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Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

ABSTRACT: Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.

SUBMITTER: Penazzato M

PROVIDER: S-EPMC5927327 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

Penazzato Martina M Gnanashanmugam Devasena D Rojo Pablo P Lallemant Marc M Lewis Linda L LL Rocchi Francesca F Saint Raymond Agnes A Ford Nathan N Hazra Rohan R Giaquinto Carlo C Belew Yodit Y Gibb Diana M DM Abrams Elaine J EJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20170601 11

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, f ...[more]

PMID: 29190337

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Project description:IntroductionThis review summarizes the current dosing recommendations for antiretroviral (ARV) drugs in the international pediatric guidelines of the World Health Organization (WHO), US Department of Health and Human Services (DHHS), and Pediatric European Network for Treatment of AIDS (PENTA), and evaluates the research that informed these approaches. We further explore the role of data generated through therapeutic drug monitoring in optimizing the dosing of ARVs in children.MethodsA PubMed search was conducted for the literature on ARV dosing published in English. In addition, the registration documentation of European Medicines Agency and the US Food and Drug Administration for currently used ARVs and studies referenced by the WHO, DHHS, and EMA guidelines were screened. Resulting publications were screened for papers containing data on the area under the concentration-time curve, trough concentration, and peak concentration. Studies with enrolled participants with a median or mean age of ≥18 years were excluded. No restriction on publishing date was applied.Discussion and conclusionPediatric ARV dosing is frequently based on data obtained from small studies and is often simplified to facilitate dosing in the context of a public health approach. Pharmacokinetic parameters of pediatric ARVs are subject to high interpatient variation and this leads to a potential risk of underdosing or overdosing when drugs are used in real life. To ensure optimal use of ARVs and validate dosing recommendations for children, it is essential to monitor ARV dosing more thoroughly with larger sample sizes and to include diverse subpopulations. Therapeutic drug monitoring data generated in children, where available and affordable, have the potential to enhance our understanding of the appropriateness of simplified pediatric dosing strategies recommended using a public health approach and to uncover suboptimal dosing or other unanticipated issues postmarketing, further facilitating the ultimate goal of optimizing pediatric ARV treatment.

Project description:Excipients are included within protein biotherapeutic solution formulations to improve colloidal and conformational stability but are generally not designed for the specific purpose of preventing aggregation and improving cryoprotection in solution. In this work, we have explored the relationship between the structure and antiaggregation activity of excipients by utilizing coarse-grained molecular dynamics modeling of protein-excipient interaction. We have studied human serum albumin as a model protein, and we report the interaction of 41 excipients (polysorbates, fatty alcohol ethoxylates, fatty acid ethoxylates, phospholipids, glucosides, amino acids, and others) in terms of the reduction of solvent accessible surface area of aggregation-prone regions, proposed as a mechanism of aggregation prevention. Polyoxyethylene sorbitan had the greatest degree of interaction with aggregation-prone regions, decreasing the solvent accessible surface area of APRs by 20.7 nm2 (40.1%). Physicochemical descriptors generated by Mordred are employed to probe the structure-property relationship using partial least-squares regression. A leave-one-out cross-validated model had a root-mean-square error of prediction of 4.1 nm2 and a mean relative error of prediction of 0.077. Generally, longer molecules with a large number of alcohol-terminated PEG units tended to interact more, with qualitatively different protein interactions, wrapping around the protein. Shorter or less ethoxylated compounds tend to form hemimicellar clusters at the protein surface. We propose that an improved design would feature many short chains of 5 to 10 PEG units in many distinct branches and at least some hydrophobic content in the form of medium-length or greater aliphatic chains (i.e., six or more carbon atoms). The combination of molecular dynamics simulation and quantitative modeling is an important first step in an all-purpose protein-independent model for the computer-aided design of stabilizing excipients.

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Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

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Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

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