An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ahizechukwu C. Eke
Keyword(s):  
Drug Exposure ◽  
Correct Diagnosis ◽  
Drug Effects ◽  
Medical Community ◽  
Physiological Changes ◽  
Physiologically Based Pharmacokinetic ◽  
Historic Data ◽  
New Evidence ◽  
Drug Pharmacokinetics ◽  
Large Prospective Cohort

Abstract For many years, the medical community has relied in clinical practice on historic data about the physiological changes that occur during pregnancy. However, some newer studies have disputed a number of assumptions in these data for not being evidence-based or derived from large prospective cohort-studies. Accurate knowledge of these physiological changes is important for three reasons: Firstly, it facilitates correct diagnosis of diseases during pregnancy; secondly, it enables us to answer questions about the effects of medication during pregnancy and the ways in which pregnancy alters pharmacokinetic and drug-effects; and thirdly, it allows for proper modeling of physiologically-based pharmacokinetic models, which are increasingly used to predict gestation-specific changes and drug–drug interactions, as well as develop new knowledge on the mode-of-action of drugs, the mechanisms underlying their interactions, and any adverse effects following drug exposure. This paper reviews new evidence regarding the physiologic changes during pregnancy in relation to existing knowledge.

scholarly journals A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 204
Author(s):  
Erik Sjögren ◽  
Joel Tarning ◽  
Karen I. Barnes ◽  
E. Niclas Jonsson
Keyword(s):  
Body Composition ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Pediatric Population ◽  
Model Performance ◽  
Vulnerable Population ◽  
Pbpk Modeling ◽  
Malnourished Children ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically-based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on (a) the differences in body composition between healthy and malnourished adults and (b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

scholarly journals Short-term oxaliplatin exposure according to established hyperthermic intraperitoneal chemotherapy (HIPEC) protocols lacks effectiveness in vitro and ex vivo

2019 ◽  
Author(s):  
Markus W. Löffler ◽  
Nick Seyfried ◽  
Markus Burkard ◽  
Benedikt Oswald ◽  
Alexander Tolios ◽  
...  
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Drug Exposure ◽  
Ex Vivo ◽  
Medical Center ◽  
Drug Effects ◽  
Patient Treatment ◽  
Cell Shrinkage ◽  
Cell Assay

AbstractCytotoxicity of oxaliplatin-containing solutions (OCS), sampled during patient treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), was assessed by well-established continuous impedance-based real-time cell analysis (RTCA) ex vivo. HIPEC treatment was replicated by exposing OAW-42 cancer cells to OCS for 30 or 60 minutes at 42 °C. In contrast to previous observations with continuous exposure, where cytotoxicity was proven, identical OCS obtained during HIPEC did not induce cell death reproducibly and showed strongly attenuated effects after only 30 minutes of application. Based on these unexpected findings, spike-ins of oxaliplatin (OX) into peritoneal dialysis solution (PDS) or dextrose 5 % in water (D5W) were used to replicate HIPEC conditions, as used in either our own protocols or the recently presented randomized controlled PRODIGE 7 trial, where OX HIPEC for 30 minutes failed to produce survival benefits in colorectal carcinoma patients. With OX-spiked into D5W or PDS at identical concentrations as used for PRODIGE 7 or conforming with own HIPEC protocols, we did not observe the expectable cytotoxic effects in RTCA, after replicating OX HIPEC for 30 minutes. These results were corroborated for both solvents at relevant drug concentrations by classical end-point assays for cytotoxicity in two cancer cell lines. Further results suggest that penetration depth, drug dosage, exposure time and drug solvents may constitute critical factors for HIPEC effectiveness. Accordingly, we witnessed substantial cell shrinkage with both PDS and D5W, potentially contributing to reduced drug effects. Based on these results, intensified pharmacological research seems warranted to establish effective HIPEC protocols.Key PointsOxaliplatin (OX)-containing solutions obtained during patient treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC) unexpectedly showed low cytotoxicity in an impedance-based ex vivo cytotoxicity cell assay.OX cytotoxicity under HIPEC conditions could be enhanced by extending drug exposure to one hour by an impedance-based ex vivo cytotoxicity cell assay.HIPEC failed to show survival benefits in the randomized controlled PRODIGE 7 trial and was questioned in the aftermath.Clinically relevant OX concentrations applied in conjunction with hyperthermia (42 °C) for 30 minutes, as used either at our own medical center or according to the PRODIGE 7 trial, proved predominantly ineffective, when used according to HIPEC routines in an impedance-based in vitro cytotoxicity cell assay.Respective findings were corroborated in two different cell lines and by two established end-point assays, showing that 50 % cell death could not be reached by the same HIPEC treatment with OX, in contrast to continuous drug exposure.As potentially relevant factor, the thickness of the exposed cell layer was identified, requiring at least ~100 µm penetration depth for our model to indicate effectiveness.Additionally, we show relevant cell shrinkage by two drug diluents used either at our own medical center or according to the PRODIGE 7 trial, potentially associated with fluid shifts out of the cell and impaired drug effects.Our own as well as recent findings by Ubink et al. (Br J Surg. 2019. doi: 10.1002/bjs.11206) support the notion that lacking effectiveness of OX HIPEC may explain the negative PRODIGE 7 trial results.

scholarly journals Regional Analysis of the Brain Transcriptome in Mice Bred for High and Low Methamphetamine Consumption

2019 ◽  
Vol 9 (7) ◽  
pp. 155 ◽  
Author(s):  
Hitzemann ◽  
Iancu ◽  
Reed ◽  
Baba ◽  
Lockwood ◽  
...  
Keyword(s):  
Large Scale ◽  
Drug Exposure ◽  
Regional Analysis ◽  
Drug Effects ◽  
Network Connectivity ◽  
Transcriptome Profiling ◽  
Rna Seq ◽  
Reward Circuitry ◽  
Brain Transcriptome ◽  
Differential Gene

Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq data from selectively bred mice with high or low risk for voluntary MA intake to construct coexpression and cosplicing networks for differential risk. Three brain reward circuitry regions were explored, the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral midbrain (VMB). With respect to differential gene expression and wiring, the VMB was more strongly affected than either the PFC or NAc. Coexpression network connectivity was higher in the low MA drinking line than in the high MA drinking line in the VMB, oppositely affected in the NAc, and little impacted in the PFC. Gene modules protected from the effects of selection may help to eliminate certain mechanisms from significant involvement in risk for MA intake. One such module was enriched in genes with dopamine-associated annotations. Overall, the data suggest that mitochondrial function and glutamate-mediated synaptic plasticity have key roles in the outcomes of selective breeding for high versus low levels of MA intake.

Bladder pain syndrome

2017 ◽  
Author(s):  
Magnus Fall
Keyword(s):  
Treatment Options ◽  
Correct Diagnosis ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Clinical Syndrome ◽  
Personal Life ◽  
Medical Community ◽  
Bladder Pain ◽  
Profound Impact ◽  
Medical Consultations

Bladder pain syndrome has a profound impact on the patients’ physical, professional, and personal life. Generally, recognition of this clinical syndrome is hampered by insufficient expertise in the medical community. The correct diagnosis is often delayed by several years and may be preceded by multiple medical consultations and treatment attempts. Still, this is one of the most painful, non-malignant conditions to be encountered in urology and it is probably more common than generally believed. Problems as to diagnosis, phenotyping, terminology, and management persist, but during the last few years there has been increasing activity to resolve those issues. In this chapter, symptoms, findings, and treatment options are outlined.

scholarly journals Does Prenatal Methamphetamine Exposure Induce Sensitization to Drugs in Adulthood?

2017 ◽  
pp. S457-S467 ◽  
Author(s):  
E. MACÚCHOVÁ ◽  
R. ŠLAMBEROVÁ
Keyword(s):  
Infant Development ◽  
Drug Exposure ◽  
Behavioral Sensitization ◽  
Drug Effects ◽  
Mechanisms Of Action ◽  
Prenatal Drug Exposure ◽  
Self Administration ◽  
Psychomotor Activity ◽  
Seeking Behavior ◽  
Reward Pathways

Behavioral sensitization is defined as augmented psychomotor activity, which can be observed after drug re-administration following withdrawal of repeated drug exposure. It has been shown that abuse of one drug can lead to increased sensitivity to certain other drugs. This effect of developed general drug sensitivity is called cross-sensitization and has been reported between drugs with similar as well as different mechanisms of action. There is growing evidence that exposure to drugs in utero not only causes birth defects and delays in infant development, but also impairs the neural reward pathways, in the brains of developing offspring, in such a way that it can increase the tendency for drug addiction later in life. This review summarizes the results of preclinical studies that focused on testing behavioral cross-sensitization, after prenatal methamphetamine exposure, to drugs administered in adulthood, with both similar and different mechanisms of action. Traditionally, behavioral sensitization has been examined using the Open field or the Laboras Test to record locomotor activity, and the Conditioned Place Preference and Self-administration test to examine drug-seeking behavior. However, it seems that prenatal drug exposure can sensitize animals not only to the locomotor-stimulating and conditioning effects of drugs, but may also be responsible for modified responses to various drug effects.

scholarly journals Regulatory Considerations for the Mother, Fetus and Neonate in Fetal Pharmacology Modeling

2021 ◽  
Vol 9 ◽  
Author(s):  
Dionna J. Green ◽  
Kyunghun Park ◽  
Varsha Bhatt-Mehta ◽  
Donna Snyder ◽  
Gilbert J. Burckart
Keyword(s):  
Pregnant Women ◽  
Drug Exposure ◽  
New Drugs ◽  
Pbpk Modeling ◽  
Specific Information ◽  
Exposure Estimation ◽  
Physiologically Based Pharmacokinetic ◽  
Institutional Review ◽  
The Us ◽  
Fetus And Neonate

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.

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