Clinical Pharmacokinetics最新文献

{"title":"Coupling Pre- and Postnatal Infant Exposures with Physiologically Based Pharmacokinetic Modeling to Predict Cumulative Maternal Levetiracetam Exposure During Breastfeeding.","authors":"Santosh V Suryavanshi, Shirley Wang, Dagmar M Hajducek, Abdullah Hamadeh, Cindy H T Yeung, Patricia D Maglalang, Shinya Ito, Julie Autmizguine, Daniel Gonzalez, Andrea N Edginton","doi":"10.1007/s40262-024-01447-3","DOIUrl":"10.1007/s40262-024-01447-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Although breastfeeding ensures optimal infant development and maternal health, mothers taking medications may abandon breastfeeding because of uncertainties regarding toxicity to infants. Current methods in predicting infant risk to maternal medication exposure do not account for breastfeeding-related variability or in utero exposure via the umbilical cord (UC). Previously, our workflow integrated variability in infant anatomy and physiology, breast milk intake volume, and drug concentrations in breast milk using physiologically based pharmacokinetic (PBPK) modeling. The upper area under the curve ratio (UAR) was then calculated to assess infant risk from maternal drug. Herein, we enhanced this workflow by coupling pre- and postnatal exposures to predict the overall levetiracetam exposure in breastfeeding infants.</p><p><strong>Methods: </strong>A published pediatric PBPK model of levetiracetam was used to simulate an infant population (n = 100). Daily infant doses were simulated using a weight-normalized milk intake model to calculate volumes ingested across age groups, alongside literature-derived or simulated milk concentrations across maternal doses to predict infant concentrations. Published UC concentrations were used to develop a cord-coupled neonatal model (CCM), which was integrated with the PBPK and milk intake models and evaluated by comparing observed and simulated infant blood concentrations using a 90% prediction interval (PI).</p><p><strong>Results: </strong>UC concentration data from 14 mothers were used to develop the CCM. A total of 16 paired (known milk concentrations) and two unpaired (unknown milk concentrations) individual infant concentrations were identified for evaluating the model along with population values of 64 infants from two age groups (2-4 and 7-31 days). The CCM improved the predictions overall compared with the original workflow, largely due to improvements for the youngest age group evaluated. Overall, 83% (10 of 12) of the individual infant plasma concentrations were successfully captured within the 90% PI for the paired, quantifiable (i.e. above the limit of quantification) evaluation datasets. After administration of a maternal dose of levetiracetam 2000 mg, the calculated UAR ranged from 0.13 to 0.27 for the 95th percentile infants.</p><p><strong>Conclusions: </strong>To our knowledge, this is the first report to combine prenatal levetiracetam exposures from the UC and postnatal exposures from breastfeeding to predict overall infant drug exposure. The results indicate that infant exposure in infants aged 0-7 days may approach therapeutic levels of levetiracetam in the highest-risk infants (i.e. 95th percentile), with a low likelihood of adverse effects based on published clinical studies. This integrated modeling approach provides a more holistic analysis of neonatal exposures. It can be applied in future studies to derive the UAR of drugs administered during b","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1735-1748"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Antiretroviral Drugs in Older People Living with HIV, Part II: Drugs Licensed Before 2005.","authors":"Thainá Toledo, Vanessa G Oliveira, Vitória Berg Cattani, Karine Seba, Valdilea Gonçalves Veloso, Beatriz Grinsztejn, Sandra Wagner Cardoso, Thiago S Torres, Rita Estrela","doi":"10.1007/s40262-024-01441-9","DOIUrl":"10.1007/s40262-024-01441-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Advances in antiretroviral therapy led to an increase in life expectancy among people living with human immunodeficiency virus (HIV). As aging is characterized by several physiological changes that can influence pharmacokinetics (PK), this systematic review aims to describe the impact of aging on the PK of antiretrovirals (ARV) approved by the Food and Drug Administration (FDA) before 2005.</p><p><strong>Methods: </strong>Searches were performed in BVS, EMBASE, and PubMed databases for publications until June 2024. Peer-reviewed published studies were included if they met the following criteria: adults (≥ 18 years) living with HIV; reporting at least one PK parameter or plasma concentration of any ARV approved by the US FDA before 2005 and still used in the clinic: lamivudine (3TC), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), abacavir (ABC), zidovudine (ZDV), efavirenz (EFV), nevirapine (NVP), atazanavir (ATV), lopinavir (LPV), ritonavir (RTV), tipranavir (TPV), and fosamprenavir (FPV); PK parameters stratified per age group as young (aged 18-49 years) or older (age ≥ 50 years) adults; and manuscripts published in English, Portuguese, or Spanish. All studies were evaluated for risk of bias. The review protocol was registered in the PROSPERO database (registration no. CRD42023463092).</p><p><strong>Results: </strong>Among 106 studies included, only 22 evaluated the PK of participants aged 50 years or older and only 5 studies compared the PK between young and older adults for ATV, RTV, EFV, and 3TC. Our analysis revealed an increase in minimal concentration (C_min) values for LPV, RTV, and ATV in older adults. While increased values of the area under the curve (AUC) and maximum concentration (C_max) were observed in older adults using ATV, 3TC, and FTC, no differences in PK were apparent between young and older adults for ABC and EFV, with no estimation possible for ZDV.</p><p><strong>Conclusion: </strong>Exposure to 3TC, TDF, FTC, ATV, LPV, and RTV increases with age, while exposure to ABC and EFV appears to be unaffected. Despite the large quantity of data on PK in young adults, there is still a gap in knowledge about the effects of aging on the PK of these ARVs.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1655-1666"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups.","authors":"Ma Ida Mohmaed Ali, A Laura Nijstad, René J Boosman, Marie-Rose B S Crombag, Shelby Barnett, Gareth J Veal, Arief Lalmohamed, Nielka P van Erp, Neeltje Steeghs, C Michel Zwaan, Jos H Beijnen, Hinke Siebinga, Alwin D R Huitema","doi":"10.1007/s40262-024-01445-5","DOIUrl":"10.1007/s40262-024-01445-5","url":null,"abstract":"<p><strong>Background: </strong>The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin.</p><p><strong>Methods: </strong>A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages. First, the effect of age in young patients was investigated, by adding a maturation function on clearance (CL), the central compartment (V1) and peripheral compartments (V2 and V3). Second, the impact of ageing was investigated by adding a maximal effect (E_max) function on CL, V1, V2, and V3. To investigate the overall impact of age on doxorubicin exposure, various simulations were conducted.</p><p><strong>Results: </strong>A total of 168 patients (age: 0.11-90 years) with 555 doxorubicin samples were included. The maturation function was relevant for V1 and V2 (13.1 and 23.7 L, respectively), leading to an increase in V1 and V2 with increasing age. In contrast, adding an E_max function only impacted V3 (1063L), resulting in a decrease of V3 with age. Simulations showed no clinically relevant difference in the exposure of doxorubicin between age groups.</p><p><strong>Conclusion: </strong>A population pharmacokinetic model with data across the age range showed that age predominantly affected volumes of distribution of the central and peripheral compartments. These effects were not considered to be clinically relevant based on performed simulations. This supports the use of currently used doxorubicin dosages of 1 mg/kg for infants and toddlers < 10 kg and body surface area-based dosing for other patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1711-1722"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Dose-Response Study of Four Fixed Weight-Based Phenylephrine Dosages in Obese Cesarean Delivery Patients to Prevent Spinal Anesthesia-Induced Hypotension.","authors":"Li Xing, Hai-Feng Xu, Yang Wang, Hong-Shu Shi, Fei Xiao, Yao-Hua Shen, Su-Feng Lin","doi":"10.1007/s40262-024-01448-2","DOIUrl":"10.1007/s40262-024-01448-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Reports have suggested the use of intravenous infusion of vasopressors as an approach to prevent spinal anesthesia-induced hypotension (SAIH) in women undergoing cesarean deliveries. However, data on the suitability of this technique for obese people are limited. As such, the current experiment was designed to clarify the dose-response relationship associated with the preventive administration of phenylephrine to avoid SAIH during cesarean delivery in obese parturients under combined spinal-epidural anesthesia.</p><p><strong>Methods: </strong>The current study included 100 parturients with a body mass index ≥30 kg/m² who were undergoing cesarean section delivery. They were randomly treated with phenylephrine at different doses: 0.375, 0.5, 0.625, or 0.75 μg/kg/min. An infusion of phenylephrine was deemed beneficial if hypotension was absent, with hypotension defined as a systolic blood pressure <90 mmHg or <80% of the baseline value between spinal injection and the delivery of the newborn. The 50% and 90% effective doses (ED₅₀ and ED₉₀, respectively) for prophylactic phenylephrine were determined via a probit regression.</p><p><strong>Results: </strong>Respective rates of hypotension in the 0.375, 0.5, 0.625, and 0.75 groups were 52% (13/25), 40% (10/25), 20% (5/25), and 0% (0/25). ED₅₀ and ED₉₀ values of 0.42 (95% confidence interval 0.30-0.48) and 0.68 (95% confidence interval 0.60-0.87) μg/kg/min were calculated for phenylephrine treatment.</p><p><strong>Conclusion: </strong>The study results indicated that prophylactic phenylephrine, which prevents SAIH in obese parturients following cesarean delivery, has calculated values of 0.42 and 0.68 μg/kg/min. These findings may contribute to developing appropriate clinical practice guidelines for improved patient management.</p><p><strong>Clinical trial registration: </strong>https://www.chictr.org.cn/bin/project/edit?pid=153050 . Identifier ChiCTR2200058125.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1749-1756"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acknowledgement to Referees.","authors":"","doi":"10.1007/s40262-024-01456-2","DOIUrl":"https://doi.org/10.1007/s40262-024-01456-2","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing.","authors":"Muhammad Waqar Ashraf, Satu Poikola, Mikko Neuvonen, Johanna I Kiiski, Vesa K Kontinen, Klaus T Olkkola, Janne T Backman, Mikko Niemi, Teijo I Saari","doi":"10.1007/s40262-024-01433-9","DOIUrl":"10.1007/s40262-024-01433-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine.</p><p><strong>Methods: </strong>We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development.</p><p><strong>Results: </strong>Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers.</p><p><strong>Conclusions: </strong>Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1547-1560"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interaction Management with the Novel Anti-Cytomegalovirus Agents Letermovir and Maribavir: Guidance for Clinicians.","authors":"David M Burger, Laura Nijboer, Mira Ghobreyal, Johan Maertens, Nicole Blijlevens, Luuk Hilbrands, Marije C Baas, Per Ljungman, Roger J M Brüggemann","doi":"10.1007/s40262-024-01437-5","DOIUrl":"10.1007/s40262-024-01437-5","url":null,"abstract":"<p><p>Letermovir and maribavir have demonstrated efficacy in the prevention and treatment, respectively, of immunosuppressed patients with cytomegalovirus (CMV) infection and disease. These patients often have polypharmacy making them at risk for drug-drug interactions. Both letermovir and maribavir can be perpetrators and victims of drug-drug interactions. Letermovir is a moderate inhibitor of CYP3A, CYP2C8 and OATP1B1/3, and a moderate inducer of CYP2C19. It is a substrate of UGT1A1/3, BCRP, P-gp and OATP1B1/3. Maribavir is a moderate CYP2C9 inhibitor and a substrate of CYP3A. Drug-drug interactions between these anti-CMV agents and a number of therapeutic classes, such as immunosuppressants, antifungal agents, and hemato-oncological agents, can have clinical consequences and deserve dose modification or close monitoring. In a number of examples, three-way drug interactions need to be assessed. The objective of this review is to provide clinicians with guidance for drug-drug interaction management, based on existing data from drug-drug interaction studies, and extrapolation to other relevant co-medications that have not (yet) been studied but that are frequently used in these patient populations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1529-1546"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology of Asciminib: A Review.","authors":"Matthias Hoch, Felix Huth, Paul William Manley, Ioannis Loisios-Konstantinidis, Francois Pierre Combes, Ying Fei Li, Yunlin Fu, Sherwin K B Sy, Vanessa Obourn, Abhijit Chakraborty, Florence Hourcade-Potelleret","doi":"10.1007/s40262-024-01428-6","DOIUrl":"10.1007/s40262-024-01428-6","url":null,"abstract":"<p><p>Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t_1/2) across studies was estimated to be between 7 and 15 h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1^IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1513-1528"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Plasma Clearance of CYP450 Probe Drugs May Not be Specific for Altered In Vivo Enzyme Activity Under (Patho)Physiological Conditions: How to Interpret Findings of Probe Cocktail Studies.","authors":"Laura M de Jong, Marinda van de Kreeke, Mariam Ahmadi, Jesse J Swen, Catherijne A J Knibbe, J G Coen van Hasselt, Martijn L Manson, Elke H J Krekels","doi":"10.1007/s40262-024-01426-8","DOIUrl":"10.1007/s40262-024-01426-8","url":null,"abstract":"<p><strong>Background and objective: </strong>CYP450 (CYP) phenotyping involves quantifying an individual's plasma clearance of CYP-specific probe drugs, as a proxy for in vivo CYP enzyme activity. It is increasingly applied to study alterations in CYP enzyme activity under various (patho)physiological conditions, such as inflammation, obesity, or pregnancy. The phenotyping approach assumes that changes in plasma clearance of probe drugs are driven by changes in CYP enzyme activity. However, plasma clearance is also influenced by protein binding, blood-to-plasma ratio, and hepatic blood flow, all of which may change under (patho)physiological conditions.</p><p><strong>Methods: </strong>Using a physiologically based pharmacokinetic (PBPK) workflow, we aimed to evaluate whether the plasma clearance of commonly used CYP probe drugs is indeed directly proportional to alterations in CYP enzyme activity (sensitivity), and to what extent alterations in protein binding, blood-to-plasma ratio, and hepatic blood flow observed under (patho)physiological conditions impact plasma clearance (specificity).</p><p><strong>Results: </strong>Plasma clearance of CYP probe drugs is sensitive to alterations in CYP enzyme activity, since alterations in intrinsic clearance between - 90% and + 150% resulted in near-proportional changes in plasma clearance, except for midazolam in the case of > 50% CYP3A4 induction. However, plasma clearance also changed near-proportionally with alterations in the unbound drug fraction, diminishing probe specificity. This was particularly relevant for high protein-bound probe drugs, as alterations in plasma protein binding resulted in larger relative changes in the unbound drug fraction. Alterations in the blood-to-plasma ratio and hepatic blood flow of ± 50% resulted in plasma clearance changes of less than ± 16%, meaning they limitedly impacted plasma clearance of CYP probe drugs, except for midazolam. In order to correct for the impact of non-metabolic determinants on probe drug plasma clearance, an R script was developed to calculate how much the CYP enzyme activity is actually altered under (patho)physiological conditions, when alterations in the unbound drug fraction, blood-to-plasma ratio, and/or hepatic blood flow also impact probe drug plasma clearance.</p><p><strong>Conclusions: </strong>As plasma protein binding can change under (patho)physiological conditions, alterations in unbound drug fraction should be accounted for when using CYP probe drug plasma clearance as a proxy for CYP enzyme activity in patient populations. The tool developed in this study can support researchers in determining alterations in CYP enzyme activity in patients with (patho)physiological conditions.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1585-1595"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia.","authors":"Carla Troisi, Pier Giorgio Cojutti, Matteo Rinaldi, Tommaso Tonetti, Antonio Siniscalchi, Coen van Hasselt, Pierluigi Viale, Federico Pea","doi":"10.1007/s40262-024-01436-6","DOIUrl":"10.1007/s40262-024-01436-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP).</p><p><strong>Methods: </strong>Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [C_ss] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (C_ss/MIC = 1-4) and sub-optimal (C_ss/MIC < 1) and the magnitude of C-RP production inhibition over time.</p><p><strong>Results: </strong>A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10).</p><p><strong>Conclusion: </strong>Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1573-1583"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}