57 research outputs found
A pharmacometrics model to define docetaxel target in early breast cancer
Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75–100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300–350 mg/m2). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.Fil: Aldaz, Azucena. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aramendía, José Manuel. Universidad de Navarra; Españ
A pharmacometrics model to define docetaxel target in early breast cancer
Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure.
Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence.
Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P 4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence.
Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients
Methotrexate Pharmacokinetics and Survival in Osteosarcomat
The aim of this study was to analyze the relationship between
exposure to high-dose methotrexate (HDMTX) and tumor response in terms of
survival in children with osteosarcoma. PROCEDURE: This study included 44
patients (479 courses) who received a median dose of 5.92 g/m2 of MTX
(interquartile range (IQR) 2.37 g/m2) in a 4-hr infusion. The mean area under the
concentration-time curve (AUC) estimated by parametric methods (non-parametric
expectation maximization, NPEM), and the mean concentration at the end of the
infusion were considered to be the exposure parameters. Tumor response was
recorded as disease-free survival (DFS), overall survival (OS), and histologic
tumor response. The relationship between MTX exposure and survival parameters was
analyzed by Cox regression. RESULTS: The group of 11 patients who were the least
exposed to MTX (AUC <2,400 micromol/L hr) presented a high DFS, probably due to
the shorter interval of time between MTX courses that led to a higher dose
density. In patients with AUC >2,400 micromol/L hr, an increase in the AUC was
related to an increase in the DFS. Significant differences were observed in the
DFS between patients whose mean AUC was below or above 4,000 micromol/L hr
(P=0.024), such that 4,000 micromol/L hr was considered as the minimum AUC to be
aimed at for future patients. CONCLUSIONS: Dose density seems to be an important
factor in osteosarcoma response, but this must be confirmed in further studies.
In order to improve the response to osteosarcoma in children, it is recommended
that the dose of MTX to be increased such as to obtain an AUC higher than 4,000
micromol/L hr
Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites
Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring.
Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion.
Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug.
Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases
Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats.
"Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant
reduction of SARS-CoV-2 replication in vitro by ivermectin
concentrations not achievable with safe doses orally. Inhaled
therapy has been used with success for other antiparasitics. An
ethanol-based ivermectin formulation was administered once to 14
rats using a nebulizer capable of delivering particles with
alveolar deposition. Rats were randomly assigned into three
target dosing groups, lower dose (80-90\xC2\xA0mg/kg), higher
dose (110-140\xC2\xA0mg/kg) or ethanol vehicle only. A
toxicology profile including behavioral and weight monitoring,
full blood count, biochemistry, necropsy and histological
examination of the lungs was conducted. The pharmacokinetic
profile of ivermectin in plasma and lungs was determined in all
animals. There were no relevant changes in behavior or body
weight. There was a delayed elevation in muscle enzymes
compatible with rhabdomyolysis, that was also seen in the
control group and has been attributed to the ethanol dose which
was up to 11\xC2\xA0g/kg in some animals. There were no
histological anomalies in the lungs of any rat. Male animals
received a higher ivermectin dose adjusted by adipose weight and
reached higher plasma concentrations than females in the same
dosing group (mean C" - " 86.2\xC2\xA0ng/ml vs.
26.2\xC2\xA0ng/ml in the lower dose group and 152\xC2\xA0ng/ml
vs. 51.8\xC2\xA0ng/ml in the higher dose group). All subjects
had detectable ivermectin concentrations in the lungs at seven
days post intervention, up to 524.3\xC2\xA0ng/g for high-dose
male and 27.3\xC2\xA0ng/g for low-dose females. nebulized
ivermectin can reach pharmacodynamic concentrations in the lung
tissue of rats, additional experiments are required to assess
the safety of this formulation in larger animals.
Proposal for the creation of a national strategy for precision medicine in cancer: a position statement of SEOM, SEAP, and SEFH
Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational, and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals, and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology, Pathology, and Hospital Pharmacy, we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer
Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation
BACKGROUND: Mosquitoes that feed on animals can survive and
mediate residual transmission of malaria even after most humans
have been protected with insecticidal bednets or indoor residual
sprays. Ivermectin is a widely-used drug for treating parasites
of humans and animals that is also insecticidal, killing
mosquitoes that feed on treated subjects. Mass administration of
ivermectin to livestock could be particularly useful for
tackling residual malaria transmission by zoophagic vectors that
evade human-centred approaches. Ivermectin comes from a
different chemical class to active ingredients currently used to
treat bednets or spray houses, so it also has potential for
mitigating against emergence of insecticide resistance. However,
the duration of insecticidal activity obtained with ivermectin
is critical to its effectiveness and affordability. RESULTS: A
slow-release formulation for ivermectin was implanted into
cattle, causing 40 weeks of increased mortality among Anopheles
arabiensis that fed on them. For this zoophagic vector of
residual malaria transmission across much of Africa, the
proportion surviving three days after feeding (typical mean
duration of a gonotrophic cycle in field populations) was
approximately halved for 25 weeks. CONCLUSIONS: This implantable
ivermectin formulation delivers stable and sustained
insecticidal activity for approximately 6 months. Residual
malaria transmission by zoophagic vectors could be suppressed by
targeting livestock with this long-lasting formulation, which
would be impractical or unacceptable for mass treatment of human
populations
Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats
Ivermectin is a widely used antiparasitic drug with known efcacy against several single-strain RNA
viruses. Recent data shows signifcant reduction of SARS-CoV-2 replication in vitro by ivermectin
concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for
other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using
a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into
three target dosing groups, lower dose (80–90 mg/kg), higher dose (110–140 mg/kg) or ethanol vehicle
only. A toxicology profle including behavioral and weight monitoring, full blood count, biochemistry,
necropsy and histological examination of the lungs was conducted. The pharmacokinetic profle
of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes
in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with
rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose
which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any
rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher
plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/
ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had
detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for
high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic
concentrations in the lung tissue of rats, additional experiments are required to assess the safety of
this formulation in larger animals
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