Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been ...approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.
Background. Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated ...with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL. Methods. Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure. Results. The overall probability of treatment failure was 21%. The time that the blood concentration was > 10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure. Conclusions. Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.
Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) ...polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug–drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug–drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure–efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure–response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug–drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure–efficacy and exposure–toxicity relationships.
Administration of single-agent docetaxel in a weekly schedule may offer similar efficacy, with a more favorable toxicity profile, compared to a three-weekly schedule in patients with metastatic ...breast cancer.
The original search of Medline, Embase, and Scopus was performed in September 2018 and references were updated with additional searches up to January 2021. Two reviewers independently screened the identified literature based on a predefined set of criteria. Randomized controlled trials investigating the use of weekly versus three-weekly docetaxel in metastatic breast cancer patients were included.
Four randomized controlled trials (N = 459 patients) were included in the final analyses. No significant differences were found in terms of objective response rate (risk ratio (RR) 0.75, 95% confidence interval (CI): 0.54 - 1.05), progression-free survival (hazard ratio (HR) 0.95, 95% CI: 0.71 - 1.26) or overall survival (HR 0.95, 95% CI: 0.70 - 1.29) between weekly and three-weekly docetaxel, respectively. Weekly docetaxel was associated with a significantly lower risk of grade 3/4 neutropenia (RR 0.16, 95% CI: 0.10 - 0.27), febrile neutropenia (RR 0.21, 95% CI: 0.08 - 0.55), and neuropathy (RR 0.29, 95% CI: 0.11 - 0.78). Although the risk of epiphora (≥ grade 3/leading to treatment withdrawal, RR 3.62, 95% CI: 1.07-12.22) and onycholysis (≥ grade 2/leading to treatment withdrawal, RR 3.90, 95% CI: 1.34 - 11.32) was increased.
Weekly docetaxel is associated with a lower risk of neutropenia, febrile neutropenia and neuropathy than the three-weekly docetaxel schedule in metastatic breast cancer patients. However, the risk of onycholysis, epiphora, and treatment discontinuation seems increased with weekly administration. No significant differences in efficacy outcomes were found. Weekly docetaxel might be an alternative for patients at risk for developing neutropenia.
Background
Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for ...HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used.
Objective
We sought to describe the population PK of fludarabine in HCT recipients of all ages.
Methods
From 258 HCT recipients aged 0.3–74 years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling.
Results
Variability was extensive where area under the curve ranged from 10 to 66 mg h/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.24 ± 20% L/h/70 kg) and renal (eGFR × 0.782 ± 11% L/h/70 kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 ± 8%, 20 ± 11%, and 50 ± 9% L/70 kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 ± 8% and 3.8 ± 13% L/h/70 kg, respectively.
Conclusion
BW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome.
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late ...effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size–based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1–5) and a grade of recommendation (A–D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
•Treating cancer in neonates and infants is challenging.•Dose optimisation of cytotoxic drugs is an important step to improving outcomes.•Clinical pharmacological evidence supporting dosing regimens in infants was collated.•All available pharmacological evidence was ranked by a level of evidence.•A grade of recommendation was derived and a recommended dose per agent provided.
Background
Olaparib is given in a fixed dose of twice-daily 300 mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient ...variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient’ cohort.
Methods
A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan–Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (C
min
), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the C
min
of patients who experienced toxicity was compared with patients who did not experience any toxicity.
Results
Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib C
min
of 1514 ng/mL. There was no statistical significant difference in PFS of patients below and above the median C
min
concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval: 0.46–2.45,
p
= 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher C
min
of olaparib in comparison with patients who had not experienced any toxicity (
n
= 33), but it was not statistically significant (
p
= 0.069).
Conclusions
Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.
Background
PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants ...who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.
Methods
Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).
Results
68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m
2
were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction.
Conclusion
The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1–18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m
2
for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
Abstract Background The objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens ...in daily clinical care. Patients and Methods A total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early – i.e. cycle one or two – severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis. Results Among 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio OR 0.85 per 10 ml/min/1.73 m2 , p = 0.0007), body surface area (BSA) (OR 0.33 per m2 , p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥3 toxicity was 0.704 (95% confidence interval 0.666–0.743, optimism-corrected AUC 0.690). Conclusion Renal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.
Idiopathic hyperammonemic encephalopathy is a rare complication of chemotherapy, which has previously mainly been associated with L-asparaginase, cytarabine and 5-FU. We present a case following ...treatment with gemcitabine–cisplatin in a patient with cholangiocarcinoma. The etiology of chemotherapy-induced idiopathic hyperammonemic encephalopathy remains unclear and existing theories differ per chemotherapeutic agent. Physicians treating patients with gemcitabine–cisplatin should be aware of the possibility of this complication, especially because it is treatable when recognized early.
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