Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression.
OBJECTIVE
A previously developed semi-physiological model of chemotherapy-induced myelosuppression has shown consistent system-related parameter and inter-individual variability (IIV) estimates across drugs. A requirement for dose individualization to be useful is relatively low variability between treatment courses (inter-occasion variability [IOV]) in relation to IIV. The objective of this study was to evaluate and compare magnitudes of IOV and IIV in myelosuppression model parameters across six different anti-cancer drug treatments.


METHODS
Neutrophil counts from several treatment courses following therapy with docetaxel, paclitaxel, epirubicin-docetaxel, 5-fluorouracil-epirubicin-cyclophosphamide, topotecan, and etoposide were included in the analysis. The myelosuppression model was fitted to the data using NONMEM VI. IOV in the model parameters baseline neutrophil counts (ANC0), mean transit time through the non-mitotic maturation chain (mean transit time [MTT]), and the parameter describing the concentration-effect relationship (slope), were evaluated for statistical significance (P < 0.001).


RESULTS
Inter-occasion variability in MTT was significant for all the investigated datasets, except for topotecan, and was of similar magnitude (8-16 CV%). IOV in slope was significant for docetaxel, topotecan, and etoposide (19-39 CV%). For all six investigated datasets, the IOV in myelosuppression parameters was lower than the IIV. There was no indication of systematic shifts in the system- or drug sensitivity-related parameters over time across datasets.


CONCLUSIONS
This study indicates that the semi-physiological model of chemotherapy-induced myelosuppression has potential to be used for prediction of the time-course of myelosuppression in future courses and is, thereby, a valuable step towards individually tailored anticancer drug therapy.
Hansson
Emma K
EK
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden. emma.hansson@farmbio.uu.se
Wallin
Johan E
JE
Lindman
Henrik
H
Sandström
Marie
M
Karlsson
Mats O
MO
Friberg
Lena E
LE
D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects*; D002452:Cell Count; D049108:Cell Enlargement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000009:adverse effects; D005047:Etoposide / Q000009:adverse effects; D005472:Fluorouracil / Q000009:adverse effects; D006801:Humans; D008954:Models, Biological; D038042:Myelopoiesis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects; D019370:Observation; D017239:Paclitaxel / Q000009:adverse effects; D057285:Precision Medicine / Q000379:methods*; D043823:Taxoids / Q000009:adverse effects; D019772:Topotecan / Q000009:adverse effects
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D005047:Etoposide; D019772:Topotecan; D017239:Paclitaxel; D005472:Fluorouracil