| 1. |
- Damoiseaux, David, et al.
(författare)
-
Physiologically‐based pharmacokinetic model to predict doxorubicin and paclitaxel exposure in infants through breast milk
- 2023
-
Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:12, s. 1931-1944
-
Tidskriftsartikel (refereegranskat)abstract
- Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%–1.7% and 0.1%–1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.
|
|
| 2. |
- Damoiseaux, David, et al.
(författare)
-
Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach
- 2023
-
Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 62:7, s. 969-980
-
Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveInformation on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to differences in milk production. Consequently, little is known about the variability of chemotherapy distribution to breast milk and the effect of milk production on the distribution of chemotherapy to breast milk. Our aim was to predict chemotherapy distribution to breast milk in a more realistic breastfeeding population and evaluate the effect of discarding breast milk on the potential chemotherapy exposure in infants.MethodsWe developed a population pharmacokinetic model that described the breast milk production and the chemotherapy distribution to breast milk of a non-breastfeeding population, linked it to plasma pharmacokinetics, and extrapolated this to a breastfeeding population.ResultsWe found that cumulative relative infant doses (RID) were higher than 10% for cyclophosphamide and doxorubicin and approximately 1% for paclitaxel. Simulations allowed us to predict the cumulative RID and its variability in the population for patients with different milk productions and the amount of breast milk that has to be discarded to reach cumulative RIDs below 1%, 0.1%, and 0.01%. Discarding 1–2, 3–6, and 0–1 days of breast milk (depending on the milk production of the patient) resulted in cumulative RID below 1% for cyclophosphamide, doxorubicin, and paclitaxel, respectively.ConclusionOur results may help clinicians to derive the optimal breast milk discarding strategy for an individual patient that wants to breastfeed during chemotherapy and minimize chemotherapy exposure in their infants.
|
|
| 3. |
- Damoiseaux, David, et al.
(författare)
-
Presence of Five Chemotherapeutic Drugs in Breast Milk as a Guide for the Safe Use of Chemotherapy During Breastfeeding : Results From a Case Series.
- 2022
-
Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 112:2, s. 404-410
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about infant's safety of chemotherapy during breastfeeding where evidence is limited to a few case reports. This lack of knowledge has led to a general tendency to advise against breastfeeding during cytotoxic therapy despite the overwhelming benefits that breastfeeding offers to both the mothers and their children. In this case series, the presence of five chemotherapies in breast milk was determined. The aim was to obtain insight into the presence of these drugs in breast milk to inform and help clinicians in making informed decisions for women who want to breastfeed. Three patients collected 24-hour samples of breast milk every day for 1, 2, or 3 weeks after chemotherapy, 210 in total. After determination of drug concentrations, the infant daily dose, relative daily infant dose (RID%) and cumulative RID were calculated. Cumulative RIDs in patients varied from 10% to values lower than 1%. Rich data allowed us to design a table which gives predictions on the amount of days that breast milk has to be discarded to reach cumulative RIDs below 5, 1, and 0.1% for each compound. For cyclophosphamide, paclitaxel, and carboplatin, cumulative RIDs below 1 or 0.1% are reached if breast milk is discarded for 1-3 days after administration. This might suggest that breastfeeding in between cycles is an option. However, other pharmacological parameters should also be taken into consideration. For doxorubicin, also the levels of the active metabolite doxorubicinol need quantification. Similarly, breastfeeding during treatment with cisplatin might give substantial exposure and we advise caution.
|
|
| 4. |
- de Jong, Karen, et al.
(författare)
-
High accumulation of nivolumab in human breast milk : A case report
- 2023
-
Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier BV. - 0753-3322 .- 1950-6007. ; 166
-
Tidskriftsartikel (refereegranskat)abstract
- Nivolumab is an immunotherapeutic monoclonal antibody (mAb) that is used for the treatment of several types of cancer. The evidence on its use during lactation is lacking. Here, we report on a 39-year-old woman with metastasized melanoma who was treated with 480 mg nivolumab every four weeks during lactation. Breast milk samples were collected over the course of 34 days, including two cycles of nivolumab. The highest measured concentration of nivolumab during the first cycle was 503 ng/mL at day 13. The cumulative relative infant dose (RID) over the first cycle (28 days) was 9.8 %. The highest overall measured nivolumab concentration was 519 ng/mL at day 33, five days after administration of the second nivolumab cycle. Nivolumab seems to accumulate in breast milk over two consecutive cycles, hence the RIDs of consecutive cycles are expected to be higher. To draw further conclusions regarding safety of breastfeeding during nivolumab therapy, more information about the oral bioavailability of nivolumab in newborns, the nivolumab steady-state concentrations in breast milk and its pharmacodynamic effects are needed.
|
|
| 5. |
|
|
| 6. |
- Garcia-Dios, Diego A, et al.
(författare)
-
High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma.
- 2013
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 128:2, s. 327-334
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies. METHODS: Primary endometrial tumors were genotyped for >100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n=1063). RESULTS: PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR=2.03; P=0.001 for grade 2 and OR=1.89; P=0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR=11.92; P<0.001) and PTEN mutations with type I tumors (OR=19.58; P=0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR=3.38; P=0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR=2.18; P=0.028). CONCLUSIONS: Mutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.
|
|
| 7. |
- Janssen, Julie M, et al.
(författare)
-
Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer : A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).
- 2021
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 60:6, s. 775-784
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy.OBJECTIVE: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women.METHODS: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates.RESULTS: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients.CONCLUSION: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Trovik, Jone, et al.
(författare)
-
Stathmin Overexpression Identifies High-Risk Patients and Lymph Node Metastasis in Endometrial Cancer.
- 2011
-
Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 17:10, s. 3368-3377
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis. EXPERIMENTAL DESIGN: A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens. RESULTS: Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival (P ≤ 0.002) both in curettage and hysterectomy specimens. CONCLUSIONS: Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined. Clin Cancer Res; 17(10); 3368-77. ©2011 AACR.
|
|
