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Prediction of expos...
Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic-pharmacodynamic model in gastrointestinal cancer patients
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- Arshad, Usman (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Ploylearmsaeng, Su-arpa (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Karlsson, Mats (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Doroshyenko, Oxana (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Langer, Dorothee (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Schömig, Edgar (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Kunze, Sabine (author)
- Univ Hosp Cologne, Dept Radiotherapy, Cologne, Germany
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- Güner, Semih A. (author)
- Univ Hosp Cologne, Dept Radiotherapy, Cologne, Germany
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- Skripnichenko, Roman (author)
- Univ Hosp Cologne, Dept Radiotherapy, Cologne, Germany
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- Ullah, Sami (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Bonn, Inst Pharm, Clin Pharm, Bonn, Germany
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- Jaehde, Ulrich (author)
- Univ Bonn, Inst Pharm, Clin Pharm, Bonn, Germany
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- Fuhr, Uwe (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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- Jetter, Alexander (author)
- Univ Zurich Hosp, Univ Zurich, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland
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- Taubert, Max (author)
- Univ Cologne, Fac Med, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Cologne, Germany
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(creator_code:org_t)
- 2020-03-09
- 2020
- English.
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In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 85:4, s. 711-722
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- PurposeTo describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.MethodsThirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics.ResultsTotal clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 109/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg).ConclusionsBSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- 5-Fluorouracil
- Pharmacokinetics
- Pharmacodynamics
- Pharmacogenetics
- Myelosuppression
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Arshad, Usman
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Ploylearmsaeng, ...
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Karlsson, Mats
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Doroshyenko, Oxa ...
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Langer, Dorothee
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Schömig, Edgar
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Kunze, Sabine
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Güner, Semih A.
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Skripnichenko, R ...
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Ullah, Sami
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Jaehde, Ulrich
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Fuhr, Uwe
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Jetter, Alexande ...
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Taubert, Max
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- Articles in the publication
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Cancer Chemother ...
- By the university
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Uppsala University