Letermovir (AIC246, MK‐8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7‐, 2.4‐, and 3.4‐fold increases in area under the plasma concentration–time curve and 1.1‐, 1.6‐, and 2.8‐fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration–time curve by 2.1‐fold and maximum plasma concentration by 1.5‐fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine.

Objective To compare test performance of hemoglobin A1c (HbA1c) for detecting diabetes/prediabetes for US adolescents vs. adults. Study design Individuals were defined as having diabetes (fasting plasma glucose (FPG) ≥126 mg/dl; 2-hour plasma glucose (2-hr PG) ≥200 mg/dl) or prediabetes (100≤FPG<126 mg/dl; 140≤2-hr PG<200 mg/dl). HbA1c test performance was evaluated using receiver operator characteristic (ROC) analyses. Results Few adolescents had undiagnosed diabetes (n=4). When assessing FPG to detect diabetes, an HbA1c of 6.5% had sensitivities of 75.0% (30.1–95.4) and 53.8% (47.4–60.0) and specificities of 99.9% (99.5–100.0) and 99.5% (99.3–99.6) for adolescents and adults, respectively. Additionally, when assessing FPG to detect diabetes, an HbA1c of 5.7% had sensitivities of 5.0% (2.6–9.2) and 23.1% (21.3–25.0) and specificities of 98.3% (97.2–98.9) and 91.1% (90.3–91.9) for adolescents and adults, respectively. ROC analyses suggested that HbA1c is a poorer predictor of diabetes (AUC 0.88 vs. 0.93), and prediabetes (FPG: AUC 0.61 vs. 0.74) for adolescents compared with adults. Performance was poor regardless of using FPG or 2-hr PG measurements. Conclusions Use of HbA1c for diagnosis of diabetes and prediabetes in adolescents may be premature, until information from more definitive studies is available.

The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

WHAT'S KNOWN ON THIS SUBJECT: Primary hypertension is a growing concern in adolescents due to its association with the obesity epidemic. Recent studies have examined underdetection and underdiagnosis of hypertension in adolescents but medical management of primary hypertension in adolescents is not welldescribed.WHAT THIS STUDY ADDS: Our study describes patterns of antihypertensive prescribing for adolescents with primary hypertension including the use of monotherapy versus combination therapy by physicians of different specialties and factors associated with receipt of antihypertensive therapy over a multi-year period. abstract BACKGROUND: Hypertension is an increasingly common problem in adolescents yet current medical management of primary hypertension in adolescents has not been well-described. METHODS:We identified adolescents with primary hypertension by International Classification of Diseases, Ninth Revision codes and looked at prescription patterns chronologically for antihypertensive drug class prescribed and the specialty of prescribing physician. We also examined patient demographics and presence of obesity-related comorbidities. During 2003During -2008, there were 4296 adolescents with primary hypertension (HTN); 66% were boys; 73% were aged 11 to 14 years; 53% were black, 41% white, and 4% Hispanic; and 48% had obesity-related comorbidity. Twenty-three percent (977) received antihypertensive prescription. White subjects (odds ratio [OR]: 1.61; confidence interval [CI]: 1.39-1.88), older adolescents ($15 years, OR: 2.11; CI: 1.79-2.48), and those with comorbidity (OR: 1.57; CI: 1.36-1.82) were more likely to receive antihypertensive prescriptions controlling for gender and years of Medicaid eligibility in logistic regression. Angiotensin converting enzyme inhibitors were the most frequently prescribed monotherapy. Nearly two-thirds of adolescents received prescriptions from adult primary care physicians (PCPs) only. More than one-quarter of adolescents who received a prescription received combination therapy, which was most often prescribed by adult PCPs. RESULTS:CONCLUSIONS: Adult PCPs were the leading prescribers of antihypertensives for adolescents with primary HTN. Race differences exist in physicians' prescribing of antihypertensives to adolescents with primary HTN. The choice of antihypertensives by physicians of different specialties warrants additional study to understand the underlying rationale for treatment decisions and to determine treatment effectiveness. Pediatrics 2012;129:e1-e8

IntroductionAZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator (SGRM), currently in development for the treatment of asthma and chronic obstructive pulmonary disease. This paper reports a randomized placebo-controlled dose escalation study in healthy Japanese male subjects.MethodsInhaled AZD7594 was administered as one single dose at day 1 (day 1–4), with subsequent multiple daily doses (day 5–16) via a multiple-dose dry powder inhaler for 12 days of once-daily treatment. At each dose level, subjects were randomized to AZD7594 (n=7) or placebo (n=2). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 were evaluated.ResultsInhaled AZD7594 was safe and well tolerated up to and including the highest dose 1600 µg tested. Plasma exposure suggested dose-proportional PK. The urinary excretion of AZD7594 was negligible (<0.02%). Dose-related effects were observed for 24 hrs plasma cortisol; however, significant cortisol suppression (25%) was only seen at the highest dose level following multiple doses. There were no or only marginal effects on other biomarkers tested (dehydroepiandrosterone sulfate [DHEA-S] and osteocalcin).ConclusionIn conclusion, the early clinical evaluation of inhaled AZD7594 suggests that this novel SGRM is well tolerated in the dose range investigated and also in a Japanese population. It shows dose-proportional plasma exposure, moderate accumulation and has limited impact on systemic markers of glucocorticoid activity.