Changes In Pharmacokinetics Of Drugs Research Articles

The effect of pregnancy-related hormones on hepatic transporters: studies with premenopausal human hepatocytes.

Pregnancy results in significant changes in drug pharmacokinetics (PK). While previous studies have elucidated the impact of pregnancy-related hormones (PRH) on mRNA or protein expression and activity of major hepatic metabolizing enzymes, their effect on hepatic drug transporters remains largely unexplored. Therefore, we investigated the effect of a cocktail of PRH on the mRNA expression and activity of hepatic transporters. Plated human hepatocytes (PHH) from 3 premenopausal donors were incubated, in triplicate, for 72h, with vehicle (DMSO < 0.01%), rifampin (10μM; positive control) or a cocktail of PRH consisting of estrone, estradiol, estriol, estetrol, progesterone, cortisol, testosterone, oxytocin, and placental growth hormone. The PRH concentrations replicated 0.1×, 1×, or 10× of the plasma concentrations of these hormones observed during each of the three trimesters of pregnancy. After treatment, mRNA expression (quantified by qPCR) of hepatic influx and efflux transporters as well as the activity of influx transporters was quantified (uptake of a selective substrate ± corresponding transporter inhibitor). The data were expressed relative to that in the control (vehicle) group. Significance was evaluated by ANOVA (followed by Dunn's multiple comparisons) or unpaired t-test when the within-lot data were analyzed, or repeated measures ANOVA (followed by Dunn's multiple comparisons) or paired t-test when data from all 3 lots were analyzed (p < 0.05). In general, a) PRH cocktails significantly induced transporter mRNA expression in the following order OAT2 ≈ NTCP ≈ OCT1 > OATP2B1 and repressed mRNA expression in the following order OATP1B3 > OATP1B1; b) these changes translated into significant induction of OAT2 (T1-T3) and NTCP (T2-T3, in only two lots) activity at the 1× PRH concentration. Compared with the influx transporters, the induction of mRNA expression of efflux transporters was modest, with mRNA expression of MRP2 and BSEP being induced the most. Once these data are verified through in vivo probe drug PK studies in pregnancy, they can be populated into physiologically based pharmacokinetic (PBPK) models to predict, for all trimesters of pregnancy, transporter-mediated clearance of any drug that is a substrate of the affected transporters.

Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD).

This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.

Potentially inappropriate medications use in a psychiatric elderly care hospital: A cross-sectional study using Beers criteria.

Potentially inappropriate medications (PIMs) carry risks that outweigh any potential benefits when compared to safer or more effective alternative treatments. Adverse drug events are more likely to occur in older adults with psychiatric diseases due to multimorbidity, polypharmacy, and age-related changes in drug pharmacokinetics and pharmacodynamics. The aim of this study was to assess the prevalence and risk factors of PIM use in an aged care hospital's psychogeriatric division, using the American Geriatrics Society Beers criteria 2019. This cross-sectional study was conducted on all current inpatients, having a mental disorder and aged ≥65 years, in one elderly care hospital in Beirut, from March to May 2022. Medications, sociodemographic and clinical characteristics were collected from patients'medical records. PIMs were evaluated based on Beers criteria 2019. Independent variables were described using descriptive statistics. Factors associated with PIM use were identified by bivariate analysis followed by binary logistic regression. A two-sided p value <0.05 was considered statistically significant. The study included 147 patients, with a mean age of 76.3 years, 46.9% of them having schizophrenia, 68.7% using 5 or more drugsand 90.5% taking at least 1PIM. The most prescribed PIMs were antipsychotics (40.2%), anticholinergics (16%), and antidepressants (7.8%). PIM use was significantly associated with polypharmacy (AOR = 20.88, 95% CI: 1.22-357.87, p = 0.04) and anticholinergic cognitive burden (ACB) score (AOR = 7.25, 95% CI: 1.13-46.52, p = 0.04). PIMs were highly prevalent among hospitalized Lebanese psychiatric elderly. Polypharmacy and ACB score were the determinants of PIM use. A multidisciplinary medication review led by a clinical pharmacist could reduce PIM use.

Is it possible to change milk secretion of drugs with soy enriched diets in lactating ruminants?

Soy is the most commonly used protein supplement in beef and dairy diets. Soy, which is also used as a common protein source in animal feed, is palatable and has a good amino acid balance and high bioavailability. In vivo and in vitro interaction of flavonoids, including isoflavones such as genistein and daidzein, with several ABC transporters, including breast cancer resistance protein (BCRP/ABCG2), has been demonstrated. BCRP presence in ruminants could affect the efflux of hydrophobic toxins and drugs, including their active secretion to milk and a reduction in the withdrawal time of the drug milk residues. As a result of inhibition of efflux transporters such as BCRP, changes in drug pharmacokinetics and drug transfer into milk have been observed. In this respect, the use of forage supplemented with BCRP inhibitors may be beneficial to control drug accumulation in milk and prevent undesirable contamination of milk. It is aimed to reduce the drug withdrawal periods for dairy animals with the procedure in question. In this review, it is aimed to give information about the importance of soy-enriched diets in the nutrition of ruminants during the lactation period and the effect of transport proteins on the transfer of drugs into milk.

Predicting changes in the pharmacokinetics of CYP3A-metabolized drugs in hepatic impairment and insights into factors driving these changes.

Physiologically based pharmacokinetic models, populated with drug-metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confidence in the predictive power of such models, they must be validated by comparing the predicted and observed PK of drugs in HI obtained by phenotyping (or probe drug) studies. Therefore, we first predicted the effect of all stages of HI (mild to severe) on the PK of drugs primarily metabolized by cytochrome P450 (CYP) 3A enzymes using the default HI module of Simcyp Version 21, populated with hepatic and intestinal CYP3A abundance data. Then, we validated the predictions using CYP3A probe drug phenotyping studies conducted in HI. Seven CYP3A substrates, metabolized primarily via CYP3A (fraction metabolized, 0.7-0.95), with low to high hepatic availability, were studied. For all stages of HI, the predicted PK parameters of drugs were within twofold of the observed data. This successful validation increases confidence in using the DMET abundance data in HI to predict the changes in the PK of drugs cleared by DMET for which phenotyping studies in HI are not available or cannot be conducted. In addition, using CYP3A drugs as an example, through simulations, we identified the salient PK factors that drive the major changes in exposure (area under the plasma concentration-time profile curve) to drugs in HI. This theoretical framework can be applied to any drug and DMET to quickly determine the likely magnitude of change in drug PK due to HI.

Clinical Pharmacist Intervention on Drug-Related Problems among Elderly Patients Admitted to Medical Wards of Northwest Ethiopia Comprehensive Specialized Hospitals: A Multicenter Prospective, Observational Study.

Background: Drug therapy in the elderly needs an emphasis on age-related changes in drug pharmacokinetics and pharmacodynamics profile. Hospitalized elderly patients are at risk of more than one disease and polypharmacy associated with these; they are at risk of drug-related problems. This study aimed to assess the role of clinical pharmacy on identifying and resolution of drug-related problems among elderly patients admitted to medical ward of Northwest Ethiopia comprehensive specialized hospitals. Methods: A multicenter prospective observational study was conducted. A systematic sampling technique was used. The identified drug-related problem was recorded and classified using Cipolle, and adverse drug reaction was assessed using Naranjo algorithm of adverse drug reaction probability scale, and Medscape was used for drug-drug interaction. Data were analyzed by using STATA software version 14.1. Logistic regression was used, and results were reported as odds ratios (ORs) with 95% Confidence intervals with P value < 0.05 statistically significant. Result: A total of 389 study participants were included in the study. About 266 (68.4%) of the participants had at least a single drug-related problem. About 503 drug-related problems were identified with a mean of 1.32 (CI: 1.27-1.36) drug-related problem per patient. The three-leading categories of drug-related problems were dose too high 108 (21.5%), nonadherence 105 (20.9%), and adverse drug reaction 96 (19.1%). Alcohol use (AOR = 2.2, 95CI%: 1.23-3.94), source of the drug (AOR = 2.85, 95CI%: 1.63-4.98), length of hospitalization (AOR = 2.32, 95CI%: 1.37-3.95), number of comorbidities (AOR = 1.48, 95CI%: 1.09-1.99), and polypharmacy (AOR = 3.06, 95CI%: 1.72-5.46) were important risk factors for drug-related problems. From the intervention provided, 84.7% were accepted by prescribers. Among the total drug-related problems 67.4% of the problem was totally solved. Conclusion: This study revealed that DRPs were high among elderly patients admitted to medical ward of Northwest Ethiopia. Comorbidity, length of hospitalization, ploy-pharmacy, payer, and alcohol drinker were more likely to developed drug-related problems. Treatment optimizations were also done by clinical pharmacists and interventions were well accepted by prescribers.

Genetic Risk Factors for Adverse Drug Reactions

The use of medicines may in some cases be associated with the development of drug-induced diseases (DIDs) аnd other adverse drug reactions (ADRs), which leads to an increase in morbidity/mortality rates, and/or symptoms forcing a patient to seek medical attention or resulting in hospitalisation. ADRs may develop due to changes in a patient’s genotype, which entail an inadequate pharmacological response. The aim of the study was to analyse and summarise literature data on genetic risk factors that cause DIDs аnd other ADRs. It was shown that the polymorphism of genes encoding enzymes of drug metabolism (CYP, UGT, NAT, TPMT, EPHX, GST, etc.) or carriers (transporters) of drugs (P-gp, BCRP, MRP, OATP, OCT, etc.) can change the pharmacokinetics of drugs, affecting their activity. Polymorphism of RYR1, CACNA1S, MT-RNR1, VKORC1, and other genes encoding receptors targeted by drugs, and human leukocyte antigen (HLA) gene, may affect drug pharmacodynamics by modifying drug targets or changing the sensitivity of biological pathways to pharmacological effects of medicines. Changes in drug pharmacokinetics and pharmacodynamics may cause DIDs аnd other ADRs. The use of pharmacogenetic tests will allow a personalised approach to patients’ treatment and prevention or timely detection of potential ADRs during therapy. Before prescribing some medicines, clinicians should use recommendations on their dosing based on pharmacogenetic tests, which are posted on the official websites of Pharmacogenomics Research Network (PGRN), Pharmacogenomics Knowledgebase (PharmGKB), and Clinical Pharmacogenetics Implementation Consortium (CPIC). The results of ongoing clinical studies on the effect of gene polymorphism on drug safety will soon allow for higher personalisation of the choice of pharmacotherapy and prevention of many ADRs, including DIDs.

Pharmacomicrobiomics: Exploiting the Drug-Microbiota Interactions in Antihypertensive Treatment.

Hypertension is a leading risk factor for cardiovascular diseases and can reduce life expectancy. Owing to the widespread use of antihypertensive drugs, patients with hypertension have improved blood pressure control over the past few decades. However, for a considerable part of the population, these drugs still cannot significantly improve their symptoms. In order to explore the reasons behind, pharmacomicrobiomics provide unique insights into the drug treatment of hypertension by investigating the effect of bidirectional interaction between gut microbiota and antihypertensive drugs. This review discusses the relationship between antihypertensive drugs and the gut microbiome, including changes in drug pharmacokinetics and gut microbiota composition. In addition, we highlight how our current knowledge of antihypertensive drug-microbiota interactions to develop gut microbiota-based personalized ways for disease management, including antihypertensive response biomarker, microbial-targeted therapies, probiotics therapy. Ultimately, a better understanding of the impact of pharmacomicrobiomics in the treatment of hypertension will provide important information for guiding rational clinical use and individualized use.

Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats

Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.

Drug dosing considerations in continuous renal replacement therapy.

Acute kidney injury (AKI) is a common complication in critically ill patients, which is associated with increased in-hospital mortality. Delivering effective antibiotics to treat patients with sepsis receiving continuous renal replacement therapy (RRT) is complicated by variability in pharmacokinetics, dialysis delivery, lack of primary literature, and therapeutic drug monitoring. Pharmacokinetic alterations include changes in absorption, distribution, protein binding (PB), metabolism, and renal elimination. Drug absorption may be significantly changed due to alterations in gastric pH, perfusion, gastrointestinal motility, and intestinal atrophy. Volume of distribution for hydrophilic drugs may be increased due to volume overload. Estimation of renal clearance is challenged by the effective delivery of RRT. Drug characteristics such as PB, volume of distribution, and molecular weight impact removal of the drug by RRT. The totality of these alterations leads to reduced exposure. Despite our best knowledge, therapeutic drug monitoring of patients receiving continuous RRT demonstrates wide variability in antimicrobial concentrations, highlighting the need for expanded monitoring of all drugs. This review article will focus on changes in drug pharmacokinetics in AKI and dosing considerations to attain antibiotic pharmacodynamic targets in critically ill patients receiving continuous RRT.

Model-Informed Dose Optimization in Pregnancy.

Pregnancy is associated with several physiological changes that can alter the pharmacokinetics (PK) and pharmacodynamics of drugs. These may require dosing changes in pregnant women to achieve drug exposures comparable to the nonpregnant population. There is, however, limited information available on the PK and pharmacodynamics of drugs used during pregnancy. Practical difficulties in performing PK studies and potential liability issues are often the reasons for the availability of limited information. Over the past several years, there has been a rapid development in the application of various modeling strategies such as population PK and physiologically based PK modeling to provide guidance on drug dosing in this special patient population. Population PK models rely on measured PK data, whereas physiologically based PK models integrate physiological, preclinical, and clinical data to quantify changes in PK of drugs in various patient populations. These modeling strategies offer a promising approach to identify the drugs with PK changes during pregnancy and guide dose adjustment in pregnant women. This review focuses on PBPK modeling to guide drug therpay in pregnancy.

Utility of Quantitative Proteomics for Enhancing the Predictive Ability of Physiologically Based Pharmacokinetic Models Across Disease States.

Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification-based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry-based quantitative proteomics as a sensitive, robust, and high-throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed.

Antiviral Agent Therapy Optimization in Special Populations of COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global outbreak of disease. The antiviral treatment acts as one of the most important means of SARS-CoV-2 infection. Alteration of physiological characteristics in special populations may lead to the change in drug pharmacokinetics, which may result in treatment failure or increased adverse drug reactions. Some potential drugs have shown antiviral effects on SARS-CoV-2 infections, such as chloroquine, hydroxychloroquine, favipiravir, lopinavir/ritonavir, arbidol, interferon alpha, and remedsivir. Here, we reviewed the literature on clinical effects in COVID-19 patients of these antiviral agents and provided the potential antiviral agent options for pregnant women, elderly patients, liver or renal dysfunction patients, and severe or critically ill patients receiving renal replacement therapy or ECMO after SARS-CoV-2 infection.

Lipid-Lowering Therapy for Primary Cardiovascular Prevention in Older Adults. Consensus Statement of the Russian Association of Gerontologists and Geriatricians, National Society on Atherosclerosis, Russian Society of Cardiology, Association of Clinical Pharmacologists

Completed randomized clinical studies did not have a sufficient statistical power for demonstrating clearly the efficacy of lipid-lowering therapy for primary prevention in patients aged 75 years and older and did not evaluate the effect of lipid-lowering therapy on development and course of key geriatric syndromes. Age-related alterations of skeletal muscles, cognitive decline, senile asthenia, comorbidities, polypragmasy, potential changes in drug pharmacokinetics and pharmacodynamics, and impaired renal function may adversely affect the benefit to harm ratio of statins in older patients. Key questions for administration of a lipid-lowering therapy for primary prevention in patients aged 75 years and older are: 1. Does the relationship between increased low-density lipoprotein cholesterol (LDL CS) and death rate persist? 2. Does a benefit from decreasing the level of LDL CS persist? 3. Is the lipid-lowering therapy safe? 4. What scales for risk stratification and determining indications for lipid-lowering therapy should be used?

Hyperlipidemia: Insights into Mechanisms Involved in Modulation of Drug Pharmacokinetics and Response

Hyperlipidemia is associated with disturbances in plasma lipoproteins. These changes were shown to modify the pharmacokinetics of some lipophilic lipoprotein-bound drugs with some of these changes being clinically significant. In this manuscript potential mechanisms that might be involved in hyperlipidemia-induced changes in drug pharmacokinetics such as modulation of p-glycoproteins and liver metabolising enzymes activities and/or expression were investigated. P-glycoprotein gene expression (MDR1A/B) and activity was assessed in porcine (LLC-PK1) and murine (NRK-52E) proximal tubular renal epithelial cells that were maintained in normolipidemic- or hyperlipidemic-serum containing media and was compared to expression levels in serum-deprived cells. Gene expression of low density lipoprotein receptor (LDLr) and MDR1A/B along with cytochrome P450 CYP3A2 and 2C11 were also investigated in hepatocytes from normolipidemic and hyperlipidemic rats using qRT-PCR. Hyperlipidemic serum did not affect MDR1A/B gene expression in LLC-PK1 and NRK-52E cells. However, it significantly reduced p-glycoprotein activity in rifampin-treated and non-treated LLC-PK1 cells. Interestingly, p-glycoprein gene expression was induced in LLC-PK1 and NRK-52E cell lines upon serum starvation. Moreover, hepatocytes from hyperlipidemic rat livers had reduced LDLr, MDR1A/B, and CYP2C11 mRNA levels compared to normolipidemic rats. It is concluded that hyperlipidemia-induced changes in drug pharmacokinetics might be attributed to modulation of drug efflux/uptake, metabolism and/or excretion. Further, p-glycoprotein gene expression is potentially inducible by serum starvation in renal proximal tubular cells, which might be a novel detoxification mechanism by which these cells adapt to stressful conditions.

Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude.

Hypoxia can alter the Pharmacokinetic (PK) characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Environmental characteristics at high altitude include but are not limited to hypobaric hypoxia, low temperature, high solar radiation, and arid climate, all of which can adversely affect normal bodily functions. Therefore, it is important to study the pharmacokinetic changes of drugs at high altitude. A systematic review of published studies was carried out to investigate the effects of hypoxia on the metabolic characteristics of some drugs and the activity and expression of drug-metabolizing enzymes in high-altitude hypoxic environments, and discussed the relevant mechanisms. The metabolism of most drugs decreases in high-altitude hypoxia, whereas Mean Residence Time (MRT), Half Time (T1/2), and Area Under the Curve (AUC) increase and Clearance (CL) decrease in this environment. The effect of hypoxia on CYP450 enzymes in animals is still a subject of debate. With the exception of CYP2C11 and CYP2C22, the widespread belief is that high-altitude hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1, and increased those of CYP3A6 and CYP2D1 in rats. The changes in the activity and expression of drug metabolizing enzymes are consistent with the changes in pharmacokinetics of some enzyme substrates in the high-altitude hypoxia environment. The findings of this review have indicated that hypoxia may play a key role in the PK changes of drugs at high altitude. It is suggested that patient living at or traveling to high altitude should be closely monitored, and the dosages of some drugs metabolized should be reduced.

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models.

During recent years there has been a surge in developing and applying physiologically based pharmacokinetic (PBPK) models in pregnant women to better understand and predict changes in drug pharmacokinetics throughout pregnancy. As a consequence, the number of publications focusing on pregnancy PBPK models has increased substantially. However, to date these models, especially across various platforms, have not been systematically evaluated. Hence, this review aims to assess published PBPK models in pregnancy used for therapeutic purposes.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients.

Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*." Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO. The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.

PP-14 Substandard prescription of drugs in a population of overweight and obese children. an observational retrospective cohort study

Background Obesity is a major area of public health concerns, since it is associated with a wide range of se-rious health complications, including diabetes type 2, musculoskeletal disorders, sleep apnea, depression, asthma, hypertension, and cancer. Consequently, obese children are more likely to receive drug treatment than their normal weight peers. Further, obesity is known to be associated with changes in pharmacokinetics of drugs (1–5). Dosing overweight (OW) and obese (OB) children by the use of traditional paediatric dosage strategies (e.g. mg per kilogram or fixed dose by age) may therefore result in a potential risk of sub-or supra-therapeutic doses. We aimed to investigate currently applied dosage strategies in OW/OB children, in a clinical treatment facility. In par-ticular, whether dosage guidelines were used and metrics of body size applied with special attention to drugs with a narrow therapeutic interval and/or loading dose of clin-ical importance. Methods A retrospective cohort study conducted at the Children’s Obesity Clinic in Denmark, in the period 2008–2015. OW/OB children≤18 years, having at least one drug prescribed, were included. 200 patient records were reviewed. The study was approved by the Data Protection Agency (BBH-2014–045, I-suite 03045) Drug treatments/prescriptions were registered with ref-erence to the Anatomical Therapeutic Chemical (ATC) Classification System. Dosage strategies were registered as dosage by total body weight (TBW), fixed dose by age (years), use of adjusted weight measures (e.g. IBW, ABW) or dose estimation by other strategies. Results A total number of 455 prescriptions were iden-tified, primarily distributed in ATC groups N, A, R and J. Guidelines for dosage of OW/OB children were not avail-able in the clinic, for any of the recorded drugs. Only one prescription of gentamicin was adjusted by weight (ABW) using metrics of body size. Otherwise, gentamicin was dosed after three different dosage regimens. In 35/455 prescriptions, dose was adjusted by an undocumented dosage strategy. Dose was primarily limited to the max-imum recommended adult dose, when dose (mg/kg) exceeded adult dose, i.e. acetaminophen. Conclusion This study highlights the shortage of dos-age guidelines in OW/OB children. We found as suspect-ed a large inter-individual variability in dosage regimens even in drugs with narrow therapeutic intervals or drugs which has loading doses important for clinical effects. The clinicians are left with ‘best practice’, as evidence based dosage regimens are missing for several drugs prescribed during childhood.

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition.

Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (−76%; confidence interval (CI), −83%, −66%; P < 0.001) and aripiprazole (−52%; CI, −62%, −39%; P < 0.001), but not for olanzapine (−9%; CI, −28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.