Effect of Scalp Cooling on the Pharmacokinetics of Paclitaxel.

Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80-100 mg/m2) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance-expressed as relative difference in geometric means-was 6.8% (90% CI: -16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.

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.

Impact of Older Age on the Exposure of Paclitaxel: a Population Pharmacokinetic Study.

PURPOSE: Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. METHODS: PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model. RESULTS: In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age. CONCLUSION: In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.