Effects of Probiotics on Chemotherapy-induced Diarrhea.

Chemotherapy-induced diarrhea (CID) is a common adverse event in cancer patients, which, unless treated, may lead to drug discontinuation and treatment failure. Some probiotics such as Lactobacillus, Bifidobacterium, and Saccharomyces species have been gaining clinical attention in alleviating chemotherapy-induced adverse events including diarrhea. This comprehensive review provides an overview and discusses preventive approaches of probiotics with respect to CID in several types of cancers. The potential mechanisms of probiotics may comprise regulation of intestinal microbiota, modulation of immune functions, or reduction of proinflammatory cytokines. The efficacy and safety precautions of probiotics in immunocompromised cancer patients are discussed. The non-pharmacological strategy using probiotics could reduce the use of anti-diarrheal or antibiotic agents. Some individuals experienced shorter length of hospital stay, better gastrointestinal function, and reduced incidence of chemotherapy dose reduction after probiotic administration. Nonetheless, some studies failed to report the benefits of probiotics in certain patients. This review also highlights preventive protocols and therapeutic implications by considering the potential influencing factors, particularly types of probiotic strains, dosages of probiotics, duration of their administration, patients' tolerability, and variations in probiotic effects over the cancer stages.

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.

Background: Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. Methods: This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. Results: From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). Conclusions: mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.

Incidence of oxaliplatin hypersensitivity reaction among colorectal cancer patients: A 5-year retrospective study.

Background: Oxaliplatin is a third-generation platinum compound that has efficacy against colorectal cancer. Hypersensitivity reactions during oxaliplatin infusion are a key problem during its use, with the varying incidences and deficiencies of clearly identified risk factors. Objective: To determine the incidence, severity and risk factors of oxaliplatin-related hypersensitivity reaction (HSR). Method: This retrospective study investigated 245 colorectal cancer patients (1,690 treatment cycles) receiving care at King Chulalongkorn Memorial Hospital, Thai Red Cross society between January 1, 2015 and December 31, 2019. The patients' demographic data, laboratory data and clinical features suggesting hypersensitivity reactions to oxaliplatin were reviewed. The Fisher's Exact test and unpaired t-test were used to determine the differences among patients with and without oxaliplatin HSR. The potential risk factors for oxaliplatin HSR were analyzed for statistical significance by logistic regression. Results: A total of 245 colorectal cancer patients (1,690 treatment cycles) were included in this study. The incidence of oxaliplatin HSR was 37.96%, according to the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (NTCAE) version 5.0, grade 1, grade 2 and higher grades were 27.35% (67 patients), 6.53% (16 patients) and 4.08% (10 patients), respectively. The proportion of male patients and patients with a history of prior exposure to platinum-based chemotherapy were statistically higher in the HSR group. The eosinophil count and serum creatinine level were also significantly greater in the HSR group. On the contrary, the total lymphocyte count and serum albumin level were significantly lower in the HSR group. The multivariate logistic regression found 5 risk factors with a significant difference. Male gender, prior exposure to platinum-based chemotherapy and elevated eosinophil count were associated with increased risk of oxaliplatin HSR, whereas elevated monocyte count and elevated serum albumin were protective factors for the development of oxaliplatin HSR. Conclusion: Colorectal cancer patients treated with an oxaliplatin-based regimen with male gender, prior exposure to platinum-based chemotherapy and elevated eosinophil count have a greater risk of oxaliplatin related hypersensitivity reactions.

Incidence of oxaliplatin hypersensitivity reaction among colorectal cancer patients: A 5-year retrospective study

Background: Oxaliplatin is a third-generation platinum compound that has efficacy against colorectal cancer. Hypersensitivity reactions during oxaliplatin infusion are a key problem during its use, with the varying incidences and deficiencies of clearly identified risk factors. Objective: To determine the incidence, severity and risk factors of oxaliplatin-related hypersensitivity reaction (HSR). Method: This retrospective study investigated 245 colorectal cancer patients (1,690 treatment cycles) receiving care at King Chulalongkorn Memorial Hospital, Thai Red Cross society between January 1, 2015 and December 31, 2019. The patients’ demographic data, laboratory data and clinical features suggesting hypersensitivity reactions to oxaliplatin were reviewed. The Fisher’s Exact test and unpaired t-test were used to determine the differences among patients with and without oxaliplatin HSR. The potential risk factors for oxaliplatin HSR were analyzed for statistical significance by logistic regression. (AU)

The impact of CASR A990G polymorphism in response to cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism.

The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT.

ABCB1 and SLCO1B1 gene polymorphisms predict methotrexate-resistant for low-risk gestational trophoblastic neoplasia.

Aim: The aim of this study was to explore the effects of ABCB1 and SLCO1B1 gene polymorphisms and the methotrexate (MTX) treatment response in patients with low-risk gestational trophoblastic neoplasia (GTN). Materials & methods: Low-risk GTN patients who received MTX as a first-line single agent were enrolled. DNA was extracted from peripheral blood samples from 18 patients and assessed for ABCB1 C3435T and SLCO1B1 T521C. Results:ABCB1 C3435T and SLCO1B1 T521C polymorphisms were not associated with the MTX response or toxicity in Thai patients Conclusion: The selected ABCB1 and SLCO1B1 polymorphism do not predict the risk of MTX resistance in low-risk GTN.

ERCC1, XRCC1, and GSTP1 Polymorphisms and Treatment Outcomes of Advanced Epithelial Ovarian Cancer Patients Treated with Platinum-based Chemotherapy.

OBJECTIVE: The first line regimen for treating epithelial ovarian cancer (EOC) is platinum-based chemotherapy. Various factors impact its effectiveness including polymorphisms of enzymes in platinum-related metabolism processes.  Methods: We conducted the study to investigate the association between polymorphisms of ERCC1, XRCC1 and GSTP1, which responsible for platinum's metabolisms in Thai epithelial ovarian cancer patients. RESULTS: Fifty-two patients with advanced epithelial ovarian cancer were enrolled into this study. Genotyping analysis of ERCC1 (C->A, rs3212986), XRCC1 (A->G, rs25487) and GSTP (A->G, rs1695) were performed which variant allele frequencies were found at 35.6%, 28.9% and 10.6%, respectively. Patients with homozygous variant type (A/A) of ERCC1 C8092A had higher rate of platinum-resistance (75% vs 16.7%, p =0.046). In addition, the significant association of GSTP1 polymorphism and grade 2 anemia was found. Patients with A/G genotype of GSTP1 had higher rate of grade 2 anemia (81.8% vs 46.3%, p =0.036). CONCLUSIONS: Genetic polymorphisms of ERCC1, and GSTP1 might be useful biomarkers for prediction of clinical benefit and toxicities of platinum-based chemotherapy in Thai epithelial ovarian cancer patients.
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Real-World Effectiveness of High- Versus Moderate-Intensity Statin Therapy in Thai Patients With Acute Coronary Syndrome and Who Had Undergone Primary Percutaneous Coronary Intervention.

Although high-intensity statins are recommended for atherosclerotic cardiovascular disease, evidence has shown that Asians may need lower dose statins to achieve similar effect when compared to Caucasians. Moreover, awareness of adverse effects leads physicians to initiate moderate-intensity statins. Comparative of high versus moderate-intensive statins on LDL-C among patients who had undergone primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) are less established in Thailand. We conducted a retrospective cohort study to identify pattern of statins prescribing and explored the effectiveness on lipid profiles, including LDL-C goal achievement (<70 mg/dL) in STEMI patients underwent PPCI. A total of 983 patients with STEMI who had undergone PPCI were identified during 2005-2015. At 3-month follow-up, 31.9% patients were investigated for their lipid profile. There was 26.11% of patients who received high-intensity statins. When compared to baseline, we found more LDL-C reduction (38.22% ± 26.75% vs 22.36% ± 35.05%, P < .01) in the high-intensity group. Eighty-one patients achieved the target LDL-C, the high-intensity group were able to achieve the LDL-C goal than moderate-intensity group, but did not reach statistical significance (24.1% vs 30.5%, P = .26). This study confirmed that high-intensity statins have superior for LDL-C reduction and tend to achieve LDL-C goal more than moderate-intensity statins.

The effect of direct hemoperfusion with polymyxin B immobilized cartridge on meropenem in critically ill patients requiring renal support.

PURPOSE: To evaluate the effect of direct hemoperfusion with polymyxin B immobilized cartridge (DHP-PMX) on meropenem pharmacokinetics in critically ill patients with sepsis requiring continuous venovenous hemofiltration (CVVH). MATERIAL AND METHODS: After intravenous infusion of 1 g meropenem over 3 h repeated every 8 h for at least 3 doses, 2 serial blood and ultrafiltration fluid samples were collected: one over a dose interval of meropenem with DHP-PMX therapy; and the other on the following day over a dose interval of meropenem with no DHP-PMX therapy. Meropenem concentrations were measured by high performance liquid chromatography. Pharmacokinetic parameters of meropenem and extraction ratio of DHP-PMX were calculated. RESULTS: Mean AUC0-8 of meropenem on DHP-PMX day was comparable to that of the DHP-PMX free day (285.2 ±â€¯138.2 vs 297.8 ±â€¯130.2 mg ∗ h/L; paired t-test, p = .618). No statistical significance of peak and trough concentrations, volume of distribution, sieving coefficient, or half-life were found. Extraction ratio of DHP-PMX on meropenem was 0 [0-0.03] and clearance by DHP-PMX was 0.04 [0-0.2] L/h which was not considered clinically significant. CONCLUSIONS: No significant effect of DHP-PMX on meropenem pharmacokinetics was observed among severe sepsis/septic shock patients during CVVH treatment. TRIAL REGISTRATION: Clinical Trial Registry detail: NCT registry: 02413541 (First registered March 3, 2015, last update October 16, 2017).

Effects of ABCC2 and SLCO1B1 Polymorphisms on Treatment Responses in Thai Metastatic Colorectal Cancer Patients Treated with Irinotecan-Based Chemotherapy

Purpose: Irinotecan is an anticancer medicine which is used mostly in metastatic colorectal cancer (mCRC) treatment as second or third line chemotherapy. Several factors affect its efficacy and toxicity, including pharmacogenomics. This study aimed to investigate the impacts of ABCC2 and SLCO1B1 polymorphisms on treatment responses in irinotecan-based chemotherapy in 49 Thai mCRC patients. Materials and Methods: Forty-nine participants with mCRC enrolled in this study received irinotecan-based chemotherapy from January to June 2017. Genotypic analyses of ABCC2 (C>T, rs717620) and SLCO1B1 (A>G, rs2306283) were performed. Treatment responses were evaluated after at least three cycles of chemotherapy were given. Results: Allele frequencies of ABCC2 (C>T) and SLCO1B1 (A>G) were found at 18.37% and 78.57%, respectively. Neither was associated with treatment responses. However, combined genotypes of ABCC2 and SLCO1B1 tended to be associated with clinical benefits in terms of partial responses (PR) and stable disease (SD). All patients (100%) with at least one variant allele of SLCO1B1 and ABCC2 were in a PR or SD group, while patients with other genotypes had progressive disease (PD) at 45.5% to 70%, (p = 0.059). Conclusion: The combined effect of ABCC2 and SLCO1B1 polymorphisms tended to be associated with treatment responses in irinotecan-based treated mCRC patients. Therefore, such polymorphisms could be factors impacting inter-individual variation of irinotecan efficacy in Thai mCRC patients.

Impact of POR and CYP3A5 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in the Early Post-operative Period Following Kidney Transplantation.

BACKGROUND: Tacrolimus, a critical dose drug, is widely used in transplantation. Knowing the contribution of genetic factors, which significantly influence tacrolimus variability, is beneficial in the personalization of its starting dose. The significant impact of CYP3A5*3 polymorphisms on tacrolimus exposure has been reported. Conflicting results of the additional influence of POR*28 polymorphisms on tacrolimus pharmacokinetic interindividual variability have been observed among different populations. The objective of this study was to explore the interaction between POR*28 and CYP3A5*3 polymorphisms and their main effects on tacrolimus trough concentration to dose ratios on day 7 after kidney transplantation. METHODS: Two hundred sixteen adult kidney transplant recipients participated in this retrospective study. All participants received a twice daily tacrolimus regimen. Blood samples and data were collected on day 7 after transplantation. A 2-way analysis of covariance was performed. Tested covariates were age, hemoglobin, serum albumin, and prednisolone dose. RESULTS: A 2 × 2 analysis of covariance revealed that the interaction between CYP3A5 polymorphisms (CYP3A5 expresser and CYP3A5 nonexpresser) and POR polymorphisms (POR*28 carrier and POR*28 noncarrier) was not significant (F(1, 209) = 2.473, P = 0.117, (Equation is included in full-text article.)= 0.012). The predicted main effect of CYP3A5 and POR polymorphisms was significant (F(1, 209) = 105.565, P < 0.001, (Equation is included in full-text article.)= 0.336 and F(1, 209) = 4.007, P = 0.047, (Equation is included in full-text article.)= 0.019, respectively). Hemoglobin, age, and steroid dose influenced log C0/dose of tacrolimus (F(1, 209) = 20.612, P < 0.001, (Equation is included in full-text article.)= 0.090; F(1, 209) = 14.360, P < 0.001, (Equation is included in full-text article.)= 0.064; and F(1, 209) = 5.512, P = 0.020, (Equation is included in full-text article.)= 0.026, respectively). CONCLUSIONS: After adjusting for the influences of hemoglobin, age, and prednisolone dose, significant impacts of the CYP3A5 and POR polymorphisms on tacrolimus exposure were found. The effect of POR*28 and CYP3A5*3 polymorphisms during the very early period after kidney transplantation is independent of each other.

Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients.

PURPOSE: This study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations. PATIENTS AND METHODS: One hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal-Wallis or Mann-Whitney U test, including the simple main effects analysis. RESULTS: The patients had stage 0-IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype. CONCLUSION: CYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

Prevalence of CTR1 and ERCC1 Polymorphisms and Response of Biliary Tract Cancer to Gemcitabine-Platinum Chemotherapy

Purpose: Biliary tract cancer (BTC)is an aggressive disease with a poor prognosis. Most patients are diagnosed at an advanced stage for which curative surgery is not possible and gemcitabine-platinum chemotherapy is the treatment of choice for advanced cases. Several studies had focused on biomarkers to predict response from platinum drugs in lung cancer, but information is limited for BTC. In this study, two single nucleotide polymorphisms (SNPs) in the copper transporter (CTR1) and excision repair cross-complementary group 1 (ERCC1) genes were investigated as predictive biomarkers of objective response to gemcitabine-platinum. Methods: This cohort study aimed to assess any associations of genetic polymorphisms of these proteins active in drug pathway with treatment response in advanced BTC patients. Twenty six patients were enrolled. DNA was extracted from peripheral blood and genetic polymorphisms were assessed by Taqman allelic discrimination assay. Response was evaluated according to RECIST version 1.1. Results: For the CTR1 polymorphism, GT was the most common genotype (61.5%) followed by GG (34.6%), and TT (3.8%). For the ERCC1 polymorphism, only 2 genotypes were found, CC and CT at 57.7% and 42.3%, respectively. Genetic polymorphisms were not found to be singly associated with response. However, when the 2 genetic polymorphisms were combined, GG/CC showed a higher response rate than the others (p=0.018, Fisher's Exact Test). Conclusion: This is the first study to show an association between CTR1 and ERCC1 polymorphisms and response to gemcitabine-platinum in advanced BTC patients. These polymorphisms might be used as biomarkers to predict response in such cases in the future.

Effect of the ERCC1 (C118T) Polymorphism on Treatment Response in Advanced Non-Small Cell Lung Cancer Patients Undergoing Platinum-Based Chemotherapy

For advanced non-small-cell lung cancer (NSCLC) cases, a platinum-based regimen is the first-line chemotherapy treatment. The excision repair cross-complementing group 1 (ERCC1) plays an important role in DNA repair and has been related to resistance to platinum chemotherapy. This study aimed to investigate the effects of the ERCC1 (C118T) polymorphism on treatment response in 26 Thai advanced NSCLC patients receiving first line platinum-based chemotherapy during January to July 2015 at King Chulalongkorn Memorial Hospital (KCMH). DNA was extracted from peripheral blood lymphocytes and the single nucleotide polymorphism of ERCC1 was genotyped using a realtime PCR method with the TaqMan assay. The distribution of C/C, C/T and T/T genotypes was 57.7 %, 34.6 % and 7.7 %, respectively. The response rate to platinum-based chemotherapy in the wild type (C/C) of ERCC1 (C118T) was better than with the variant types (C/T and T/T) but the difference was not statistically significant (29.7% vs 9.1%, P=0.274). The results showed that a genetic polymorphism in ERCC1 might influence patient response to platinumbased chemotherapy. Further multicenter studies are now required to confirm the results of our study.

Impact of the Copper Transporter Protein 1 (CTR1) Polymorphism on Adverse Events among Advanced NonSmall Cell Lung Cancer Patients Treated with a Carboplatin/Gemcitabine Regimen.

BACKGROUND: Platinum-based regimens are effective treatments for advanced non-small cell lung cancer (NSCLC), but the five-year survival rate is still less than 20%. One possible factor appears to be resistance involving polymorphisms in the CTR1 gene which plays an importance role in accumulation of platinum in the cytoplasm. PURPOSE: To establish both prevalence of CTR1 polymorphism and its impact on treatment related toxicity in Thai advanced NSCLC patients. MATERIALS AND METHODS: Thirty-two advanced NSCLC participants received carboplatin and gemcitabine during January to June 2016 at King Chulalongkorn Memorial Hospital (KCMH) were recruited for analysis of the CTR1 rs12686377 genotype. These participants were planning to be treated with platinum-based chemotherapy for at least two cycles. RESULTS: Allele frequency of CTR1 polymorphism G?T was found to be 25%. The results showed that genetic polymorphism at CTR1 rs12686377 was associated with emesis side effects (P = 0.020) and neuropathic symptoms (P = 0.010). In addition, hematologic side effects in terms of anemia also tended to be related to this polymorphism. CONCLUSIONS: This is the first study suggesting that polymorphism at CTR1 rs12686377 may be associated with toxicity from platinum-based regimens. Therefore, it could be a factor to aid in treatment decision-making.

Prevalence of CYP2D6*2, CYP2D6*4, CYP2D6*10, and CYP3A5*3 in Thai breast cancer patients undergoing tamoxifen treatment.

BACKGROUND: Tamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment. PATIENTS AND METHODS: In total, 134 Thai breast cancer patients were randomly invited to join the Thai Tamoxifen Project. Their blood samples were collected and extracted for individual DNA. The alleles and genotypes were determined by real-time polymerase chain reaction with TaqMan(®) Drug Metabolism Genotyping Assays. RESULTS: The patients were aged from 27.0 years to 82.0 years with a body mass index range from 15.4 to 40.0, with the majority (103/134) in the early stage (stages 0-II) of breast cancer. The median duration of TAM administration was 17.2 months (interquartile range 16.1 months). Most (53%) of the patients were premenopausal with an estrogen receptor (ER) and progesterone receptor (PR) status of ER+/PR+ (71.7%), ER+/PR- (26.9%), ER-/PR+ (0.7%), and ER-/PR- (0.7%). The allele frequencies of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP3A5*1, and CYP3A5*3 were 72.9%, 3.2%, 1.1%, 22.8%, 37.3%, and 62.7%, respectively, while the genotype frequencies of CYP2D6*1/*1, CYP2D6*1/*2, CYP2D6*2/*2, CYP2D6*4/*4, CYP2D6*1/*10, CYP2D6*2/*10, CYP2D6*4/*10, CYP2D6*10/*10, CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 were 9.7%, 2.2%, 3.7%, 1.5%, 15.7%, 9.7%, 3.7%, 53.7%, 13.4%, 47.8%, and 38.8%, respectively. CONCLUSION: The majority (97.8%) of Thai breast cancer patients undergoing TAM treatment carry at least one incomplete functional allele, including 20.9% of the patients who carry only incomplete functional alleles for both the CYP2D6 and CYP3A5 genes. This research indicates the high prevalence of these defective alleles that are involved in TAM-metabolic pathways that might further affect TAM treatment.

Effects of SULT1A1 Copy Number Variation on Estrogen Concentration and Tamoxifen-Associated Adverse Drug Reactions in Premenopausal Thai Breast Cancer Patients: A Preliminary Study.

Tamoxifen is a pharmacological estrogen inhibitor that binds to the estrogen receptor (ER) in breast cells. However, it shows an estrogenic effect in other organs, which causes adverse drug reactions (ADRs). The sulfotransferase 1A1 (SULT1A1) enzyme encoded by the SULT1A1 gene is involved in estrogen metabolism. Previous research has suggested that the SULT1A1 copy number is linked with the plasma estradiol (E2) concentration. Here, a total of 34 premenopausal breast cancer patients, selected from the Thai Tamoxifen (TTAM) Project, were screened for their SULT1A1 copy number, plasma E2 concentration and ADRs. The mean age was 44.3±11.1 years, and they were subtyped as ER+/ progesterone receptor (PR) + (28 patients), ER+/ PR- (5 patients) and ER-/PR- (1 patient). Three patients reported ADRs, which were irregular menstruation (2 patients) and vaginal discharge (1 patient). Most (33) patients had two SULT1A1 copies, with one patient having three copies. The median plasma E2 concentration was 1,575.6 (IQR 865.4) pg/ml. Patients with ADRs had significantly higher plasma E2 concentrations than those patients without ADRs (p = 0.014). The plasma E2 concentration was numerically higher in the patient with three SULT1A1 copies, but this lacked statistical significance.

Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation.

PURPOSE: The purpose of this study is to determine the impacts of CYP3A5 polymorphism on tacrolimus concentration and the proportion of patients within a target therapeutic range during the first week after transplantation together with the 3-month acute rejection rate in kidney transplant patients receiving a minimized tacrolimus regimen. METHODS: A total of 164 patients participated in the study. All received oral tacrolimus twice daily starting on the day of surgery with the target pre-dose (trough) concentration of 4-8 ng/ml for prevention of allograft rejection. Cytochrome P450 (CYP) 3A5 genotypes were determined. The patients were divided into CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (homozygous CYP3A5*3). Whole blood tacrolimus concentrations on days 3 and 7 posttransplantation and the incidence of biopsy-proven acute rejection (BPAR) at 3-month posttransplantation were compared between groups. RESULTS: On day 3, the median (IQR) dose-and-weight-normalized trough concentration in expressers and nonexpressers were 54.61 (31.98, 78.87) and 91.80 (57.60, 130.20) ng/ml per mg/kg/day, respectively (p < 0.001). Although only 47 and 42% of expressers and nonexpressers were within the target range on day 3, approximately 60% of both groups were within the target range on day 7. Proportions of BPAR among expressers and nonexpressers were 6.0 and 7.4 %, respectively (p = 0.723). The median (IQR) times to the first rejection in CYP3A5 expressers and nonexpressers were 32 (12, 68) and 15 (12, 37) days, respectively (p = 0.410). CONCLUSIONS: Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on BPAR was not observed in this study.

Pharmacokinetics of sirolimus in Thai healthy volunteers.

Sirolimus, a novel immunosuppressive drug, has been used in kidney transplant recipients to minimize calcineurine inhibitor (CNI) and steroid toxicities. Likewise CNI, Sirolimus's pharmacokinetics have both inter and intra-individual pharmacokinetic variations. Due to ethnic differences, the recommended oral loading dose of 6 mg and oral maintenance dose of 2 mg per day for Caucasian patients and oral loading dose of 10 mg and oral maintenance dose of 5 mg per day for African-American patients may not be appropriate for Asian recipients. We, therefore conducted the pharmacokinetic study of sirolimus in Thai population, aimed to delineate the appropriate sirolimus dose for further clinical use. The study was performed in 12 healthy Thai volunteers. After an over night fasting, a single oral dose of 6 mg sirolimus was given. The complete pharmacokinetic study was done by UVhigh performance liquid chromatography (HPLC-UV) to measure the whole blood sirolimus level at 0.5 hour after the dose (C0.5) and then C1, C1.5, C2, C2.5, C3, C4, C6, C8, C12, and C24 hours. A complete area under the concentration time curve from 0-24 hours (AUC(0-24 hr)) was calculated by using the trapezoidal rule. The mean (+/- SD) time to maximal concentration (Tmax) was 1.45 +/- 0.5 hr (range 1-3 hrs). The maximal (Cm) and minimal plasma concentration (Ctroug) for sirolimus were 25.3 +/- 6.1 ng/ml (range 18.10 - 40 ng/ml) and 4.47 +/- 0.57 ng/ml (range 2.90 - 7.20) ng/ml respectively. The AUC(0-24 hr) were 187.9 +/- 48.2 ng * hr/ml (range 151.3 - 294.8 ng * hr/ml). Sirolimus level at 4 hr post-dose had the best of correlation with AUC(0-24 hr) (Pearson correlation = 0.76, p < 0.007). One volunteer had a very high sirolimus level. This subject's pharmacokinetic data showed AUC(0-24 hr) of 256 ng * hr/ml and Cmax of 40 ng/ml. In conclusion, the oral loading dose of 6 mg of sirolimus in Thai volunteers did not achieve the recommended therapeutic level (5-10 ng/ml) in most subjects. There are differences in pharmacokinetics of sirolimus between Thais and Caucasians.