Chemotherapy-induced myelosuppression by vinorelbine: a comparison between different dose schedules by simulation.
A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to simulate the plasma profile and the toxicity of vinorelbine after multiple oral dose treatment to humans. The PK drug profile was described by a three-compartment open model linked to a PD model aimed to describe the drug toxicity on the circulating neutrophils. Different dose schedules were simulated holding the total administered dose constant (100 mg p.o. during two weeks): 7.7 mg daily (13 doses), 20 mg every 3 days (5 doses) and 33.3 mg every 6 days (3 doses). The lowest values of the circulating neutrophils were observed after 18 days from the start of the treatment and at nadir the fraction of the circulating neutrophils were 0.733, 0.703 and 0.681 after the three doses in decreasing order. These differences were not clinically significant, however the drug bioavailability, which was fixed to 0.35 in the simulation, might be highly variable among subjects contributing to a large extent to the observed variability in drug toxicity.
Urso
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R
Department of Pharmacology Giorgio Segre, University of Siena, Italy. urso@unisi.it
Nencini
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C
Giorgi
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Fiaschi
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AI
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004334:Drug Administration Schedule; D006801:Humans; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014747:Vinblastine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine