Obstetric Pharmacokinetic Dosing Studies are Urgently Needed

McCormack, Shelley A.; Best, Brookie M.

doi:10.3389/fped.2014.00009

Cited by 52 publications

(51 citation statements)

References 106 publications

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“…As highlighted in recent reviews, pharmacokinetic data for drugs in pregnancy are scarce, and there are large knowledge gaps (40). 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).…”

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. This may lead to over or under dosing and may reduce efficacy and increase risk of toxicity.…”

Section: Identification Of Potentially Useful or Experimental Drmentioning

confidence: 99%

“…344,345,346 In addition, their safety, tolerability, efficacy and dosing were extrapolated from studied conducted in men or non-pregnant women. This leads to under or over dosing and affects efficacy and toxicity of these medications.…”

Section: Identification Of Potentially Useful or Experimental Drmentioning

confidence: 99%

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

237

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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“…Exclusion of pregnant women from research is still common practice [19, 20]. A recent review demonstrated that between 1960 and 2013 only about 1% of pharmacokinetic clinical trials were conducted for pregnant women, and the ones that were undertaken had a strong focus on acute labor and delivery issues [21]. Not surprisingly, a 2011 study on all medications approved by the FDA from 1980 to 2010 found that 91% of the medications approved for use by adults did not have sufficient data on safety, efficacy and fetal risk of medication taken during pregnancy [22].…”

Section: Introductionmentioning

confidence: 99%

“…Not surprisingly, a 2011 study on all medications approved by the FDA from 1980 to 2010 found that 91% of the medications approved for use by adults did not have sufficient data on safety, efficacy and fetal risk of medication taken during pregnancy [22]. At the same time, the number of pregnant women who take medications, as well as the number of medications that these pregnant women take, has increased [6, 21]. …”

Section: Introductionmentioning

confidence: 99%

Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach

Graaf

Zande

Ruijter

et al. 2018

Trials

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BackgroundSince pregnant women are severely underrepresented in clinical research, many take the position that the exclusion of pregnant women from research must be justified unless there are compelling “scientific reasons” for their exclusion. However, it is questionable whether this approach renders research with pregnant women fair. This paper analyzes and evaluates when research with pregnant women can be considered as fair and what constitutes scientific reasons for exclusion.MethodsConceptual ethical and methodological analysis and evaluation of fair inclusion.ResultsFair inclusion of pregnant women means (1) that pregnant women who are eligible are not excluded solely for being pregnant and (2) that the research interests of pregnant women are prioritized, meaning that they ought to receive substantially more attention. Fairness does not imply that pregnant women should be included in virtually every research project, as including only a few pregnant women in a population consisting only of women will not help to determine the effectiveness and safety of a treatment in pregnant women. Separate trials in pregnant women may be preferable once we assume, or know, that effects of interventions in pregnant women differ from the effects in other subpopulations, or when we assume, or know, that there are no differences. In the latter case, it may be preferable to conduct post-marketing studies or establish registries. If there is no conclusive evidence indicating either differences or equivalence of effects between pregnant and non-pregnant women, yet it seems unlikely that major differences or exact equivalence exist, the inclusion of pregnant women should be sufficient. Depending on the research question, this boils down to representativeness in terms of the proportion of pregnant and non-pregnant women, or to oversampling pregnant women.ConclusionsFair inclusion of pregnant women in research implies that separate trials in pregnant women should be promoted. Inclusion of pregnant women has to be realized at the earliest phases of the research process. In addition to researchers and research ethics committees, scientific advisory councils, funders, drug regulatory agencies, pharmaceutical companies, journal editors and others have a joint responsibility to further develop the evidence base for drug use in pregnant women.

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Obstetric Pharmacokinetic Dosing Studies are Urgently Needed

Cited by 52 publications

References 106 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

Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach

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