Lower Mycophenolic Acid Exposure in Patients Undergoing Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide/ Cyclosporine a-Based GvHD Prophylaxis - Need for Dose Intensification

Despite great therapeutic advances in the field of biologics, small synthetic molecules such as thiopurines, including azathioprine, mercaptopurine, and thioguanine, remain an important therapeutic pillar in the treatment of inflammatory bowel disease, other autoimmune disorders, and cancer. This review presents the latest guidelines for thiopurine administration, highlighting the importance of individualized therapy guided by pharmacogenomics. It emphasizes dose adjustment based on nudix hydrolase 15 (NUDT15) and thiopurine S-methyltransferase (TPMT) genotype, along side thiopurine S-methyltransferase activity and thiopurine metabolic profile. In addition, the article takes a critical look at emerging research in the field of thiopurine pharmaco genomics featuring novel genetic markers and technological developments in genetic testing. Finally, the potential of integrated approaches that combine genetic, meta bolic, and clinical factors to further individualize thiopurine therapy is highlighted.

This study assesses the readiness and willingness of community pharmacists in England to deliver the pharmacogenomic (PG) testing service. A survey covering demographics and four key themes including awareness and training, general views and experience, barriers, willingness, and confidence was distributed to community pharmacies in the boroughs of Croydon and Sutton in South London. A total of 51 pharmacists responded to the survey. The study revealed that most respondents had a limited familiarity or understanding of pharmacogenomics (n = 32, 63%). Moreover, on average, around 60% of participants were unable to accurately identify drugs that currently have or could have potentials for PG testing. They indicated that their pharmacogenomic education and training is inadequate, with only 2/51 pharmacists reported receiving relevant training. Time constraints, shortage of staff and lack of knowledge were identified as barriers that could hinder the implementation of PG. Over 60% of respondents expressed willingness to provide PG testing service after receiving adequate training. The study found that currently not all community pharmacists are prepared to provide PG testing services, with newly qualified pharmacists appearing to have an upper hand when it comes to understanding the subject. Therefore, consistent, and uniform training is required to allow community pharmacists with all years of experience to equally contribute to the implementation of PG testing.

Factors Predicting Efficacy and Toxicity of Post Transplantation Cyclophosphamide for Graft Versus Host Disease Prevention in Hematopoietic Cell Transplantation Recipients: Interim Data of an Ongoing Study

Pharmacogenomics and Its Importance

Hepatitis C infection affects an estimated 71 million people globally and is responsible for 399,000 fatalities annually. Research advancing hepatitis C treatment practices are rapidly advancing, with abundant focus given to increasing optimizing efficacy of treatment and safety of the patients taking them. Considered a key drug in treating hepatitis C, sofosbuvir is widely used though expensive. Failed treatments are costly to the healthcare system and expose patients unnecessarily to risks of severe adverse reactions. Treatment failures are presumed to be due to viral or clinical risk factors, while patient-specific genetic factors are largely unexplored. This study recruited 359 real-world patients to assess the influence of genetic variation on the risks sofosbuvir-based treatment failure. The study replicated associations with IFNL4 (rs12979860; OR:2.25, 95%CI:1.15-4.06; P:0.0071), and found variants novel predictors in CES1 (rs115629050 or rs4513095; odds ratio (OR):5.43, 95%CI:1.64-18.01; P:0.0057) which activates sofosbuvir and IL10RB (rs2834167; OR:1.81, 95%CI:1.01-3.24; P:0.047) the receptor for IFNL4. Combining genetic risk factors with treatment regimen choice significantly improved the ability to predict treatment failure (P:0.0080). Once a staple of interferon-based regimens, ribavirin is currently used to increase treatment effectiveness in difficult-to-treat chronic hepatitis C patients. Its usefulness is constrained by the development of ribavirin-induced anemia requiring dosage modification or discontinuation in 30% of treated patients. Genetic variants in ITPA have been identified to predict this adverse effect, however known clinical and genetic factors do not entirely explain the risk. In 188 patients, this study replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P:8.66x10⁻⁵; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P:0.0437). Genome-wide analyses identified a novel association in GYPC (rs6741425; OR:0.12, 95%CI:0.04-0.34, P: 2.94 x10⁻⁶) that protects against ribavirin-induced anemia by increasing erythrocyte structural strength. Addition of GYPC significantly improved the model for predicting ribavirin-induced anemia (P:0.00216) in comparison to ITPA and VDR alone. Overall, patient-specific genetic factors were found to identify patients with double the risk of sofosbuvir treatment failure and five-fold reduced likelihood of serious ribavirin-induced anemia. The implementation of these findings can allow for patients to receive safer, more effective therapy sooner.

Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4×(HCT/0.3)-0.729 ×0.837 (combination with WZC)×e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15ng/ml was 4mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4mg of TAC q12h when co-administered with WZC. Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response). Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS). N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777). Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients. ACTRN12610000897066, Date registered: 21/10/2010.

Welcome to the 22nd volume of Pharmacogenomics.

AKT answer relating to pharmacogenomics

AKT question relating to pharmacogenomics

AKT answer relating to pharmacogenomics

AKT question relating to pharmacogenomics

Pharmacogenomics of dyslipidaemia drugs in Portugal

Pharmacogenomics Drives Lenalidomide Efficacy and MRD Kinetics in Mantle Cell Lymphoma after Autologous Transplantation: Results from the MCL0208 Multicenter, Phase III, Randomized Clinical Trial from the Fondazione Italiana Linfomi (FIL)

The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction.

Pharmacogenomics (PG) is a modern tool of personalising treatment protocols to improve the efficacy and safety of drug prescriptions. These benefits are offset by a slow uptake in clinical application due to a host of physician factors, patient factors and/or health system factors. Our study, thus, aimed to determine the knowledge, attitude, future expectations and perceived barriers of medical students and physicians in Jordan regarding PG testing. A descriptive, cross-sectional study was conducted between February and August 2019. Physicians and senior medical students from academic and non-academic institutions in North Jordan (n=424) were surveyed. A structured, self-administered questionnaire was designed and piloted for the purpose of the study. A scoring system for each dimension assessed was calculated and presented using means. Mean scores were compared by sociodemographic and professional variables. The response rate was 70.7%. The mean total PG knowledge score (±SD) was 5.42 (±1.51) out of 10, with a significantly higher mean among respondents aged <30years (5.54±1.43) compared with those ≥30years old (5.21±1.62; P=.03). The mean total PG attitude score was 21.18 (±2.58) out of 24, with significant differences by seniority levels evident (P=.03). The future expectations of PG among our sample were high, with a mean score of 10.44 (±1.64) out of 12. The top three perceived barriers in applying PG were the high cost, lack of clinical guidelines, and limited knowledge and awareness. Physicians and medical students in Jordan have low overall knowledge, albeit strongly positive attitude and future expectations towards PG, despite the perceived high cost and lack of clinical guidelines. Thus, we strongly recommend adopting a comprehensive educational strategy that aims to integrate PG concepts into medical curricula, and promote the culture of continuous medical education about PG among practitioners.

Depression in older adults can have a negative impact on other chronic medical conditions. Although antidepressant response rates are similar in older

Problem: Depression during pregnancy affects 10-15% of women. Practice guidelines recommend that clinicians support women to make treatment decisions that are informed by the risks of both untreated depression and antidepressant use during pregnancy. However, there is minimal evidence regarding how women make these decisions or how clinicians can best support them. Purpose: To advance knowledge and understanding regarding women’s decision making about perinatal depression treatment through qualitative (QUAL) and quantitative (QUANT) studies. The QUAL purpose was to develop a constructivist grounded theory, within a feminist theoretical framework, of women’s perinatal depression treatment decision making. The QUANT purpose was to test the hypothesis that women with deleterious variants in the pharmacogenes CYP2D6 or CYP2C19, taking selective serotonin reuptake inhibitors (SSRIs) prenatally, would have more depression symptoms than women whose pharmacogenetic variants have been associated with normal SSRI metabolism. Methods (QUAL): Semi-structured interviews were conducted with purposively-sampled, pregnant/preconception women who had experienced depression. Iterative data collection and analysis, along with theoretical sampling, in the context of reflexive journaling, peer debriefing, and expert audit, culminated in a cohesive theoretical model. Methods (QUANT): Testing of CYP2D6 and CYP2C19 were performed as secondary analyses on two longitudinal cohorts of pregnant women taking SSRIs. The Kruskal-Wallis Test compared mean depression scores across four predicted metabolizer groups: 1) poor, 2) intermediate, 3) extensive, and 4) ultra-rapid. Results (QUAL): Participants’ (N=31) decision-making processes were complex and dynamic, and highly influenced by contextual factors - particularly stigma, patriarchy, privilege, and their emotional/cognitive environments. Participants navigated towards a decision, in a non-linear manner, between three clusters of decision-making activities: 1) seeking information, 2) making sense of information, and 3) self-soothing. Results (QUANT): There were no significant differences between mean depression scores across the four metabolizer groups (N=83; H(3)=.73, p=.87). Conclusions: The grounded theory provides insight into how women have made this decision, which can be useful both practically and emotionally. Evidence from the pharmacogenetic study clarifies the limitations of this field, which is especially vital in this era of direct-to-consumer genetic testing. Together, they can support patient-oriented decision making regarding perinatal maternal mental health.

37P The CellMiner and CellMinerCDB web-applications as a base for pharmacogenomics