Pharmacometrics
We develop and use mathematical models to understand drug and disease mechanisms, and to optimise drug development and therapy.
Our research
Pharmacometric research focuses on nonlinear mixed effects (”population”) models. Such models describe data, generally the response-time profiles observed in a clinical trial, by a basic model, accounting for the general structure of the underlying system, and a set of hierarchical variability components, accounting for variability between subjects, within subjects over time and remaining between observation variability.
Research at the pharmacometrics group is divided into four main areas:
- We develop and evaluate methods for efficient and robust model building. This involves development of estimation algorithms, methods for model diagnosis and sequential procedures for model building. The result of the research, when applicable, is made available as free software.
- We develop platform models for the use in specific therapeutic areas or particular therapeutic/ pharmacological principles. Such models may involve the time-course of a biomarker or a system of biomarkers during normal, diseased and/or provoked conditions.
- We utilize the developed models for the purpose of designing studies, deciding upon dosing strategies and other developmental decisions.
- We analyse dose-concentration-response data from trials to understand therapies with existing drugs with the aim of allowing improved therapy.
Faculty News
Department Calendar
Group Publications
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Siebinga, Hinke; de Wit-van der Veen, Berlinda J. J.; Beijnen, Jos H.; Dorlo, Thomas P. C.; Huitema, Alwin D. R.; Hendrikx, Jeroen J. M. A.
A physiologically based pharmacokinetic model for [Ga-68]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients
2023
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Prins, H. A. B.; Zino, L.; Svensson, Elin M.; Verbon, A.; de Bree, G. J.; Prins, J. M.; Reiss, P.; Burger, D. M.; Rokx, C.; Colbers, A.; Team, NOVA Study
Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naive individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA)
2023
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Wilkins, Justin J.; Svensson, Elin; Ernest, Jacqueline P.; Savic, Radojka M.; Simonsson, Ulrika S. H.; McIlleron, Helen
Pharmacometrics in tuberculosis: progress and opportunities
2022
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Tanneau, Lénaïg; Karlsson, Mats; Rosenkranz, Susan L.; Cramer, Yoninah S.; Shenje, Justin; Upton, Caryn M.; Morganroth, Joel; Diacon, Andreas H.; Maartens, Gary; Dooley, Kelly E.; Svensson, Elin
Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens
2022
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Abulfathi, Ahmed A.; Chaba, Linda A.; Svensson, Elin; Pillai, Goonaseelan C.; Rosenkranz, Bernd
Pharmacometrics - tools to assure optimal medicine use in low- and middle-income countries: Editorial
2022
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Denti, Paolo; Wasmann, Roeland E.; van Rie, Annelies; Winckler, Jana; Bekker, Adrie; Rabie, Helena; Hesseling, Anneke C.; van der Laan, Louvina E.; Gonzalez-Martinez, Carmen; Zar, Heather J.; Davies, Gerry; Wiesner, Lubbe; Svensson, Elin; McIlleron, Helen M.
Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study
2022
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Dreesen, Erwin; Gijsen, Matthias; Elkayal, Omar; Annaert, Pieter; Debaveye, Yves; Wauters, Joost; Karlsson, Mats O.; Spriet, Isabel
Ceftriaxone dosing based on the predicted probability of augmented renal clearance in critically ill patients with pneumonia
2022
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Musa, Ahmed M; Mbui, Jane; Mohammed, Rezika; Olobo, Joseph; Ritmeijer, Koert; Alcoba, Gabriel; Muthoni Ouattara, Gina; Egondi, Thaddaeus; Nakanwagi, Prossy; Omollo, Truphosa; Wasunna, Monique; Verrest, Luka; Dorlo, Thomas P. C.; Musa Younis, Brima; Nour, Ali; Taha Ahmed Elmukashfi, Elmukashfi; Ismail Omer Haroun, Ahmed; Khalil, Eltahir A G; Njenga, Simon; Fikre, Helina; Mekonnen, Tigist; Mersha, Dagnew; Sisay, Kasaye; Sagaki, Patrick; Alvar, Jorge; Solomos, Alexandra; Alves, Fabiana
Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.
2022
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Damoiseaux, David; Li, Wenlong; Beijnen, Jos H; Schinkel, Alfred H; Huitema, Alwin D R; Dorlo, Thomas P. C.
Population Pharmacokinetic Modelling to Support the Evaluation of Preclinical Pharmacokinetic Experiments with Lorlatinib.
2022
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Chu, Wan-Yu; Annink, Kim V; Nijstad, A Laura; Maiwald, Christian A; Schroth, Michael; Bakkali, Loubna El; van Bel, Frank; Benders, Manon J N L; van Weissenbruch, Mirjam M; Hagen, Anja; Franz, Axel R; Dorlo, Thomas P. C.; Allegaert, Karel; Huitema, Alwin D R
Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.
2022
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Roseboom, Ignace C; Thijssen, Bas; Rosing, Hilde; Alves, Fabiana; Mondal, Dinesh; Teunissen, Marcel B M; Beijnen, Jos H; Dorlo, Thomas P. C.
Development and validation of an HPLC-MS/MS method for the quantification of the anti-leishmanial drug miltefosine in human skin tissue.
2022
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Palić, Semra; Beijnen, Jos H; Dorlo, Thomas P. C.
An update on the clinical pharmacology of miltefosine in the treatment of leishmaniasis.
2022
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Molenaar-Kuijsten, Laura; Verheijen, Remy B; Jacobs, Bart A W; Thijssen, Bas; Rosing, Hilde; Dorlo, Thomas P. C.; Beijnen, Jos H; Steeghs, Neeltje; Huitema, Alwin D R
Everolimus Concentration in Saliva to Predict Stomatitis: A Feasibility Study in Patients with Cancer.
2022
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Damoiseaux, David; Calpe, Silvia; Rosing, Hilde; Beijnen, Jos H; Huitema, Alwin D R; Lok, Christianne; Dorlo, Thomas P. C.; Amant, Frédéric
Presence of Five Chemotherapeutic Drugs in Breast Milk as a Guide for the Safe Use of Chemotherapy During Breastfeeding: Results From a Case Series.
2022
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van der Heijden, Lisa; van Nuland, Merel; Beijnen, Jos; Huitema, Alwin; Dorlo, Thomas P. C.
A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens.
2022
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Simeoli, Raffaele; Dorlo, Thomas P. C.; Hanff, Lidwien M; Huitema, Alwin D R; Dreesen, Erwin
Editorial: Therapeutic Drug Monitoring (TDM)
2022
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Janssen, Julie M; Verheijen, Remy B; van Duijl, Tirsa T; Lin, Lishi; van den Heuvel, Michel M; Beijnen, Jos H; Steeghs, Neeltje; van den Broek, Daan; Huitema, Alwin D R; Dorlo, Thomas P. C.
Longitudinal nonlinear mixed effects modeling of EGFR mutations in ctDNA as predictor of disease progression in treatment of EGFR-mutant non-small cell lung cancer.
2022
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van Eijk, Maarten; Yu, Huixin; Sawicki, Emilia; de Weger, Vincent A; Nuijen, Bastiaan; Dorlo, Thomas P. C.; Beijnen, Jos H; Huitema, Alwin D R
Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies.
2022
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Roseboom, Ignace C; Thijssen, Bas; Rosing, Hilde; Alves, Fabiana; Sundar, Shyam; Beijnen, Jos H; Dorlo, Thomas P. C.
Development and validation of a high-performance liquid chromatography tandem mass spectrometry method for the quantification of the antiparasitic and antifungal drug amphotericin B in human skin tissue.
2022
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Roseboom, Ignace C; Thijssen, Bas; Rosing, Hilde; Alves, Fabiana; Younis, Brima M; Musa, Ahmed M; Beijnen, Jos H; Dorlo, Thomas P. C.
Development and validation of an ultra-high performance liquid chromatography coupled to tandem mass spectrometry method for the quantification of the antileishmanial drug paromomycin in human skin tissue.
2022
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Roseboom, Ignace C; Rosing, Hilde; Beijnen, Jos H; Dorlo, Thomas P. C.
Bioanalytical methods for pharmacokinetic studies of antileishmanial drugs.
2022
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Kempen, Thomas; Hedman, Anton N.; Hadziosmanovic, Nermin; Lindner, Karl‐Johan; Melhus, Håkan; Nielsen, Elisabet I.; Sulku, Johanna; Gillespie, Ulrika
Risk factors for and preventability of drug‐related hospital revisits in older patients: A post‐hoc analysis of a randomized clinical trial
2022
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Hinds, Terry D.; Valoti, Massimo; Lai, Yurong; Dorlo, Thomas P. C.; Li, Yan
Emerging talents in Frontiers in Pharmacology: Drug metabolism and transport 2022
2022
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Kunina, Hanna; Al-Mashat, Alex; Chien, Jenny Y.; Garhyan, Parag; Kjellsson, Maria C.
Optimization of trial duration to predict long-term HbA1c change with therapy: A pharmacometrics simulation-based evaluation
2022
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Kempen, Thomas Gerardus Hendrik; Hedman, Anton; Gillespie, Ulrika
Drug-related emergency department visits in older patients: an applicability and reliability study of an existing assessment tool
2022
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Zou, Yuanxi; Nedelman, Jerry; Lombardi, Antonio; Pappas, Frances; Karlsson, Mats; Svensson, Elin
Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling
2022
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Waalewijn, Hylke; Stol, Kim; van der Knaap, Linda; Fraaij, Pieter L. A.; Vermont, Clementien; van Rossum, Annemarie M. C.; Strik-Albers, Riet; Burger, David M.; Svensson, Elin; Colbers, Angela
Adequate exposure of 50 mg dolutegravir in children weighing 20 to 40 kg outside of sub-Sahara Africa
2022
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Chu, Wan-Yu; Allegaert, Karel; Dorlo, Thomas P. C.; Huitema, Alwin D R
Semi-mechanistic Modeling of Hypoxanthine, Xanthine, and Uric Acid Metabolism in Asphyxiated Neonates
2022
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Lopez-Varela, Elisa; Abulfathi, Ahmed A.; Strydom, Natasha; Goussard, Pierre; van Wyk, Abraham C.; Demers, Anne Marie; Van Deventer, Anneen; Garcia-Prats, Anthony J.; van der Merwe, Johannes; Zimmerman, Matthew; Carter, Claire L.; Janson, Jacques; Morrison, Julie; Reuter, Helmuth; Decloedt, Eric H.; Seddon, James A.; Svensson, Elin; Warren, Rob; Savic, Radojka M.; Dartois, Veronique; Hesseling, Anneke C.
Drug concentration at the site of disease in children with pulmonary tuberculosis
2022
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Aoki, Yasunori; Hayami, Ken; Toshimoto, Kota; Sugiyama, Yuichi
Cluster Gauss-Newton method An algorithm for finding multiple approximate minimisers of nonlinear least squares problems with applications to parameter estimation of pharmacokinetic models
2022
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Alffenaar, J. W. C.; Stocker, S. L.; Forsman, L. Davies; Garcia-Prats, A.; Heysell, S. K.; Aarnoutse, R. E.; Akkerman, O. W.; Aleksa, A.; van Altena, R.; de Onata, W. Arrazola; Bhavani, P. K.; Van't Boveneind-Vrubleuskaya, N.; Carvalho, A. C. C.; Centis, R.; Chakaya, J. M.; Cirillo, D. M.; Cho, J. G.; Ambrosio, L. D.; Dalcolmo, M. P.; Denti, P.; Dheda, K.; Fox, G. J.; Hesseling, A. C.; Kim, H. Y.; Koser, C. U.; Marais, B. J.; Margineanu, I; Martson, A. G.; Torrico, M. Munoz; Nataprawira, H. M.; Ong, C. W. M.; Otto-Knapp, R.; Peloquin, C. A.; Silva, D. R.; Ruslami, R.; Santoso, P.; Savic, R. M.; Singla, R.; Svensson, Elin; Skrahina, A.; van Soolingen, D.; Srivastava, S.; Tadolini, M.; Tiberi, S.; Thomas, T. A.; Udwadia, Z. F.; Vu, D. H.; Zhang, W.; Mpagama, S. G.; Schon, T.; Migliori, G. B.
Clinical standards for the dosing and management of TB drugs
2022
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Dorlo, Thomas P. C.
No evidence for cardiotoxicity of miltefosine
2022
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Radtke, Kendra K.; Svensson, Elin; van der Laan, Louvina E.; Hesseling, Anneke C.; Savic, Radojka M.; Garcia-Prats, Anthony J.
Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis
2022
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Haas, David W.; Abdelwahab, Mahmoud Tareq; van Beek, Stijn W.; Baker, Paxton; Maartens, Gary; Bradford, Yuki; Ritchie, Marylyn D.; Wasserman, Sean; Meintjes, Graeme; Beeri, Karen; Gandhi, Neel R.; Svensson, Elin; Denti, Paolo; Brust, James C. M.
Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
2022
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Bukkems, V. E.; van Hove, H.; Roelofsen, D.; Freriksen, J. J. M.; Kolmer, E. W. J. Van Ewijk-Beneken; Burger, D. M.; van Drongelen, J.; Svensson, Elin; Greupink, R.; Colbers, A.
Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments
2022
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Aoki, Yasunori; Hayami, Ken; Toshimoto, Kota; Sugiyama, Yuichi
Cluster Gauss-Newton method: An algorithm for finding multiple approximate minimisers of nonlinear least squares problems with applications to parameter estimation of pharmacokinetic models
2022
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Tanneau, Lénaïg; Karlsson, Mats; Diacon, Andreas H; Shenje, Justin; De los rios, Jorge; Wiesner, Lubbe; Upton, Caryn M; Dooley, Kelly E; Maartens, Gary; Svensson, Elin
Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline
2022
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Leohr, Jennifer; Kjellsson, Maria C.
Impact of Obesity on Postprandial Triglyceride Contribution to Glucose Homeostasis, Assessed with a Semimechanistic Model
2022
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Damoiseaux, David; Li, Wenlong; Martínez-Chávez, Alejandra; Beijnen, Jos H; Schinkel, Alfred H; Huitema, Alwin D R; Dorlo, Thomas P. C.
Predictiveness of the Human-CYP3A4-Transgenic Mouse Model (Cyp3aXAV) for Human Drug Exposure of CYP3A4-Metabolized Drugs.
2022
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van Beek, Stijn W.; Tanneau, Lénaïg; Meintjes, Graeme; Wasserman, Sean; Gandhi, Neel R.; Campbell, Angie; Viljoen, Charle A.; Wiesner, Lubbe; Aarnoutse, Rob E.; Maartens, Gary; Brust, James C. M.; Svensson, Elin
Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment
2022
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Keutzer, Lina; You, Huifang; Farnoud, Ali; Nyberg, Joakim; Wicha, Sebastian G.; Maher-Edwards, Gareth; Vlasakakis, Georgios; Moghaddam, Gita Khalili; Svensson, Elin; Menden, Michael P.; Simonsson, Ulrika S. H.
Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data: Differences, Similarities and Challenges Illustrated with Rifampicin
2022
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Llanos-Paez, Carolina C.; Ambery, Claire; Yang, Shuying; Beerahee, Misba; Plan, Elodie L.; Karlsson, Mats O.
Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model: Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients
2022
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Yngman, Gunnar; Nyberg, Henrik B.; Nyberg, Joakim; Jonsson, E. Niclas; Karlsson, Mats
An introduction of the full random effects model
2022
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Ruth, Mike Marvin; Raaijmakers, Jelmer; van den Hombergh, Erik; Aarnoutse, Rob; Svensson, Elin; Susanto, Budi Octasari; Simonsson, Ulrika S. H.; Wertheim, Heiman; Hoefsloot, Wouter; van Ingen, Jakko
Standard therapy of Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fibre system that simulates human plasma and epithelial lining fluid pharmacokinetics
2022
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Litjens, Carlijn H. C.; Verscheijden, Laurens F. M.; Bolwerk, Celine; Greupink, Rick; Koenderink, Jan B.; van den Broek, Petra H. H.; van den Heuvel, Jeroen J. M. W.; Svensson, Elin; Boeree, Martin J.; Magis-Escurra, Cecile; Hoefsloot, Wouter; van Crevel, Reinout; van Laarhoven, Arjan; van Ingen, Jakko; Kuipers, Saskia; Ruslami, Rovina; Burger, David M.; Russel, Frans G. M.; Aarnoutse, Rob E.; Te Brake, Lindsey H. M.
Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling
2022
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De Jager, Veronique; Gupte, Nikhil; Nunes, Silvia; Barnes, Grace L.; Van Wijk, Rob C; Mostert, Joni; Dorman, Susan E.; Abulfathi, Ahmed A.; Upton, Caryn M.; Faraj, Alan; Nuermberger, Eric L.; Lamichhane, Gyanu; Svensson, Elin; Simonsson, Ulrika S. H.; Diacon, Andreas H.; Dooley, Kelly E.
Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial
2022
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Grisic, Ana-Marija; Xiong, Wenyuan; Tanneau, Lénaïg; Jönsson, Siv; Friberg, Lena; Karlsson, Mats; Dai, Haiqing; Zheng, Jenny; Girard, Pascal; Khandelwal, Akash
Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab
2022
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Sasaki, Tomohiro; Svensson, Elin; Wang, Xiaofeng; Wang, Yanlin; Hafkin, Jeffrey; Karlsson, Mats; Mallikaarjun, Suresh
Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis
2022
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Koele, Simon E.; van Beek, Stijn W.; Maartens, Gary; Brust, James C. M.; Svensson, Elin
Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment
2022
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Swartling, Maria; Smekal, Anna-Karin; Furebring, Mia; Lipcsey, Miklós; Jönsson, Siv; Nielsen, Elisabet I.
Population pharmacokinetics of cefotaxime in intensive care patients
2022