Pharmacogenetics of irinotecan and oxaliplatin in advanced colorectal cancer

In this thesis, we focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. We investigated the potential associations of germline genetic variations with the efficacy or toxicity of treatment. We genotyped a selection of SNPs in paired tumor tissue and blood samples of colorectal cancer patients (Chapter 3). Next, we present an overview of clinical and pharmacogenetic factors that have been described to influence irinotecan toxicity (Chapter 4). We investigated the association of febrile neutropenia and drug efficacy with the UGT1A1 genotype in Chapter 5. In Chapter 6, we investigated the GSTP1 Ile105Val SNP with regard to irinotecan efficacy in terms of progression-free survival. We also provide an overview of pharmacogenetic, pharmacokinetic and pharmacodynamic data on this platinum derivative (Chapter 7). In Chapter 8, we transfected ERCC1 negative cells with an ERCC1 gene, containing either the codon 118C or 118T genotype, in order to establish differences in cell survival or DNA repair. In chapter 9 we describe our investigations on the cumulative neurotoxicity and efficacy of oxaliplatin. In chapter 10, an explorative study is described that investigates associations of survival and toxicity in patients receiving oxaliplatin, using a SNP array.UBL - phd migration 201

3D printed furosemide and sildenafil tablets: innovative production and quality control

Three-dimensional (3D) printing of pharmaceuticals has the potential to revolutionise personalised medicine but is as yet largely unexplored. A proof-of-concept study of a novel heated, piston-driven semi-solid extrusion 3D printer was performed by producing furosemide and sildenafil tablets for paediatric patients. The average weight of the tablets was 141.1 mg (RSD 1.26%). The acceptance values of the content uniformity were 4.2 & ndash;10.6 (concentration RSD 0.41 & ndash;0.63%), 4.8 & ndash;8.9 (concentration RSD 0.76 & ndash;0.97%) and 6.6 & ndash;9.2 (concentration RSD 0.94 & ndash;1.44%) for furosemide 2 mg, 10 mg and sildenafil 4 mg, respectively. The dissolution rate limiting step was the dissolving and eroding of the tablet matrix and showed an immediate release. The tablets complied to the requirements of the European Pharmacopoeia (EP) for uniformity of mass (EP 2.9.5), content uniformity (EP 2.9.40) and conventional release (EP 2.9.3). While they complied, not all of these quality tests for tablets might be suitable for 3D printed tablets due to the layering of the tablets and the small batch production. To assess adequate layer adhesion adjusted friability (EP 2.9.7) and resistance to crushing (EP 2.9.8) tests are proposed.Personalised Therapeutic

Busulfan interlaboratory proficiency testing program revealed worldwide errors in drug quantitation and dose recommendations

Background:The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively.Methods:A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with +/- 15% for busulfan concentrations and +/- 10% for busulfan plasma exposure. The dose recommendations were deemed accurate.Results:Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values.Conclusions:The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.Personalised Therapeutic

Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array.

PURPOSE: To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC). METHODS: We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates. RESULTS: A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene (ATM) rs1801516 or excision repair cross-complementing gene (ERCC5) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations (P>0.01) with OS or toxicity. DISCUSSION: This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC

The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption

Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor. Out of 84 patients 30 patients (36%) were identified as insufficient absorbers. Treatment failure due to pheneticillin malabsorption can be avoided by performing an OAT, and these patients should be treated by another antibiotic, which is known to be absorbed well.Immunogenetics and cellular immunology of bacterial infectious disease

Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib

Item does not contain fulltextAIM: Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring-based dose optimization in daily practice. METHODS: A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high-performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels. RESULTS: In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels. CONCLUSIONS: Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments

Does a glass of Coke boost the exposure to imatinib in gastrointestinal stromal tumour patients after gastrectomy?

Contains fulltext : 176994.pdf (publisher's version ) (Closed access

The simplified oral flucloxacillin absorption test: an accurate method to identify patients with inadequate oral flucloxacillin absorption

Background: The preferred treatment for severe methicillin-sensitive Staphylococcus aureus infections is flucloxacillin, a small-spectrum antibiotic administered intravenously (IV) and orally. However, clinicians switch to the less preferred broad-spectrum antibiotics because of the variable absorption after oral administration of flucloxacillin. A classical oral absorption test (OAT) requires overnight fasting and interruption of IV therapy, and is laborious. In the current study, we investigated whether a simplified OAT can be utilized in a clinical setting to guide antibiotic treatment in patients with severe S. aureus infections. For this, OAT IV therapy is continued and oral dosing is performed after a one-hour fast and implemented after a small study.Methods: In 196 patients receiving IV flucloxacillin by continuous infusion, a classical OAT (test A) or simplified version of the OAT (test B) was performed. In both tests, 1 g oral flucloxacillin was given and serum samples were taken prior to intake and at one and two hours after administration. Flucloxacillin concentrations were determined by high-performance liquid chromatography. Adequate absorption was defined as an increase of flucloxacillin concentration of at least 10 mg/l after one or two hours compared to baseline.Results: In a sample of 196 patients (85 F/111 M), test A was performed in 28 patients, and test B in 168 patients. Age, gender, and baseline values of creatinine and albumin were similar in both groups. The maximal increase of flucloxacillin absorption was highly variable between patients. In 26 (13%) of the 196 patients, the flucloxacillin increase did not reach the value of 10 mg/l. The median (interquartile range, IQR) maximal increase of flucloxacillin absorption was 22.0 (15-31.25) mg/l for test A and 21.5 (13-32.25) mg/l for test B. There was no significant difference in maximal increase of flucloxacillin absorption between test A and B (p = 0.74), nor between males and females (p = 0.95). Age, creatinine, and albumin were not correlated with flucloxacillin levels.Conclusions: The simplified version of the OAT is useful to identify patients with adequate oral flucloxacillin absorption, and to ensure the effective continuation of an oral small-spectrum treatment

The simplified oral flucloxacillin absorption test: an accurate method to identify patients with inadequate oral flucloxacillin absorption

Background: The preferred treatment for severe methicillin-sensitive Staphylococcus aureus infections is flucloxacillin, a small-spectrum antibiotic administered intravenously (IV) and orally. However, clinicians switch to the less preferred broad-spectrum antibiotics because of the variable absorption after oral administration of flucloxacillin. A classical oral absorption test (OAT) requires overnight fasting and interruption of IV therapy, and is laborious. In the current study, we investigated whether a simplified OAT can be utilized in a clinical setting to guide antibiotic treatment in patients with severe S. aureus infections. For this, OAT IV therapy is continued and oral dosing is performed after a one-hour fast and implemented after a small study.Methods: In 196 patients receiving IV flucloxacillin by continuous infusion, a classical OAT (test A) or simplified version of the OAT (test B) was performed. In both tests, 1 g oral flucloxacillin was given and serum samples were taken prior to intake and at one and two hours after administration. Flucloxacillin concentrations were determined by high-performance liquid chromatography. Adequate absorption was defined as an increase of flucloxacillin concentration of at least 10 mg/l after one or two hours compared to baseline.Results: In a sample of 196 patients (85 F/111 M), test A was performed in 28 patients, and test B in 168 patients. Age, gender, and baseline values of creatinine and albumin were similar in both groups. The maximal increase of flucloxacillin absorption was highly variable between patients. In 26 (13%) of the 196 patients, the flucloxacillin increase did not reach the value of 10 mg/l. The median (interquartile range, IQR) maximal increase of flucloxacillin absorption was 22.0 (15-31.25) mg/l for test A and 21.5 (13-32.25) mg/l for test B. There was no significant difference in maximal increase of flucloxacillin absorption between test A and B (p = 0.74), nor between males and females (p = 0.95). Age, creatinine, and albumin were not correlated with flucloxacillin levels.Conclusions: The simplified version of the OAT is useful to identify patients with adequate oral flucloxacillin absorption, and to ensure the effective continuation of an oral small-spectrum treatment.Personalised Therapeutic

Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients.

Item does not contain fulltextPURPOSE: Oxaliplatin is detoxified by conjugation to glutathione via the enzyme Glutathione-S-transferase pi (GSTP1). The aim of this study is to investigate the association of GSTP1 Ile105Val genetic polymorphism with oxaliplatin efficacy and toxicity in advanced colorectal cancer (ACC) patients. EXPERIMENTAL DESIGN: A total of 91 ACC patients received capecitabine and oxaliplatin (CAPOX) as a part of a multicentre phase-III study of the Dutch Colorectal Cancer Group. Tumour response was evaluated according to RECIST, toxicity was graded using CTC, and GSTP1 Ile105Val was determined by pyrosequencing. RESULTS: Overall survival after CAPOX was similar for patients with the Ile/Ile (11.5 mo), Ile/Val (11.6 mo) and Val/Val (12.6 mo) genotypes (p=0.602). Likewise, there were no statistically significant differences in progression-free survival (p=0.252). Overall grades 3-4 toxicity was not related to genotype (p=0.313). There were no differences in any grade or grades 3-4 neurotoxicity amongst the patients who received > or =500 mg/m(2) of oxaliplatin (p-values of 0.376 and 0.772, respectively). CONCLUSIONS: The results of this study indicate that the GSTP1 genotype is not predictive for progression-free survival or overall survival in ACC patients treated with CAPOX. Moreover, overall neurotoxicity and neurotoxicity in patients receiving 500 mg/m(2) of oxaliplatin was not associated with GSTP1 genotype