| 1. |
- Crombag, Marie-Rose B S, et al.
(författare)
-
Exposure to Docetaxel in the Elderly Patient Population : a Population Pharmacokinetic Study.
- 2019
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 36:12, s. 181-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK.METHODS: Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005.RESULTS: Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively.CONCLUSION: In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors.
|
|
| 2. |
- Crombag, Marie-Rose B S, et al.
(författare)
-
Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?
- 2019
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 36:12, s. 163-
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Crombag, Marie-Rose B S, et al.
(författare)
-
Impact of Older Age on the Exposure of Paclitaxel : a Population Pharmacokinetic Study.
- 2019
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 36:2, s. 33-
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 4. |
- van Erp, Nielka P, et al.
(författare)
-
Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
- 2007
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:24, s. 7394-7400
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) mu g.h/mL and 41.2 (32.1-53.1) mu g.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 mu mol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.
|
|
