy adults, 18–55 years of age. Three treatments were administered: single-dose doravirine 1200 mg, placebo, and positive control (single-dose moxifloxacin 400 mg). QT interval measurements were collected at serial time points following treatment administration. Clinically significant placebo-corrected, baseline-adjusted QTc interval prolongation was defined when the upper bound of the two-sided 90% confidence interval (CI) for the mean effect on double delta QTc exceeded 10 ms. Doravirine tolerability and pharmacokinetics were also evaluated. Results Forty-five subjects were enrolled and 39 completed the study per protocol. Fridericia’s QT correction for heart rate was demonstrated to be inadequate; therefore, a population-specific correction was applied (QTcP). Assay sensitivity was confirmed with moxifloxacin. Following doravirine administration, QTc intervals did not exceed the pre-specified significance threshold – upper 90% CIs were ≤5.42 ms across all time points. Categorical analyses identified no outliers or clinically meaningful deviations. Doravirine geometric mean area under the time-concentration curve from dosing until 24 h post-dose (AUC 0–24 ) and maximum plasma concentration ( C max ) were 119 µM·h and 9240 nM, respectively, which exceeded values expected following therapeutic dose administration of doravirine 100 mg, even in the setting of intrinsic and extrinsic factors that may cause increases in doravirine concentrations. All treatments were generally well tolerated. Conclusion A single oral supratherapeutic dose of doravirine 1200 mg does not cause clinically meaningful QTc interval prolongation in healthy adults.