Publications by authors named "Gareth Veal"
Current methods of dose determination have contributed to suboptimal and inequitable health outcomes in underrepresented patient populations. The persistent demand to individualise patient treatment, alongside increasing technological feasibility, is leading to a growing adoption of model-informed precision dosing (MIPD) at point of care. Population pharmacokinetic (popPK) modelling is a technique that supports treatment personalisation by characterising drug exposure in diverse patient groups.
View Article and Find Full Text PDFBackground: The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin.
Methods: A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages.
Article Synopsis
- * Study results show that olaparib effectively targets PARP-1 in glioblastoma cells, leading to reduced cell growth and increased apoptosis, particularly when combined with radiation.
- * Findings indicate that delivering olaparib directly to the tumor area, alongside standard treatments like temozolomide or etoposide, significantly improves long-term survival in glioma models.
Article Synopsis
- * A study reviewed 29 infants treated with carboplatin in the UK, showing that therapeutic drug monitoring (TDM) enabled real-time dosing adjustments, improving treatment outcomes.
- * The results indicated that TDM significantly reduced the risk of under or over-dosing and led to effective treatment responses with minimal side effects, suggesting it should be standard care for infants under 6 months with retinoblastoma.
Article Synopsis
- Hearing loss affects 50-70% of children receiving cisplatin treatment, but a pediatric formula of intravenous sodium thiosulfate (STS) has been approved for its protection by major health agencies.
- A review of 31 studies indicates that systemic STS can effectively reduce cisplatin-induced hearing loss (CIHL) in both children and adults, with its effectiveness depending on the timing and dosage of STS relative to cisplatin administration.
- Although STS reduces CIHL, further research is necessary to better understand the pharmacokinetics of STS with cisplatin, its effects on patients with widespread disease, and its capability to stop the worsening of existing hearing loss.
Article Synopsis
- TP53 mutations are rare in acute lymphoblastic leukemia (ALL), making the MDM2 antagonist idasanutlin a promising treatment option for most ALL cases.
- Combining idasanutlin with the BCL-x/BCL-2 inhibitor navitoclax has shown significant antileukemic effects in laboratory models, leading to a synergistic reduction in leukemia cell viability.
- These findings highlight the potential of using both drugs together in treating high-risk and relapsed ALL patients, with the combination demonstrating effectiveness at safe drug concentration levels seen in clinical trials.
Article Synopsis
- NUC-3373 is an experimental drug designed to improve the treatment of advanced solid tumors by being a more effective alternative to 5-fluorouracil (5-FU), which has drawbacks like poor conversion to active form and high toxicity.
- The drug was tested on patients with persistent tumors, administered through IV, and aimed to determine the maximum tolerated dose (MTD) and assess its effectiveness and safety.
- Results showed NUC-3373 was generally well-tolerated, had a favorable pharmacokinetic profile, and provided stable disease responses in patients previously treated with traditional therapies, with the MTD established at 2500 mg/m weekly.
Article Synopsis
- To effectively treat childhood cancer patients, it's important to use evidence-based dosing for carboplatin, which targets specific cumulative exposure levels (AUC) between 5.2-7.8 mg/ml.min.
- The study analyzed data from 165 treatment cycles in 82 patients weighing 10 kg or less, using Bayesian modeling to establish the relationship between body weight and necessary dosages to achieve the target AUCs.
- Results indicated that the current dosing for infants under 5 kg was inadequate, suggesting optimized daily doses of 6 mg/kg and 9 mg/kg for patients ≤10 kg to ensure effective treatment and reduce variability.
Physiologically-based pharmacokinetic model to predict doxorubicin and paclitaxel exposure in infants through breast milk.
CPT Pharmacometrics Syst Pharmacol
December 2023
Article Synopsis
- The study examines how chemotherapy drugs paclitaxel and doxorubicin in breast milk affect infants, focusing on potential toxicity and exposure levels.
- A physiologically-based pharmacokinetic (PBPK) model predicted that infants' exposure to these drugs through breast milk is relatively low, with specific peak concentrations measured.
- Discarding breast milk for the first three days post-chemotherapy significantly reduces infants' exposure to these drugs, lowering the risk of adverse effects, particularly in the gastrointestinal tract.
Article Synopsis
- - A Phase I trial tested the safety and tolerability of MOv18 IgE, a new type of chimeric IgE antibody, in cancer patients whose tumors express folate receptor-alpha, with a focus on minimizing allergic reactions.
- - The study involved dose escalation from 70 μg to 12 mg, using skin prick and basophil activation tests to identify low-risk patients; the main side effect noted was temporary hives, with one case of anaphylaxis linked to pre-existing reactive basophils.
- - Results indicate that MOv18 IgE therapy is tolerable and shows potential anti-tumor activity, evidenced by a positive response in a patient with ovarian cancer, suggesting that IgE-based
Article Synopsis
- The study evaluates 2-OHOA, a synthetic lipid, in a Phase 1/2A trial to determine its safety, tolerability, and efficacy for treating gliomas and advanced solid tumors in 54 patients.
- The trial found that 2-OHOA was well-tolerated at dosage levels, with common side effects being mild gastrointestinal issues, while establishing a recommended phase-2 dose of 12,000 mg daily.
- Some patients, particularly those with high-grade gliomas, showed promising clinical benefits, with 24% experiencing significant positive responses, including one lasting over 2.5 years.
Article Synopsis
- - Dubin-Johnson syndrome is a rare genetic condition that leads to increased conjugated bilirubin levels in the blood, caused by a mutation in the MRP2 gene, affecting bile excretion.
- - A case study of a 4-year-old girl with this syndrome, undergoing chemotherapy for acute lymphoblastic leukemia, revealed significantly elevated vincristine levels after standard dosing, about three times higher than expected.
- - The findings suggest that healthcare providers should adjust vincristine doses in patients with Dubin-Johnson syndrome due to altered drug metabolism, highlighting the need for awareness of how genetic conditions can affect treatment outcomes.
Article Synopsis
- This study was a Phase 1/2 trial evaluating the novel drug SRA737, a checkpoint kinase 1 inhibitor, for patients with advanced solid tumors, focusing on its safety and dosage.
- A total of 107 patients were treated, determining the maximum tolerated dose to be 1000 mg daily, with mild to moderate side effects like diarrhea and nausea; however, no significant tumor responses were observed.
- The findings suggest that while SRA737 is generally well tolerated, its effects as a single agent are limited, indicating it may be more effective when used in combination with other therapies.
Article Synopsis
- Brain and spinal tumors impact 1 in 1000 individuals by age 25, with a 30-40% mortality rate but a majority achieving cure, though often with lifelong disabilities due to brain injury before and after treatment.
- Only four drugs have been approved for brain tumors in the last 40 years, highlighting a significant gap in treatment, particularly for children, and many new drugs struggle to penetrate the blood-brain barrier (BBB).
- This review discusses innovative methods for enhancing drug delivery to brain tumors, including strategies to facilitate BBB penetration and bypass, aiming to improve patient outcomes and possibly re-evaluate previously ineffective drugs.
Article Synopsis
- The study investigates AZD3965, a novel inhibitor of monocarboxylate transporter 1 (MCT1), intended to evaluate its safety and effectiveness in treating advanced cancers in patients with no standard treatment options.
- During the trial's dose escalation, 40 patients were treated, with common side effects including mild fatigue and changes in retinal function; dose-limiting toxicities mainly occurred at higher doses.
- The findings suggest that AZD3965 is generally well-tolerated at effective doses, establishing an optimal dosage of 10 mg twice daily for further testing in cancers with high MCT1 expression.
Article Synopsis
- HMBD-001 is a humanized IgG1 monoclonal antibody that targets HER3, a receptor commonly found on certain cancer cells.
- A selective bioanalytical method using a bridging ELISA was created to accurately measure HMBD-001 levels in human serum without interference from HER3.
- This assay is sensitive (with a lower limit of 250 ng/ml), has a wide range (250-7000 ng/ml), and is now being used in clinical trials to quantify HMBD-001.
Article Synopsis
- Vincristine is a chemotherapy drug often dosed based on age and weight, but there's limited evidence for optimal dosing in infants compared to older children.
- A study analyzed data from 206 patients to understand how factors like age and body weight affect the drug's pharmacokinetics, using a semi-mechanistic model.
- The findings suggest that younger children may tolerate higher doses of vincristine due to a decrease in the drug's binding capacity to β-tubulin as they age.
Article Synopsis
- * Out of 25 patients enrolled, 20% showed some form of response after three cycles, with a one-year progression-free survival (PFS) of 24% and overall survival (OS) of 56%.
- * Although etoposide demonstrated some activity, the study emphasizes the urgent need for new treatment options due to the overall poor prognosis and significant toxicity observed in patients.
Article Synopsis
- Infantile myofibroma is a rare, noncancerous tumor found in infants, usually treated with surgery; however, some cases may require chemotherapy with vinblastine and methotrexate despite limited supporting evidence.
- Administering chemotherapy to infants poses significant challenges due to unknown effects and dosages of drugs like vinblastine, which complicates treatment protocols.
- A study involving four infants highlighted significant differences in how the drug behaves in each patient, emphasizing the need for personalized dosing strategies to ensure effective treatment while managing potential risks.
Article Synopsis
- * The study aims to identify the recommended dose of selumetinib while evaluating its effectiveness in reducing leukaemia symptoms, enrolling a total of 26 to 42 patients across multiple countries.
- * Ethical approval has been obtained from medical committees in participating countries to ensure the study adheres to ethical standards.
Article Synopsis
- Therapeutic Drug Monitoring (TDM) is underused in childhood cancer treatment, even though cytotoxic chemotherapies are common, due to variability in drug effectiveness and toxicity among patients.
- *Recent advances in TDM have encouraged its adoption in pediatric oncology, especially for vulnerable groups like infants and patients with kidney issues, allowing for more personalized dosing strategies.
- *The article reviews experiences and perspectives on TDM implementation in childhood cancer care, highlighting its potential to optimize dosing and improve outcomes among challenging patient populations.
Article Synopsis
- * Current dosing regimens for anticancer drugs in infants lack solid evidence, often leading to inconsistent practices across different tumor types and treatments.
- * A systematic review compiled pharmacological evidence for dosing strategies, with nine drugs receiving strong recommendations (Grade A) and guidelines provided for therapeutic monitoring, revealing gaps in dosing evidence for many commonly used medications.
Article Synopsis
- Vincristine, an anticancer drug, has side effects that limit its dosage and lacks sufficient pharmacological data for neonates and infants, prompting a study on its dosing and monitoring in these young patients.
- The investigation analyzed pharmacokinetic data from 57 childhood cancer patients, including 26 under one year, and found that lower doses in neonates and infants resulted in significantly lower drug exposure compared to older children.
- The study concluded that doses below 0.05 mg/kg should be avoided in neonates and infants due to the risk of suboptimal drug exposure, while therapeutic drug monitoring is feasible and recommends a target therapeutic window of 50-100 μg/l*h.
Article Synopsis
- A randomized crossover study was conducted to compare a new oral liquid formulation of 13-retinoic acid (13-CRA) with the current capsule method in neuroblastoma treatment, focusing on pharmacokinetics, safety, and patient satisfaction.
- The study involved 20 children, with pharmacokinetic evaluations showing that the liquid formulation’s bioavailability was 65% higher than that of the capsules, along with significant increases in maximum concentration and overall drug exposure.
- Parents reported that administering the liquid formulation was much easier, and there were no significant differences in adverse effects between the two methods.