Clinical Pharmacokinetics最新文献

{"title":"Penetration of Antibiotics into Subcutaneous and Intramuscular Interstitial Fluid: A Meta-Analysis of Microdialysis Studies in Adults.","authors":"Pieter-Jan De Sutter, Eline Hermans, Pieter De Cock, Jan Van Bocxlaer, Elke Gasthuys, An Vermeulen","doi":"10.1007/s40262-024-01394-z","DOIUrl":"10.1007/s40262-024-01394-z","url":null,"abstract":"<p><strong>Background and objective: </strong>The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution.</p><p><strong>Methods: </strong>A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations.</p><p><strong>Results: </strong>In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration.</p><p><strong>Conclusions: </strong>This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491146","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 Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.","authors":"Jen-Hao Wu, Edoardo Pennesi, Francisco Bautista, May Garrett, Kei Fukuhara, Erica Brivio, Anneke C J Ammerlaan, Franco Locatelli, Inge M van der Sluis, Claudia Rossig, Christiane Chen-Santel, Bella Bielorai, Arnaud Petit, Jan Starý, Cristina Díaz-de-Heredia, Susana Rives, Aengus O'Marcaigh, Carmelo Rizzari, Gernot Engstler, Karsten Nysom, Alba Rubio-San-Simón, Benedicte Bruno, Yves Bertrand, Benoît Brethon, Fanny Rialland, Geneviève Plat, Uta Dirksen, Lucie Sramkova, C Michel Zwaan, Alwin D R Huitema","doi":"10.1007/s40262-024-01386-z","DOIUrl":"10.1007/s40262-024-01386-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL.</p><p><strong>Methods: </strong>From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data.</p><p><strong>Results: </strong>Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 10³ ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants.</p><p><strong>Conclusions: </strong>The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440269","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":"Characterizing Enoxaparin's Population Pharmacokinetics to Guide Dose Individualization in the Pediatric Population.","authors":"Fernando O Carreño, Jacqueline G Gerhart, Victória E Helfer, Jaydeep Sinha, Karan R Kumar, Carl Kirkpatrick, Christoph P Hornik, Daniel Gonzalez","doi":"10.1007/s40262-024-01388-x","DOIUrl":"10.1007/s40262-024-01388-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct.  METHODS: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0-18 years, TBW) or fat-free mass (2-18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity.</p><p><strong>Results: </strong>A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied.</p><p><strong>Conclusion: </strong>Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491145","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":"The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.","authors":"Niels A D Guchelaar, Stefan A J Buck, Leni van Doorn, Koen G A M Hussaarts, Yorick Sandberg, Annemieke van der Padt-Pruijsten, Robbert J van Alphen, Laura Poppe-Manenschijn, Isolde Vleut, Peter de Bruijn, Roelof W F van Leeuwen, Bianca Mostert, Ferry A L M Eskens, Esther Oomen-de Hoop, Stijn L W Koolen, Ron H J Mathijssen","doi":"10.1007/s40262-024-01390-3","DOIUrl":"10.1007/s40262-024-01390-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine.</p><p><strong>Methods: </strong>In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction.</p><p><strong>Results: </strong>Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil.</p><p><strong>Conclusions: </strong>Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure.</p><p><strong>Clinical trial registration: </strong>NL8067 (registered 04-10-2019).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476100","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 Pharmacokinetics and Pharmacodynamics of Letermovir in Allogenic Hematopoietic Cell Transplantation.","authors":"Kimitaka Suetsugu, Tomohiro Shigematsu, Takahiro Nakamura, Takeshi Hirota, Ichiro Ieiri","doi":"10.1007/s40262-024-01392-1","DOIUrl":"10.1007/s40262-024-01392-1","url":null,"abstract":"<p><p>Letermovir is a newly developed antiviral agent used for the prophylaxis of human cytomegalovirus infections in patients undergoing allogeneic hematopoietic cell transplantation. This novel anti-cytomegalovirus drug, used for the prophylaxis of cytomegalovirus reactivation until approximately 200 days after transplantation, effectively reduces the risk of clinically significant cytomegalovirus infection. No human counterpart exists for the terminase complex; letermovir is virus specific and lacks some toxicities previously observed with other anti-cytomegalovirus drugs, such as cytopenia and nephrotoxicity. The absolute bioavailability of letermovir in healthy individuals is estimated to be 94% based on a population-pharmacokinetic analysis. In contrast, oral administration of letermovir to patients undergoing hematopoietic cell transplantation results in lower exposure than that in healthy individuals. Renal or hepatic impairment does not influence the intrinsic clearance of letermovir. Co-administration of letermovir may alter the plasma concentrations of other drugs, including itself, as it acts as a substrate and inhibitor/inducer of several drug-metabolizing enzymes and transporters. In particular, attention should be paid to the drug-drug interactions between letermovir and calcineurin inhibitors or azole antifungal agents, which are commonly used in patients undergoing hematopoietic cell transplantation. This article reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of letermovir, focusing on patients undergoing hematopoietic cell transplantation, healthy individuals, and specific patient subsets.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619535","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":"Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.","authors":"Jérôme Alexandre, Stephane Oudard, Lisa Golmard, Luca Campedel, Mourad Mseddi, Sylvain Ladoire, Ahmed Khalil, Denis Maillet, Christophe Tournigand, Blaise Pasquiers, Françoise Goirand, Joseph Berthier, Jérôme Guitton, Charles Dariane, Florence Joly, Evanguelos Xylinas, Jean Louis Golmard, Hendy Abdoul, Alicja Puszkiel, Xavier Decleves, Edith Carton, Audrey Thomas, Michel Vidal, Olivier Huillard, Benoit Blanchet","doi":"10.1007/s40262-024-01396-x","DOIUrl":"10.1007/s40262-024-01396-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Trough abiraterone concentration (ABI C_min) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression.</p><p><strong>Methods: </strong>This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone C_min was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (C_min < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of C_min from samples collected outside the sampling guidelines (22-26 h).</p><p><strong>Results: </strong>In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI C_min in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (C_min > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI C_min was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis.</p><p><strong>Conclusion: </strong>The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497326","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":"Investigating the Bioavailability and Insulin-like Growth Factor-I Release of Two Different Strengths of Somapacitan: A Randomised, Double-Blind Crossover Trial.","authors":"Sarah Louise Dombernowsky, Birgitte Bentz Damholt, Michael Højby Rasmussen, Claus Sværke, Rasmus Juul Kildemoes","doi":"10.1007/s40262-024-01395-y","DOIUrl":"10.1007/s40262-024-01395-y","url":null,"abstract":"<p><strong>Study design and objective: </strong>Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses.</p><p><strong>Methods: </strong>Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18-45 years and body mass index 18.5-24.9 kg/m². Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC_0-t), maximum serum concentration (C_max), time to C_max and terminal half-life of somapacitan and safety were assessed.</p><p><strong>Results: </strong>In total, 33 participants were randomised. For AUC_0-t, estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90% CIs were within the acceptance range (0.80-1.25). For C_max, ETR was 0.77 (90% CI 0.68-0.89). Point estimate and 90% CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified.</p><p><strong>Conclusions: </strong>Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC_0-t but not for C_max. The two strengths had equivalent IGF-I responses.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT03905850 (3 April 2019).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537621","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":"Correction to: Hyperinflammation Reduces Midazolam Metabolism in Critically Ill Adults with COVID‑19.","authors":"Tim J L Smeets, Abraham J Valkenburg, Mathieu van der Jagt, Birgit C P Koch, Henrik Endeman, Diederik A M P J Gommers, Sebastian D T Sassen, Nicole G M Hunfeld","doi":"10.1007/s40262-024-01389-w","DOIUrl":"10.1007/s40262-024-01389-w","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466665","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":"Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.","authors":"Marinda Meertens, Eline L Giraud, Maud B A van der Kleij, Kim Westerdijk, Niels A D Guchelaar, Roos F Bleckman, Amy Rieborn, Alex L T Imholz, Hans-Martin Otten, Annelie Vulink, Maartje Los, Paul Hamberg, Winette T A van der Graaf, Hans Gelderblom, Dirk Jan A R Moes, K Esther Broekman, Daan J Touw, Stijn L W Koolen, Ron H J Mathijssen, Alwin D R Huitema, Nielka P van Erp, Ingrid M E Desar, Neeltje Steeghs","doi":"10.1007/s40262-024-01399-8","DOIUrl":"10.1007/s40262-024-01399-8","url":null,"abstract":"<p><strong>Introduction and objective: </strong>Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing.</p><p><strong>Methods: </strong>A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications.</p><p><strong>Results: </strong>A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%).</p><p><strong>Conclusion: </strong>TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619536","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-Pharmacodynamics Modeling for Evaluating Drug-Drug Interactions in Polypharmacy: Development and Challenges.","authors":"Di Zhao, Ping Huang, Li Yu, Yu He","doi":"10.1007/s40262-024-01391-2","DOIUrl":"10.1007/s40262-024-01391-2","url":null,"abstract":"<p><p>Polypharmacy is commonly employed in clinical settings. The potential risks of drug-drug interactions (DDIs) can compromise efficacy and pose serious health hazards. Integrating pharmacokinetics (PK) and pharmacodynamics (PD) models into DDIs research provides a reliable method for evaluating and optimizing drug regimens. With advancements in our comprehension of both individual drug mechanisms and DDIs, conventional models have begun to evolve towards more detailed and precise directions, especially in terms of the simulation and analysis of physiological mechanisms. Selecting appropriate models is crucial for an accurate assessment of DDIs. This review details the theoretical frameworks and quantitative benchmarks of PK and PD modeling in DDI evaluation, highlighting the establishment of PK/PD modeling against a backdrop of complex DDIs and physiological conditions, and further showcases the potential of quantitative systems pharmacology (QSP) in this field. Furthermore, it explores the current advancements and challenges in DDI evaluation based on models, emphasizing the role of emerging in vitro detection systems, high-throughput screening technologies, and advanced computational resources in improving prediction accuracy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418107","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}