Exclusion of Pregnant Women From Industry-Sponsored Clinical Trials

Shields, Kristine E.; Lyerly, Anne Drapkin

doi:10.1097/aog.0b013e3182a9ca67

Cited by 149 publications

(134 citation statements)

References 6 publications

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“…Given that "pregnant women get sick and sick women get pregnant," that pregnancy can have a significant and sometimes unpredictable impact on drug disposition, and that pregnant women are routinely excluded from trials of new drugs (limiting our knowledge of safety and optimal dosing in this special population), assessment of drugs in pregnancy is a high priority (41). This is especially true for diseases like TB for which treatment options are extremely limited.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

Denti

Martinson

Cohn

et al. 2016

Antimicrob Agents Chemother

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Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

Denti

Martinson

Cohn

et al. 2016

Antimicrob Agents Chemother

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“…343,344,345 In a recent review of the literature, less than 2% of all PK studies involved pregnant women. 346 This is concerning since the lack of data on pregnancy specific dosage of many medications leads physicians to extrapolate drug dosage regimens from non-pregnant subjects or men.…”

Section: Identification Of Potentially Useful or Experimental Drmentioning

confidence: 99%

“…This will lead to more effective treatment of pregnant women, while reducing the risks of adverse events. 344 The new FDA rule regarding drug classification represents a huge current opportunity to encourage research in this field.…”

Section: Identification Of Potentially Useful or Experimental Drmentioning

confidence: 99%

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Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

Ilekis

Tsilou

Fisher

et al. 2016

American Journal of Obstetrics and Gynecology

232

167

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Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

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“…This reality is clearly evident in the data showing pregnant women are actively excluded from 98% of trials involving drug administration [3]. Hence, trials of new drugs and formulations applicable to pregnancy are left primarily to small companies and university-affiliated clinical academics and scientists with limited funding and resources ( Figure 1A & B).…”

mentioning

confidence: 99%

Therapeutic and Safety Considerations of Nanoparticle-Mediated Drug Delivery in Pregnancy

Keelan

Leong

et al. 2015

Nanomedicine (Lond.)

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Advances in nanotechnology have resulted in the design of effective, safe and tissue-selective nanocarriers for delivering therapeutics to treat malignancies, infections and other diseases. In pregnancy, nanoparticle-based drug formulations could have the potential to selectively target either the placenta and/or fetus, enabling 'fetal-friendly' drugs to be administered in pregnancy with minimal risk of off-target effects. A considerable amount of research has been carried out on maternal-placental-fetal nanoparticle uptake, transfer and toxicity using rodent and ex vivo models. However, the development of placental targeting strategies and the therapeutic evaluation of nanoformulations in pregnancy remains in its infancy. While some promising avenues are currently under investigation, much work is needed to bring the advantages of nanoparticle-based drug therapy in pregnancy to clinical reality.

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Exclusion of Pregnant Women From Industry-Sponsored Clinical Trials

Cited by 149 publications

References 6 publications

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

Therapeutic and Safety Considerations of Nanoparticle-Mediated Drug Delivery in Pregnancy

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