Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?
Purpose: There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. Methods: Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where systemic paclitaxel exposure was linked to reduced proliferation of neutrophils. The impact of age was evaluated on relevant variables in the model, using a significance threshold of p < 0.005. Results: Paclitaxel PK-PD data was evaluated from 300 patients, with a median age of 65 years (range 23–84 years), containing 116 patients ≥70 years (39%). First cycle neutrophil counts were adequately described by a threshold effect model of paclitaxel on the proliferation rate of neutrophils. Age as a continuous or dichotomous variable (≥70 versus <70 years) did not significantly impact sensitivity of the bone marrow to paclitaxel nor the average maturation time of neutrophils (both p > 0.005), causing a decline in the respective interindividual variability of <1%. Conclusion: Results from this large retrospective patient cohort do not suggest elderly patients to be at an increased risk of developing paclitaxel-associated neutropenia during the first treatment cycle. Reflexive dose reductions of paclitaxel in elderly patients are unlikely to improve the risk of severe neutropenia and may be deleterious.
|Keywords||age differences, elderly patients, neutropenia, paclitaxel, pharmacokinetics-pharmacodynamics|
|Persistent URL||dx.doi.org/10.1007/s11095-019-2697-1, hdl.handle.net/1765/120322|
Crombag, M.-R.B.S. (Marie-Rose B. S.), Koolen, S.L.W, Wijngaard, S, Joerger, M, Dorlo, T.P.C. (Thomas P. C.), Erp, N.P, … Huitema, A.D.R. (2019). Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?. Pharmaceutical Research, 36(12). doi:10.1007/s11095-019-2697-1