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Overview of the pharmacokinetics of intravenous (iv) paracetamol in cohorts of women as retrieved in literature
Source publication
Background:
There is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women.
Methods:
Population PK parameters using non-linear mixed effect modelling were estimated in a poo...
Context in source publication
Context 1
... the impact of pregnancy and oral contraceptives on intravenous paracetamol clearance have been reported earlier in literature (Table 3) [9,10,14,16,18,19]. In the current pooled analysis, we clearly linked this raised clearance with a raised paracetamol glucuronidation activ- ity and initially hypothesized that this was associated with oestradiol as biomarker. ...
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Objective:
To assess the relationship between abdominal pain severity during the menopausal transition (MT) and age, MT stage, reproductive biomarkers, stress biomarkers, and stress perceptions.
Methods:
Women ages 35-55 were recruited from multiethnic neighborhoods in the greater Seattle area from 1990 to 1992, for an original study cohort of 5...
Citations
... The popPK of oral administered paracetamol has been described in the literature using a one-, two-or three-compartment model [20][21][22][23]. Therefore, it was decided to start the modelling exercise using a one-compartment model with a first-order absorption. ...
To date, food–drug interactions in the pediatric population remain understudied. The current food effect studies are mostly performed in adults and do not mimic the real-life situation in the pediatric population. Since the potential benefits of food effect studies performed in pediatrics should be counterbalanced with the burden that these studies pose to the patients, alternative research strategies should be evaluated. The present study aimed to evaluate whether population pharmacokinetics (popPK) using data in beagle dogs and human adults could reliably assess food effects relevant for the pediatric population. PopPK was utilized to understand the performance of paracetamol under different dosing conditions (when the participants were fasted, with a reference meal, and with infant formula) in human adults (n = 8) and beagle dogs (n = 6) by constructing models to derive the pharmacokinetic parameters and to evaluate the food effects in both species. A two-compartment model with a single input function for the absorption phase best described the profiles of paracetamol in the beagle dogs. In the human adults, a one-compartment model with a dual input function for the absorption phase best described the data. The simulated profiles for the different dosing conditions demonstrated that both the human adults’ and beagle dogs’ simulations were able to acceptably describe the plasma concentration–time profiles of paracetamol observed in a representative pediatric population, which opens up perspectives on pediatric-relevant food effect predictions. However, the obtained results should be carefully interpreted, since an accurate validation of these findings was not possible due to the scarcity of the literature on observed pediatric data.
... For example, paracetamol metabolic clearance by glucuronidation via UDP-glucuronosyltransferase (UGT) enzyme activity is affected by oestradiol levels. This results in a lower paracetamol clearance during early postpartum in lactating women (as their oestradiol levels are lower) [70]. This indicates the need to further explore and incorporate postpartum clearance of medicines and more specifically, endocrine driven enzyme activity. ...
Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed infant PBPK models. For instance, most women retain pregnancy weight during the postpartum period, especially after excessive gestational weight gain, while breastfeeding might be associated with lower postpartum weight retention and long-term weight control. Based on a structured search, an equation for human milk intake reported the maximum intake of 153 mL/kg/day in exclusively breastfed infants at 20 days, which correlates with a high risk for medicine reactions at 2–4 weeks in breastfed infants. Furthermore, the changing composition of human milk and its enzymatic activities could affect pharmacokinetics in breastfed infants. Growth in breastfed infants is slower and gastric emptying faster than in formula-fed infants, while a slower maturation of specific metabolizing enzymes in breastfed infants has been described. The currently available PBPK models for these populations lack structured systematic acquisition of population-specific data. Future directions include systematic searches to fully identify physiological data. Following data integration as mathematical equations, this holds the promise to improve postpartum, lactation and infant PBPK models.
... 1A1 and cytochrome-P-450 (CYP) 2E1 to pregnancy (13,19). The predicted acetaminophen pharmacokinetics in the maternal blood were previously verified in the first trimester with clinical data from Beaulac-Baillargeon and Rocheleau (22); predicted acetaminophen pharmacokinetics in the maternal and umbilical vein blood at delivery were previously evaluated with data from Allegaert et al. (23) and Nitsche et al. (17), respectively. ...
Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.
... Intravenous (IV) acetaminophen is used, besides treating fever and pain, as analgesic during and following cesarean delivery, as part of multimodal analgesia [5]. In non-pregnant healthy adults receiving acetaminophen within the therapeutic dose range, acetaminophen The PK of acetaminophen in pregnant women has been studied across different trimesters of pregnancy and at delivery, using different PK analysis techniques [1,6,[12][13][14][15][16]. Dosing in pregnancy is, among other things, dependent on the pregnant patient's PK, which is typically quantified by determining different PK metrics. ...
... The pharmacometric tools supporting PK analysis, which are often applied to special populations, can be roughly divided into two approaches. One is the datadriven method, this approach is based on observed drug concentrations in, e.g., blood The PK of acetaminophen in pregnant women has been studied across different trimesters of pregnancy and at delivery, using different PK analysis techniques [1,6,[12][13][14][15][16]. Dosing in pregnancy is, among other things, dependent on the pregnant patient's PK, which is typically quantified by determining different PK metrics. ...
... The second model, by Allegaert et al. [16], was based on data from 69 young women (Table 5). Similarly to Kulo et al. [15], this model found that delivery was the most significant covariate for formation CL to acetaminophen-glucuronide (factor 2.03 higher CL at delivery vs. postpartum). ...
This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5–60.7%) and an increase in the clearance (36.8–84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis.
... CLpo was 58% higher and half-life was 28% lower in pregnant (31)(32)(33)(34)(35)(36)(37)(38) GWs) compared to non-pregnant women [92]. CLpo (glucuronidation) increases at delivery compared with nonpregnant women [93,94] No dose adjustments are required due to increased metabolite formation [94] Maternal and umbilical cord PK prediction [95] Acyclovir (renal) Similar PK parameters at [ 35 GWs to those of non-pregnant adults [96,97] No dose changes Maternal and umbilical cord PK prediction [98] Amoxicillin (renal) During 2nd and 3rd trimesters both renal CL(total) and renal CL (secretion) were 1.6-fold higher than the non-pregnant value [99] Increase dose/more frequent dosing may be needed [99] NA Ampicillin (renal) Increased renal clearance, lower AUC and shorter half-life during 3rd trimester [100,101] Increase dose/more frequent dosing [100] NA Betamethasone (hepatic) A 1.2-1.6 fold increase in clearance and volume of distribution [102] Increase dosing frequency for sustained plasma levels [103] or dosing per kg lean body weight to reduce variability [102] Maternal PK prediction [104] Buprenorphine (CYP3A4, UGT1A1 and UGT2B7) ...
Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed.
... It is believed to have a lower availability due to increased hepatic clearance and first pass excretion, with a bioavailability averaging 20-40%. Its clearance is dependent on phase II metabolism that is enhanced during the second and third trimester compared to the post-partum period, which is similar to metabolism of acetaminophen during pregnancy [62,64]. As a consequence, labetalol is often dosed using twice or three times daily regimens. ...
The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties. Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses. Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable ‘orphan’ population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.
... Regarding phase II metabolism, UGT-conjugation (or glucuronidation) of some drugs (oxazepam, paracetamol) has been reported to have faster clearance in men. A study on paracetamol clearance in young women found that oral contraceptives increased paracetamol glucuronidation clearance by a factor of 1.46 compared to women without oral contraception (Allegaert et al., 2015). There was also an increase of glucuronidation in women at delivery (factor 2.03), and a decrease in the early postpartum (factor 0.55). ...
Cardiovascular disease (CVD) is the leading cause of mortality worldwide in both sexes. Despite considerable progress in better understanding the patterns of disease in women, they are still often undertreated and benefit less from evidence-based treatment. Hypertension is a key contributor to CVD and is also one of the most potent risk factors for heart failure in women. Even with the wide variety of available drugs, blood pressure control is globally suboptimal. Current guidelines do not suggest differential treatment of hypertension for women; however, a growing body of research suggests gender dimorphism in the pathophysiology of hypertension and pharmacological response to cardiovascular drugs. The clinical relevance of theses sex-divergent effects of drugs is still under investigation. Owing to the exponential relationship between blood pressure and cardiovascular mortality, even a modest decrease in blood pressure or therapeutic adhesion could be clinically \relevant. In this review, we explore the known pharmacological and pharmacokinetic sex differences with special attention to the main classes of antihypertensive treatment. Current data shows frequently higher drug exposures in women and more frequent adverse drug reactions in all antihypertensive drug groups. As far as cardiovascular prevention is concerned, sex-specific data is often lacking in clinical trials, highlighting the necessity to further study CVD and their treatment in both men and women.
... In brief, first, a PBPK model was previously developed for both intravenous and oral acetaminophen administration in non-pregnant women. The predictive performance of the model was evaluated by comparing simulations with observed in vivo pharmacokinetic profiles of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulphate, and unchanged acetaminophen after both oral and intravenous acetaminophen administration of standard dosages [20][21][22]. Once the non-pregnant PBPK model captured the observed pharmacokinetics adequately, all drug-specific parameters were fixed and pregnancy-specific changes were incorporated. Model performance was evaluated by comparing simulations with observed in vivo pharmacokinetic profiles of acetaminophen, acetaminophenglucuronide, acetaminophen-sulphate, and unchanged acetaminophen obtained from third-trimester pregnant women [20]. ...
... Once the non-pregnant PBPK model captured the observed pharmacokinetics adequately, all drug-specific parameters were fixed and pregnancy-specific changes were incorporated. Model performance was evaluated by comparing simulations with observed in vivo pharmacokinetic profiles of acetaminophen, acetaminophenglucuronide, acetaminophen-sulphate, and unchanged acetaminophen obtained from third-trimester pregnant women [20]. For more detailed information about parameterization and validation of the previously developed pregnancy PBPK model we refer to Mian et al. [17]. ...
Background and Objective
Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus.
Methods
An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations.
Results
Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L.
Conclusion
The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.
... Two main enzymes, Uridyldiphosphoglucuronosyltransferases and sulfotransferases, respectively, are involved in the inactivation of the drug to its metabolites, Acetyl p-amino-phenolgluc and APAP-sulfate (acetyl p-aminophenol-gluc and acetyl p-aminophenol sulfate, which constitute 52%-57% and 30%-44% of urinary metabolites, respectively). [5] Through these pathways, approximately 90%-95% of the drug is metabolized and only 5%-10% acetaminophen is metabolically activated by cytochrome P450 2E1 to form a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPBQI), which is the main culprit of hepatotoxicity. [6,7] This metabolite has a wide clinical implication as is associated with the pathogenesis of urinary, nasopharyngeal, colonic, and gastric malignancies. ...
... Regarding the plasma concentration-time profiles of oral acetaminophen 1000 mg in non-pregnant and pregnant populations (ESM_2A), maximum concentration (C max ) values were higher in non-pregnant women and decreased with increasing duration of gestational week, while the AUC from time zero to 6 h (AUC 0-6h ) decreased with increasing duration of gestational age. Regarding the plasma concentration-time profiles of NAPQI after administration of oral [31] acetaminophen plasma concentration-time profiles (left) and predicted and observed [31] acetaminophen inactive metabolites urine concentration-time profiles (right) in populations of a non-pregnant women after administration of intravenous acetaminophen 2000 mg and b third trimester pregnant women after administration of an intravenous acetaminophen 2000 mg loading dose followed by 1000 mg every 6 h. For the inactive metabolites, orange, pink, and green indicate acetaminophen glucuronide, acetaminophen sulfate, and unchanged acetaminophen in urine concentrations, respectively. ...
... Regarding the plasma concentration-time profiles of oral acetaminophen 1000 mg in non-pregnant and pregnant populations (ESM_2A), maximum concentration (C max ) values were higher in non-pregnant women and decreased with increasing duration of gestational week, while the AUC from time zero to 6 h (AUC 0-6h ) decreased with increasing duration of gestational age. Regarding the plasma concentration-time profiles of NAPQI after administration of oral [31] acetaminophen plasma concentration-time profiles (left) and predicted and observed [31] acetaminophen inactive metabolites urine concentration-time profiles (right) in populations of a non-pregnant women after administration of intravenous acetaminophen 2000 mg and b third trimester pregnant women after administration of an intravenous acetaminophen 2000 mg loading dose followed by 1000 mg every 6 h. For the inactive metabolites, orange, pink, and green indicate acetaminophen glucuronide, acetaminophen sulfate, and unchanged acetaminophen in urine concentrations, respectively. ...
... Fig. 4Goodness-of-fit plot (predicted concentration versus observed concentration) for acetaminophen and its metabolites (acetaminophen unchanged, acetaminophen glucuronide, acetaminophen sulfate). For non-pregnant women, observed acetaminophen data were taken from Allegaert et al.[31], Mitchell et al.[34], and Beaulac-Baillargeon and Rocheleau[33]; for pregnant women, observed acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate data were taken from Allegaert et al.[31] and Beaulac-Baillargeon and Rocheleau[33]. The solid line denotes the line of identity. ...
Background and Objective
Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy.
Methods
PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated.
Results
PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8–5.1] mg/L), while Css,avg was 6.7 [5.9–7.4], 5.6 [4.7–6.3], and 4.9 [4.1–5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1–13.4%]), followed by the second (9.0% [7.5–11.0%]) and third trimester (8.2% [6.8–10.1%]), compared with non-pregnant women (7.7% [6.4–9.4%]).
Conclusion
Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.
