Transfer of daclatasvir and sofosbuvir’s main metabolite, GS-331007, across the human placenta ex vivo

Freriksen, Jolien J. M.; Meijerhof, Miriam; Drongelen, J. van; Drenth, Joost P.H.; Burger, David M.; Rüssel, Frans G. M.; Colbers, Angela; Greupink, Rick

doi:10.1016/j.ajog.2020.08.107

Cited by 3 publications

(1 citation statement)

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“…In a drug development setting, the PBPK approach may be used to predict human maternal and foetal exposure during pregnancy in an early stage of drug trials and, therefore, can help inform the probability that the dose selected for phase 2b/3 in pregnancy generates effective plasma concentrations in the mother. With respect to foetal exposure, PBPK models have also been successfully extended and parameterized with data from ex vivo human placenta perfusion studies or data from human cellular systems that mimic the human placental barrier in vitro [ 19 , 20 , 21 , 22 , 23 ]. Further standardization of the experimental approaches, consensus on how such data can be best incorporated in PBPK models and systematic evaluation of the models will help further advance this field in the coming years.…”

Section: Discussionmentioning

confidence: 99%

Non‐clinical considerations for supporting accelerated inclusion of pregnant women in pre‐licensure clinical trials with anti‐HIV agents

et al. 2022

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Introduction:To allow the continued participation of women enrolled in pre-licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non-clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre-licensure trials. Discussion: Completing all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre-licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non-clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non-clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non-clinical findings and the overall benefit-risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre-licensure trials to remain on study will depend on the totality of the evidence and benefit-risk considerations. Conclusions: We propose that industry completes non-clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal.

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