title: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs.
abstract: OBJECTIVE
  To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.
  
  
  METHODS
  Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.
  
  
  RESULTS
  For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.
  
  
  CONCLUSIONS
  This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
authors.affiliation: Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden. lena.friberg@farmbio.uu.se
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Anja
authors.initials: A
authors.lastname: Henningsson
authors.forename: Hugo
authors.initials: H
authors.lastname: Maas
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D007962:Leukocytes / Q000187:drug effects; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D043823:Taxoids; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C111217:vinflunine; D014747:Vinblastine; D005047:Etoposide; D000077146:Irinotecan; C056034:2'-deoxy-2'-methylenecytidine; D017239:Paclitaxel; D002166:Camptothecin