18, * on behalf of the participants of the WHO-IMPAACT workshop on "Approaches to Optimize and Accelerate Pharmacokinetic Studies in Pregnant and Lactating Women" † Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middleincome countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical. BACKGROUND Pregnancy is associated with profound physiologic, immunologic, structural, and inflammatory changes. 1 These dynamic changes occur in the maternal and feto-placental units during pregnancy, and significantly influence the pharmacokinetic (PK) processes of drug absorption, 2 distribution, 3,4 metabolism, 1,5 and excretion. 6 For women living with HIV, altered pharmacokinetics during pregnancy can often result in lower antiretroviral (ARV) drug exposures, 7-9 possibly increasing the risk of treatment failure, 10 maternal HIV disease progression, perinatal transmission, drug resistance, 11 and maternal death. 11 Some guidelines recommend dose adaptation of certain ARVs in pregnancy because of lower drug exposures (lopinavir/ritonavir; darunavir/ritonavir). 12
Despite significant progress in paediatric HIV treatment, optimal antiretroviral formulations for infants, children and adolescents remain limited. The paediatric antiretroviral drug optimization group regularly reviews medium-and long-term priorities for antiretroviral drug development, to guide industry and other stakeholders on formulations most needed for low-and middle-income countries. Ongoing medium-term priorities include a scored dispersible dolutegravir tablet (10mg), a dolutegravir-containing fixed-dose combination, and fixed-dose combinations containing tenofovir alafenamide. Darunavir/ritonavir combination tablet remain a priority for second-line treatment. Future treatment options of potential interest for paediatrics include broadly neutralizing antibodies, long acting/extended release formulations, and novel technologies. Issues specific to neonatal prophylaxis and treatment, and to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women are also discussed. Continued focus on identifying, prioritizing and ensuring access to optimal formulations suitable for infants, children and adolescents is key to ensuring that global HIV treatment targets can be met.
Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis.
Background: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. Setting: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10–12, 2018, in Geneva, Switzerland. Methods: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. Results: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely—under certain conditions—allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. Conclusion: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.