Background Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. Objective To provide recommendations for systematic evaluation of evidence from the scientific literature, drug product labeling, and regulatory documents with respect to DDIs for clinical decision support. Methods A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 15 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. Results We developed expert-consensus answers to three key questions: 1) What is the best approach to evaluate DDI evidence?; 2) What evidence is required for a DDI to be applicable to an entire class of drugs?; and 3) How should a structured evaluation process be vetted and validated? Conclusion Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug information systems that implement these recommendations should be able to provide higher quality information about DDIs in drug compendia and clinical decision support tools.

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Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA.

The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.

Objective: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared to postpartum and in infant washout samples after delivery. Design: Nonrandomized, open-label, parallel-group, multi-center phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the U.S. Methods: Intensive steady-state 24 hour pharmacokinetic profiles after 150 mg of elvitegravir and 150 mg of cobicistat given orally in fixed dose combination once-daily were performed during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Elvitegravir and cobicistat were measured in plasma by a validated LC-MS/MS assay with a lower quantitation limit of 10 ng/mL. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. Results: Thirty pregnant women taking elvitegravir and cobicistat once-daily enrolled in the study. Compared to paired postpartum data, elvitegravir AUC0–24 was 24% lower in the second trimester (n=14, P=0.058, GMR=0.76, 90% CI 0.57–1.0) and 44% lower in the third trimester (n=24, P=0.0001, GMR=0.56, 90% CI 0.42–0.73), while cobicistat AUC0–24 was 44% lower in the second trimester (n=14, P=0.0085, GMR=0.56, 90% CI 0.37 – 0.85) and 59% lower in the third trimester (n=24, p<.0001, GMR=0.41, 90% CI 0.30 – 0.57). Median cord blood elvitegravir concentration was 540.6 ng/mL and the median ratio of cord blood to maternal plasma elvitegravir concentrations was 0.91. Conclusions: Standard elvitegravir and cobicistat dosing during pregnancy results in significantly lower exposure which may increase the risk of virologic failure and mother-to-child transmission. Additional studies are needed to optimize elvitegravir and cobicistat dosing regimens in pregnant women.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.