Adaptation of clinical practice guidelines for osteoporosis in a Mexican context. Experience using methodologies ADAPTE, GRADE-ADOLOPMENT, and RAND/UCLA.

High quality guidelines are required to enhance clinical practice, but its development is time consuming and a complex process. Adaptation might shorten development time and prevent double effort adjusting recommendations for a local context. BACKGROUND AND OBJECTIVE: The aim of this article is to present our experience in a process in which we combined two methodologies for the adaptation of high quality osteoporosis CPGs for a primary health care context, with the inclusion of a formal consensus. METHODS: We began an adaptation process with ADAPTE, and required to migrate to GRADE-ADOLOPMENT methodology, based on GIN-McMaster Guideline Development Checklist. To identify high quality clinical practice guidelines, we performed a systematic review as per the PRISMA-statement methodology (PROSPERO: CRD42019138548, August 19th, 2019); methodological quality was assessed using the Appraisal of Guidelines for Research & Evaluation version II system. We developed a RAND/UCLA consensus to support the inclusion of good practice statements and feasibility of selected recommendations. RESULTS: Thirteen clinical questions were integrated, and fracture risk was selected as the main outcome for intervention recommendations analysis. Six high quality guidelines were selected. We prepared final recommendations from selected guides in an evidence synthesis framework. After the consensus, we integrated 50 recommendations. CONCLUSION: By starting the adaptation process with ADAPTE, we experienced a time consuming process, which we could overcome when migrating to GRADE-Adolopment in combination with a consensus panel.

The future trajectory of adverse outcome pathways: a commentary.

The advent of adverse outcome pathways (AOPs) has provided a new lexicon for description of mechanistic toxicology, and a renewed enthusiasm for exploring modes of action resulting in adverse health and environmental effects. In addition, AOPs have been used successfully as a framework for the design and development of non-animal approaches to toxicity testing. Although the value of AOPs is widely recognised, there remain challenges and opportunities associated with their use in practise. The purpose of this article is to consider specifically how the future trajectory of AOPs may provide a basis for addressing some of those challenges and opportunities.

Legacy data sharing to improve drug safety assessment: the eTOX project.

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility.

Telaprevir: pharmacokinetics and drug interactions.

Telaprevir is an inhibitor of the HCV NS3/4A protease. When used in combination with pegylated interferon and ribavirin, telaprevir has demonstrated a substantial increase in sustained virological response compared with pegylated interferon and ribavirin used alone. Telaprevir has good oral bioavailability, which is enhanced when administered with food. Telaprevir is extensively metabolized and primarily eliminated via faeces. No dose adjustment of telaprevir is needed in patients with mild to severe renal impairment or mild liver impairment. Telaprevir is a substrate and inhibitor of cytochrome P450 3A and P-glycoprotein and, thus, might interact with coadministered drugs that affect or are affected by these metabolic/transport pathways. This article reviews the pharmacokinetic and drug interaction profile of telaprevir.

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A.

AIM: The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP(1) antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg). METHOD: GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction. RESULTS: Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V(ss) ) and terminal elimination half-life (t(1/2) ) of GSK269984A were 9.8 l h(-1) , 62.8 l and 8.2 h. C(max) and AUC(0,∞) were 3.2 ng ml(-1) and 10.2 ng ml(-1) h, respectively; the corresponding oral parameters were 1.8 ng ml(-1) and 9.8 ng ml(-1) h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey). CONCLUSION: For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

Calidad de vida en dermatología / Quality of life in dermatology

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