A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model
2012 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 30, no 2, 833-845 p.Article in journal (Refereed) Published
Purpose: To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously.
Experimental Design: The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM.
Results: A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types.
Conclusions: A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.
Place, publisher, year, edition, pages
2012. Vol. 30, no 2, 833-845 p.
Docetaxel, NONMEM, Myelosuppression, Neutropenia, Population pharmacokineticpharmacodynamic modeling, Pharmacometrics
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-150427DOI: 10.1007/s10637-010-9603-3ISI: 000300160800048PubMedID: 21153753OAI: oai:DiVA.org:uu-150427DiVA: diva2:407342