Tamoxifen pharmacokinetics and pharmacodynamics in older patients with non-metastatic breast cancer.

BACKGROUND: We aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer. METHODS: Data for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS). RESULTS: 668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms. CONCLUSION: Serum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.

Development of a UPLC-MS/MS Assay for the Quantitative Determination of Capecitabine, 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5'-fluorouracil (5-FU), and α-fluoro-ß-alanine (FBAL).

Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples. Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-ß-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples.

Estimated nationwide impact of implementing a preemptive pharmacogenetic panel approach to guide drug prescribing in primary care in The Netherlands.

BACKGROUND: Pharmacogenetics (PGx) is currently implemented in hospitals to optimize therapy with high-risk drugs. However, many drugs with dosing recommendations from the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium are used in primary care. Actionable phenotypes for the genes covered in these guidelines are common with estimates ranging from 85 to 95% of the population carrying at least one actionable phenotype. The goal of this study was to estimate the clinical impact of implementation of an upfront panel-based pharmacogenetic screening for eight genes related to drugs used in primary care for 2016. METHODS: For this study, dispensing data concerning first prescription for the period January 1-December 31, 2016, were combined with frequency data obtained in the "Implementation of Pharmacogenetics into Primary Care Project" (IP3) study to estimate the occurrence of actionable gene-drug pairs in daily practice in community pharmacies. RESULTS: In 23.6% of all new prescriptions of 45 drugs (n = 856,002 new prescriptions/year), an actionable gene-drug interaction (GDI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group. More importantly, these GDIs would result in a dose adjustment or switch to another drug in 5.4% of all new prescriptions. CONCLUSIONS: Consequently, with an anticipated near future where healthcare professionals will be regularly confronted with PGx test results, adjusting pharmacotherapy based on this information will become a routine task in healthcare.

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation.

AIMS: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.

The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine.

The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.

Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457-12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013-4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216-5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518-33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

A pharmacological rationale for improved everolimus dosing in oncology and transplant patients.

AIMS: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity. METHODS: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. RESULTS: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (<6 µg l-1 ) and that a higher starting dose of 2.25-3 mg BID is required. CONCLUSION: For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma.

The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.

Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism.

BACKGROUND: Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. METHODS: DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. RESULTS: CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non-carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R 2 of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). CONCLUSION: Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype.

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients.

PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients. RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients.

INTRODUCTION: Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab. METHODS: A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40% was free from progression, comparable to, though slightly lower than in KRAS wild-type patients. RESULTS: Four of 18 included patients (22.2%) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. CONCLUSION: Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.

CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.

Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials.

Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K(+) and increase of Na(+) and Ca(2+); intracellular acidification; inhibition of IL-8 production and of the TNF-α/NF-κB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment.

Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients.

BACKGROUND: Many adverse events (AEs) associated with aromatase inhibitors (AIs) involve symptoms related to the depletion of circulating estrogens, and may be related to efficacy. We assessed the relationship between specific AEs [hot flashes (HF) and musculoskeletal AEs (MSAE)] and survival outcomes in Dutch and Belgian patients treated with exemestane (EXE) in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Additionally, the relationship between hormone receptor expression and AEs was assessed. METHODS: Efficacy end points were relapse-free survival (RFS), overall survival (OS) and breast cancer-specific mortality (BCSM), starting at 6 months after starting EXE treatment. AEs reported in the first 6 months of treatment were included. Specific AEs comprised HF and/or MSAE. Landmark analyses and Cox proportional hazards models assessed survival differences up to 5 years. RESULTS: A total of 1485 EXE patients were included. Patients with HF had a better RFS than patients without HF [multivariate hazard ratio (HR) 0.393, 95% confidence interval (CI) 0.19-0.813; P = 0.012]. The occurrence of MSAE versus no MSAE did not relate to better RFS (multivariate HR 0.677, 95% CI 0.392-1.169; P = 0.162). Trends were maintained for OS and BCSM. Quantitative hormone receptor expression was not associated with specific AEs. CONCLUSIONS: Some AEs associated with estrogen depletion are related to better outcomes and may be valuable biomarkers in AI treatment.

Feasibility of pharmacy-initiated pharmacogenetic screening for CYP2D6 and CYP2C19.

PURPOSE: Our purpose was to investigate the feasibility of pharmacy-initiated pharmacogenetic (PGt) screening in primary care with respect to patient willingness to participate, quality of DNA collection with saliva kits, genotyping, and dispensing data retrieved from the pharmacy. METHODS: Polypharmacy patients aged >60 years who used at least one drug with Anatomical Therapeutic Chemical (ATC) code N06AA01-N06AX19 (antidepressants), A02BC01-A02BC05 (proton-pump inhibitors), N05AA01-N05AH04 (antipsychotics), or C07AB02 (metoprolol) in the preceding 2 years were randomly selected. DNA was collected with saliva kits and genotyped for CYP2D6 and CYP2C19 with the AmpliChip. Pharmacy dispensing records were retrieved and screened for drugs interacting with the patient's CYP2D6 and CYP2C19 genotype by using the evidence-based PGt guidelines from the Dutch Pharmacogenetics Working Group. RESULTS: Out of the 93 invited patients, 54 (58.1%) provided informed consent. Nine saliva samples (16.7%) contained too little DNA. Call rates for CYP2D6 and CYP2C19 were 93.3% and 100%, respectively. Frequencies of genotype-predicted phenotype were 2.4%, 38.1%, 54.8%, and 4.8% for CYP2D6 poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM) respectively. For CYP2C19 genotype-predicted phenotype, frequencies were 2.2%, 15.6%, and 82.2% for PM, IM, and EM, respectively. CONCLUSIONS: This study shows that pharmacy-initiated PGt screening is feasible for a primary care setting.

Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands.

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8-20.7), 16.3 months (95%CI, 9.3-not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4-NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1-50.9 months), 39.3 months (95%CI, 29.5-NE) for pazopanib, and 28.1 months (95%CI, 7.0-NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.

Pharmacogenetic interaction analysis for the efficacy of systemic treatment in metastatic colorectal cancer.

BACKGROUND: Pharmacogenetic markers related to drug metabolism and mechanisms of action could help to better select patients with metastatic colorectal cancer (mCRC) for treatment. Genetic interaction analysis is used as a rational tool to study the contribution of polygenic variation in relation to drug response. PATIENTS AND METHODS: A selection of 17 polymorphisms in genes encoding drug targets, pathway molecules and detoxification enzymes was analyzed in 279 previously untreated mCRC patients treated with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Multifactor dimensionality reduction analysis was used to identify a genetic interaction profile for progression-free survival (PFS). RESULTS: Median PFS was 10.9 [95% confidence interval (CI) 9.4-12.4] months. A genetic interaction profile consisting of the TYMS enhancer region and VEGF +405G>C polymorphisms was significantly associated with PFS. Median PFS was 13.3 (95% CI 11.4-15.3) and 9.7 (95% CI 7.6-11.8) months for the beneficial and unfavorable genetic profiles, respectively, corresponding to a hazards ratio for PFS of 1.58 (95% CI 1.14-2.19). None of the studied polymorphisms were individually associated with PFS. CONCLUSIONS: Our results support a genetic interaction between the TYMS enhancer region and VEGF +405G>C polymorphisms as a predictor of the efficacy of CAPOX-B in mCRC patients.