Changes In Pharmacokinetics Research Articles

Characterization of lacosamide pharmacokinetics in older adults with epilepsy (P4-1.007)

<h3>Objective:</h3> This study aimed to characterize the relationship between lacosamide pharmacokinetics and renal function in older adults with epilepsy. <h3>Background:</h3> Lacosamide is an anti-seizure medication (ASM) indicated for focal-onset seizures which is primarily excreted through the renal route. Changes in clearance with increased age could lead to pharmacokinetic changes in medications that are eliminated via the kidney; therefore, older adults, being more sensitive to these changes may need lower doses than younger adults. <h3>Design/Methods:</h3> Data on patients diagnosed with epilepsy according to ICD10 codes and having at least one steady-state lacosamide concentration measurement between January 2015 and July 2020 met inclusion. A linear mixed model was developed to characterize differences in lacosamide dose normalized concentrations (DNCs = blood concentration/total daily dose) with respect to creatinine clearance (CLCR). CLCR was calculated using the Cockcroft-Gault equation as indicated for lacosamide dosing (package insert), thus incorporating the effect of patient age and sex. The model was controlled for covariates including ethnicity, route of administration (oral/intravenous), aspartate aminotransferase concentration, alanine aminotransferase concentration, regime (monotherapy/polytherapy), presence of CYP450 inducers &amp; inhibitors, and critically ill status as signified by prescription. Model significance was set to α≤0.05 (R software (version 4.1.2)). <h3>Results:</h3> 2291 lacosamide DNCs from 676 patients were included. The median[range] dose and DNC were 300 mg [50–1000 mg] and 23(ug/L)/mg [1–480(ug/L)/mg], respectively. For a given subject the mean DNC of lacosamide decreased by 6% (95% confidence interval: 3.5–8.9%, p&lt;0.01) per unit increase in the CLCR. Route of administration (p=0.01) and presence of a CYP450 inducer (p&lt;0.01) showed a statistically significant effect on DNCs. <h3>Conclusions:</h3> Creatinine clearance was a significant predictor of lacosamide DNCs in older patients with epilepsy. Thus, as CLCR changes are more pronounced as one ages, modification in dosing regimens may be required to maintain lacosamide concentrations in the tolerable and effective range. <b>Disclosure:</b> Miss Avachat has nothing to disclose. The institution of Dr. Reeder has received research support from American Epilepsy Society . Mr. Long has received personal compensation for serving as an employee of PharmaVelox. Dr. Leppik has nothing to disclose. The institution of Dr. Patel has received research support from Ucb. The institution of Dr. Birnbaum has received research support from National Institutes of Health. Dr. Birnbaum has received intellectual property interests from a discovery or technology relating to health care.

Translation and cultural adaptation of MedStopper®-A web-based decision aid for deprescribing in older adults: A protocol.

Older patients are more likely to have medication-related problems, which are associated with changes in pharmacokinetics and pharmacodynamics, multimorbidity, and polypharmacy. Polypharmacy and inappropriate prescribing are well-known risk factors which commonly cause adverse clinical outcomes in older people. Prescribers struggle to identify potentially inappropriate medications and to choose an adequate tapering approach. The goal of the study is to translate and culturally adapt MedStopper®, an original English language web-based decision aid system in deprescribing medication, to the Portuguese population. A translation-back translation method, with validation of the obtained Portuguese version of MedStopper® will be used, followed by a comprehension test. This is the first research in the Portuguese primary care setting that aims to provide a useful online tool for the appropriate prescription of older patients. The translated version in Portuguese version of the MedStopper® tool will represent an advance that seeks to continue improving the management of medications in the elderly. The adaptation into Portuguese of the educational tool provides clinicians with a screening tool to detect potentially inappropriate prescribing in patients older than 65 that reliable and easier to use. Retrospectively registered.

Considerations for Treating Nonobstetric Diseases in Pregnant Patients in the Emergency Department Setting.

To provide nonobstetric practitioners with an overview of key concepts for the pregnant patient and review treatment of 3 common acute nonobstetric diseases encountered in the emergency department setting. A literature search of PubMed was performed (1997-February 2023) using key search terms related to pregnancy, pain, urinary tract infection (UTI), venous thromboembolism (VTE), and anticoagulants. Relevant articles in English and humans were considered. When caring for a pregnant patient, it is important to utilize appropriate assessments, understand terms used in this population, and recognize how the physiological and pharmacokinetic changes that occur in pregnancy can influence medication use. Pain, UTIs, and VTE are common in this population. Acetaminophen is the most widely used medication for the management of pain during pregnancy and the drug of choice for mild pain in pregnancy not responsive to nonpharmacologic treatment. Pyelonephritis is the most common nonobstetric cause of hospitalization for pregnant patients. Antimicrobial treatment should consider maternal-fetal safety and local resistance patterns. Pregnant and postpartum patients have a 4- to 5-fold increased risk of developing a VTE compared with nonpregnant patients. Low-molecular-weight heparin is the preferred treatment. Pregnant patients often seek acute care in the emergency department setting for nonobstetric needs. Pharmacists in this setting should understand appropriate assessment questions and terms used within this population, the basics of physiological and pharmacokinetic changes in pregnancy that can impact treatment, and which resources are best to utilize for drug information of the pregnant patient. Practitioners in the acute care setting commonly encounter pregnant patients seeking care for nonobstetric concerns. This article covers key pregnancy-related information for the nonobstetric practitioner and focuses on the management of acute pain, UTI, and VTE during pregnancy.

Abstract CT058: TROPION-PanTumor03: Phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients (pts) with advanced/metastatic solid tumors

Abstract Background: Pts with metastatic epithelial tumors who progress after initial therapy have a poor prognosis; new therapeutic agents could potentially improve outcomes. Trophoblast cell surface protein 2 (TROP2) is a transmembrane glycoprotein that is over-expressed on the cell surface of many epithelial cancers representing a promising target for surface-directed therapeutic modalities. Dato-DXd is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd monotherapy demonstrated encouraging efficacy and safety in pts with lung and breast cancer (TROPION-PanTumor01 study; NCT03401385). Methods: The phase 2, multicenter, open-label TROPION-Pantumor03 study (NCT05489211) is exploring safety and efficacy of Dato-DXd as monotherapy and in combination with various anticancer agents (e.g. durvalumab, AZD5305, nivolumab, bevacizumab, chemotherapies) that may be active in the tumor types being evaluated. TROPION-Pantumor03 is a master trial comprising independent substudies to enable simultaneous evaluation of the recommended phase 2 dose (RP2D), safety, and preliminary efficacy of Dato-DXd across several tumor types and treatment combinations. Pts with endometrial, gastric, metastatic castration-resistant prostate (mCRPC), ovarian, and colorectal (CRC) cancer are being enrolled. Eligible pts: age ≥18 years, histologically/cytologically documented advanced or metastatic disease, ≥1 measurable target lesion (RECIST 1.1) not previously irradiated (mCRPC substudy: non-measurable bone metastatic disease permitted), and adequate bone marrow and organ function. An FFPE tumor sample must be available for all pts. Prospective selection for TROP2 expression is required in pts with CRC; in all other cohorts, TROP2 expression will be analyzed retrospectively. In all monotherapy cohorts, pts will receive Dato-DXd 6 mg/kg IV infusion Q3W; in the combination cohorts, Dato-DXd 4 or 6 mg/kg Q3W, as appropriate for each combination. Pts will receive treatment until disease progression, unacceptable toxicity, or withdrawal. Primary Endpoints: Objective response rate, PSA50 response (mCRPC substudy only), and safety/tolerability. Secondary Endpoints: Progression-free survival, duration of response, disease control rate, best % change in tumor size, pharmacokinetics, and immunogenicity (anti-drug antibodies). Exploratory endpoints incl. overall survival, pt-reported outcomes, and biomarker analysis (incl. TROP2 and PD-L1 expression, tumor mutational profiling, proteomics and ctDNA profiling). Recruitment is ongoing as of Jan 2023. Citation Format: Funda Meric-Bernstam, Yelena Janjigian, Joshua Lang, Kristen K. Ciombor, Isabelle Ray-Coquard, Amit Oza, Kan Yonemori, Ruihua Xu, Jimmy L. Zhao, Srikanth Gajavelli, Justyna Filant, Tina Hovey, Ana Oaknin. TROPION-PanTumor03: Phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT058.

Pharmacogenomic Considerations In Propofol: A Review

Pharmacogenomics is one of the pivotal fields of science in the era of precision medicine. It helps provide an understanding of what causes the differences in terms of pharmacokinetics and pharmacodynamics of a particular drug in patients. Hence, this leads to better efficacy. This branch of medicine also applies to sedative drugs in the anesthesia field, one of which is propofol. Changes in propofol pharmacokinetics and pharmacodynamics properties might lead to toxicity and inadequate sedation. This review wishes to better understand how pharmacogenomics is applied in anesthesia, especially in propofol, one of its most commonly used medications.

Effects of bariatric surgery on drug pharmacokinetics-Preclinical studies.

With the rising worldwide obesity rates, bariatric surgeries are increasing. Although the surgery offers an effective treatment option for weight loss, the procedure causes dramatic physiological and metabolic changes. Animal models in rodents provide a valuable tool for studying the systemic effects of the surgery. Since the surgery may significantly influence the pharmacokinetic properties of medications, animal studies should provide essential insight into mechanisms underlying changes in how the body handles the drug. This review summarizes research work in rodents regarding the impact of standard bariatric procedures on pharmacokinetics. A qualitative literature search was conducted via PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE. Studies that examined bariatric surgery's effects on drug pharmacokinetics in rodent models were included. Clinical studies and studies not involving drug interventions were excluded. A total of 15 studies were identified and assessed in this review. These studies demonstrate the possible impact of bariatric surgery on drug absorption, distribution, metabolism, excretion, and potential mechanisms. Pharmacokinetic changes exhibited in the limited pre-clinical studies highlight a need for further investigation to fully understand the impact and mechanism of bariatric surgery on drug responses.

In vivo assessment of the pharmacokinetic interactions between donafenib and dapagliflozin, donafenib and canagliflozin in rats

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium–glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib–dapagliflozin and donafenib–canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (Cmax) to increase 37.01%. Canagliflozin increased donafenib Cmax 1.77-fold and the area under the plasma concentration–time curves (AUC0−t and AUCinf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CLz) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC0−t 1.61-fold, AUCinf 1.77-fold, whereas its CLz reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.

Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers.

In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated. Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4h: AUC2-4 and estimated partial metabolic clearance: eClmet ) before, at steady-state, and after discontinuation of 3× 1000 mg metamizole/day orally for 8days. Significant changes in pharmacokinetic parameters were detected already 3 days after start of metamizole treatment. At the steady-state of enzyme induction, the geometric mean ratio of midazolam AUC2-4 was substantially reduced to 0.18 (90% confidence interval: 0.14-0.24) with a corresponding 5.43-fold (4.15-7.10) increase of eClmet . After discontinuation of metamizole, the changes slowly recovered, but were still significant at the end of the observation period on the fifth day after discontinuation of metamizole therapy (AUC2-4 reduced to 0.50 [0.41-0.63] and eClmet 1.99-fold increased [1.60-2.47, P< 0.05]). Metamizole acts as a strong inducer of CYP3A already few days after start of metamizole administration and, thus, should be avoided in patients using drugs with narrow therapeutic index and major clearance via CYP3A. If their administration is essential, close monitoring and dose adjustment of comedication should be performed as early as the first week after the initiation and after discontinuation of metamizole therapy.

Developing a Warning Model of Potentially Inappropriate Medications in Older Chinese Outpatients in Tertiary Hospitals: A Machine-Learning Study.

Due to multiple comorbid illnesses, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics in older adults, the prevalence of potentially inappropriate medications (PIMs) is high, which affects the quality of life of older adults. Building an effective warning model is necessary for the early identification of PIMs to prevent harm caused by medication in geriatric patients. The purpose of this study was to develop a machine learning-based model for the warning of PIMs in older Chinese outpatients. This retrospective study was conducted among geriatric outpatients in nine tertiary hospitals in Chengdu from January 2018 to December 2018. The Beers criteria 2019 were used to assess PIMs in geriatric outpatients. Three problem transformation methods were used to tackle the multilabel classification problem in prescriptions. After the division of patient prescriptions into the training and test sets (8:2), we adopted six widely used classification algorithms to conduct the classification task and assessed the discriminative performance by the accuracy, precision, recall, F1 scores, subset accuracy (ss Acc), and Hamming loss (hm) of each model. The results showed that among 11,741 older patient prescriptions, 5816 PIMs were identified in 4038 (34.39%) patient prescriptions. A total of 41 types of PIMs were identified in these prescriptions. The three-problem transformation methods included label power set (LP), classifier chains (CC), and binary relevance (BR). Six classification algorithms were used to establish the warning models, including Random Forest (RF), Light Gradient Boosting Machine (LightGBM), eXtreme Gradient Boosting (XGBoost), CatBoost, Deep Forest (DF), and TabNet. The CC + CatBoost model had the highest accuracy value (97.83%), recall value (89.34%), F1 value (90.69%), and ss Acc value (97.79%) with a good precision value (92.18%) and the lowest hm value (0.0006). Therefore, the CC + CatBoost model was selected to predict the occurrence of PIM in geriatric Chinese patients. This study's novelty establishes a warning model for PIMs in geriatric patients by using machine learning. With the popularity of electronic patient record systems, sophisticated computer algorithms can be implemented at the bedside to improve medication use safety in geriatric patients in the future.

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance.

Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

Safety and Tolerability of Antimicrobial Agents in the Older Patient.

Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing.

Prediction of gastric pH-mediated drug exposure using physiologically-based pharmacokinetic modeling: A case study of itraconazole.

Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling in the prediction of gastric pH-mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle-out manner from a stepwise in vitro-in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole-induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH-mediated exposure observed in the clinical investigation. Based on the model-based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH-mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH-mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.

Optimizing pharmacotherapy regimens in adult patients receiving extracorporeal membrane oxygenation: A narrative review for clinical pharmacists

AbstractExtracorporeal membrane oxygenation (ECMO) is a complex therapy aimed at providing mechanical support for patients with severe, life‐threating cardiac and/or respiratory failure. Research has demonstrated variability in pharmacokinetic changes in the critically ill patient population receiving ECMO. There is a need to understand the complexity of these pharmacokinetic changes to provide optimal pharmacotherapeutic regimens thereby maximizing effectiveness and mitigating harm. However, the number of pharmacokinetic studies in patients receiving ECMO remains small, and very few prospective studies have been published addressing optimal analgesic, sedative, or antimicrobial therapy. Anticoagulation is an additional important component of ECMO therapy but the preferred agent as well as dosing and monitoring strategy are unclear. The purpose of this narrative review is to discuss analgesia and sedation, antimicrobial, and anticoagulation management strategies in adult patients receiving ECMO.

Mechanisms of Obesity-Induced Changes in Pharmacokinetics of IgG in Rats.

To evaluate how obesity affects the pharmacokinetics of human IgG following subcutaneous (SC) and intravenous (IV) administration to rats and the homeostasis of endogenous rat IgG. Differences in body weight and size, body composition, and serum concentration of endogenous rat IgG in male Zucker obese (ZUC-FA/FA) and control (ZUC-LEAN) rats were measured from the age of 5weeks up to 30weeks. At the age of 23-24weeks animals received a single IV or SC dose of human IgG (1g/kg of total body weight), and serum pharmacokinetics was followed for 7weeks. A mechanistic model linking obesity-related changes in pharmacokinetics with animal growth and changes in body compositionwas developed. Significant differences were observed in both endogenous and exogenous IgG pharmacokinetics between obese and control groups. The AUC for human IgG was lower in obese groups (57.6% of control after IV and 48.1% after SC dosing), and clearance was 1.75-fold higher in obese animals. The mechanistic population model successfully captured the data and included several major components: endogenous rat IgG homeostasis with age-dependent synthesis rate; competition of human IgG and endogenous rat IgG for FcRn binding and its effect on endogenous rat IgG concentrations following injection of a high dose of human IgG; and the effect of body size and composition (changing over time and dependent on the obesity status) on pharmacokinetic parameters. We identified important obesity-induced changes in the pharmacokinetics of IgG. Results can potentially facilitate optimization of the dosing of IgG-based therapeutics in the obese population.

Organic anion-transporting polypeptide 2B1 knockout and humanized mice; insights into the handling of bilirubin and drugs

Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1-/- and combination Slco1a/1b/2b1-/-) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1-/- compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice. Single Slco2b1-/- mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1-/- mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.

Bariatric surgery as a risk factor for alcohol use disorder: a clinical case and literature review

IntroductionBariatric surgery is a relatively safe surgical procedure with high success rates. The improvement on patient’s self-esteem and overall quality of life are expected benefits that extend beyond physical health. Nonetheless, current literature describes a higher risk of developing alcohol use disorder (AUD) in patients undergoing bariatric surgery that is not better explained by differences in baseline characteristics such as socioeconomic factors. This reinforces the need to optimize mental health professionals’ intervention in these patients.ObjectivesReport a clinical case and conduct a literature review on the etiology of the increased risk of alcohol use disorder in patients after bariatric surgery.MethodsDescription of a clinical case and a non-systematic review of literature on the PubMed database, selecting articles published in the last decade and their included reference lists, combining the following MESH terms: “bariatric surgery” and “abuse, alcohol”.ResultsThe clinical case presented is a 45 years old woman, with a college degree, that was diagnosed with AUD in 2020, 6 years after being submitted to bariatric surgery. She didn’t have any alcohol-related problems before the procedure but she describes the death of her mother in 2020 as the trigger for her current heavy drinking habits. Injuries induced by alcohol intoxication have since then caused multiple visits to the emergency room and she has now a reported cognitive impairment that severely compromises her ability for self-care. The association between AUD and bariatric surgery, as presented in the reported clinical case, is well established in current literature. The switch of patient’s coping mechanisms from eating to drinking, surgical-induced alcohol pharmacokinetics changes or adaptations of neuroendocrine mechanisms (such as ghrelin and it’s impact on the mesolimbic dopamine system) that contribute to the augmentation of brain reward signaling are all factors that could play a role in the increased reinforcing value of alcohol in these patients. Psychosocial factors were also identified as variables that could impact alcohol-misuse post-operatively. Furthermore, data suggests differences between surgical procedures: while both Roux-en-Y-Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) dramatically impact alcohol pharmacokinetics, Laparoscopic Adjustable Gastric Banding (LAGB) does not.ConclusionsThere is a strong possibility that the patient’s drinking habits started as a coping mechanism, but her surgery may have also contributed to her AUD. Our review found multiple biopsychosocial factors that could explain the link between bariatric surgery and AUD and some predictors for its development, but future research is needed to fully elucidate its complexities. Nonetheless, health professionals must be well informed for thetimely prevention, diagnosis and treatment of eventual AUD in these patients.Disclosure of InterestNone Declared

Emerging Roles of Uremic Toxins and Inflammatory Cytokines in the Alteration of Hepatic Drug Disposition in Patients with Kidney Dysfunction.

Patients with kidney dysfunction exhibit distinct pharmacokinetic profiles compared to those with normal kidney function. Hence, it is desirable to monitor the drug efficacy and toxicity caused by fluctuations in plasma drug concentrations associated with kidney dysfunction. Recently, pharmacokinetic information of drugs excreted mainly through the urine of patients with kidney dysfunction has been reported via drug-labeling information. Pharmacokinetic changes in drugs mainly eliminated by the liver cannot be overlooked as drug metabolism and/or transport activity in the liver may also be altered in patients with kidney dysfunction; however, the underlying mechanisms remain unclear. To plan an appropriate dosage regimen, it is necessary to clarify the underlying processes of functional changes in pharmacokinetic proteins. In recent years, uremic toxins have been shown to reduce the activity and/or expression of renal and hepatic transporters. This inhibitory effect has been reported to be time-dependent. In addition, inflammatory cytokines, such as interleukin-6, released from immune cells activated by uremic toxins and/or kidney injury can reduce the expression levels of drug-metabolizing enzymes and transporters in human hepatocytes. In this mini-review, we have summarized the renal and hepatic pharmacokinetic changes as well as the potential underlying mechanisms in kidney dysfunction, such as the chronic kidney disease and acute kidney injury. SIGNIFICANCE STATEMENT: Patients with kidney dysfunction exhibit distinct pharmacokinetic profiles compared to those with normal kidney function. Increased plasma concentrations of uremic toxins and inflammatory cytokines during kidney disease may potentially affect the activities and/or expression levels of drug-metabolizing enzymes and transporters in the liver and kidneys.

Antimicrobial Pharmacokinetics and Pharmacodynamics in Critical Care: Adjusting the Dose in Extracorporeal Circulation and to Prevent the Genesis of Multiresistant Bacteria

Critically ill patients suffering from severe infections are prone to pathophysiological pharmacokinetic changes that are frequently associated with inadequate antibiotic serum concentrations. Minimum inhibitory concentrations (MICs) of the causative pathogens tend to be higher in intensive care units. Both pharmacokinetic changes and high antibiotic resistance likely jeopardize the efficacy of treatment. The use of extracorporeal circulation devices to support hemodynamic, respiratory, or renal failure enables pharmacokinetic changes and makes it even more difficult to achieve an adequate antibiotic dose. Besides a clinical response, antibiotic pharmacokinetic optimization is important to reduce the selection of strains resistant to common antibiotics. In this review, we summarize the present knowledge regarding pharmacokinetic changes in critically ill patients and we discuss the effects of extra-corporeal devices on antibiotic treatment together with potential solutions.

CYP2D6 isoenzyme and ABCB1 gene polymorphisms associated with postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy: a randomized trial

IntroductionPostoperative nausea and vomiting is still a common complication. Serotonin receptor antagonists are commonly used in clinical practice for antiemetic prophylaxis. Interindividual variations in drug response, including single nucleotide polymorphisms, are related to pharmacokinetic and pharmacodynamic changes in these drugs and may lead to a poor therapeutic response. This study aimed to evaluate the influence of CYP2D6 isoenzyme and ABCB1 gene polymorphisms on the frequency of postoperative nausea and vomiting with the use of ondansetron or palonosetron. MethodsA randomized, double-blind clinical trial including 82 women aged 60 years or over undergoing laparoscopic cholecystectomy was conducted. Patients were randomized to receive either ondansetron or palonosetron for postoperative nausea and vomiting prophylaxis. DNA was extracted from saliva. Genetic polymorphisms were analyzed by real-time polymerase chain reaction. The following polymorphisms were analyzed: rs3892097 C/T, rs1128503 A/G, rs16947 A/G, rs1065852 A/G, rs1045642 A/G, rs2032582 C/A, and rs20325821 C/A. ResultsOverall, vomiting, and severe nausea occurred in 22.5% and 57.5% of patients, respectively. In the palonosetron group, patients with the GG genotype (rs16947 A/G) experienced more severe nausea (p = 0.043). In the ondansetron group, patients with the AA genotype (rs16947 A/G) presented mild nausea (p = 0.034), and those with the AA genotype (rs1065852 A/G) experienced more vomiting (p = 0.034). ConclusionA low antiemetic response was observed with ondansetron in the presence of the AA genotype (rs16947 A/G) and the AA genotype (rs1065852 A/G), and a low therapeutic response was found with palonosetron in the presence of the GG genotype (rs16947 A/G) in laparoscopic cholecystectomy. RegisterClinicalTrials.gov.

A possible but unrecognized risk of acceptable daily intake dose triazole pesticides exposure—bile acid disturbance induced pharmacokinetic changes of oral medication

Triazole antifungal pesticides work by inhibiting the activity of lanosterol-14-α-demethylase, a member of cytochrome P450 enzymes (CYPs), but this effect is non-specific. Bile acids (BAs) are important physical surfactants for lipids absorption in intestine, and synthesized by CYPs 7A1/27A1. Thus, we presume that triazole exposure might influence the therapeutic effect or safety of oral medication through disturbing the BAs pool, even though the exposure is under an acceptable daily intake (ADI) dose. Short- and long-term of ADI dose tebuconazole (TEB) exposure animal models were established through various routes, and statins with different hydrophilic and lipophilic properties were gavaged. It exhibited that the activity of CYP7A1/27A1 was indeed inhibited but the expression was up-regulated, the BAs pool was changed either the content and the composition, and the absorption behavior of statins with strong and medium degree of lipid-solubility were significantly changed. A series of experiments performed on models of intestinal mucus, Caco-2 cell monolayer and Caco-2/HT29 co-culture system revealed that the TEB-exposure induced BAs disturbance made impacts on drug absorption in many aspects, including drug solubility and the structure of intestinal barriers. This study suggests us to be more alert about the hazard of pesticides residues for elderly and chronically ill groups.