Genetic and clinical predictors of rifapentine and isoniazid pharmacokinetics in paediatrics with tuberculosis infection.

OBJECTIVES: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM. METHODS: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed. RESULTS: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid. CONCLUSIONS: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.

Host genetic factors of COVID-19 susceptibility and disease severity in a Thai population.

Host genetic factors have been shown to play a role in SARs-CoV-2 infection in diverse populations. However, the genetic landscape differs among various ethnicities; therefore, we explored the host genetic factors associated with COVID-19 disease susceptivity and disease severity in a Thai population. We recruited and genotyped 212 unrelated COVID-19 Thai patients and 36 controls using AxiomTM Human Genotyping SARs-COV-2 array, including 847,384 single nucleotide polymorphisms related to SARs-COV-2 pathogenesis, immune response, and related comorbidity No SNPs passed the genome-wide significance threshold of p value <1 × 10-8. However, with a threshold of p value <1 × 10-5, a locus on chromosome 5q32 was found to have a suggestive association with COVID-19 disease susceptibility (p value 6.9 × 10-6; Q-Q plot λ = 0.805, odds ratio 0.02). Notably, IL17B is a gene located in this linkage disequilibrium block and is previously shown to play a part in inflammation and pneumonia. Additionally, a suggestive locus on chromosome 12q22, harboring EEA1 and LOC643339, was associated with COVID-19 disease severity (p value 1.3 × 10-6 - 4.4 × 10-6, Q-Q plot λ = 0.997, odds ratio 0.28-0.31). EEA1 is involved in viral entry into cells, while LOC643339 is a long non-coding RNA. In summary, our study suggested loci on chromosomes 5q32 and 12q22 to be linked to COVID-19 disease susceptibility and disease severity, respectively. The small sample size of this study may lessen the likelihood that the association found is real, but it could still be true. Further study with a larger cohort is required to confirm these findings.

Comparative efficacy between hemodialysis using super high-flux dialyzer with hemoperfusion and high-volume postdilution online hemodiafiltration in removing protein bound and middle molecule uremic toxins: A cross-over randomized controlled trial.

BACKGROUND: Hemodialysis (HD) using super high-flux dialyzer (HD + SHF) comparably removed uremic toxins to high-volume postdilution online hemodiafiltration (olHDF). Integration of hemoperfusion (HP) to HD + SHF (HD + SHF + HP) might provide superior uremic toxin removing capability to high-volume postdilution olHDF. METHOD: The present study was conducted in thrice-a-week HD patients to compare the efficacy in removing indoxyl sulfate (IS), beta-2 microglobulin (ß2 M), and urea between high-volume postdilution ol-HDF and HD + SHF + HP, comprising HD + SHF as the main treatment plus HD + SHF + HP 1/week in the first 4 weeks and 1/2 weeks in the second 4 weeks. RESULTS: Ten prevalent HD patients with blood flow rate (BFR) above 400 ml/min were randomized into two sequences of 8-week treatment periods of HD + SHF + HP and later high-volume postdilution olHDF or vice versa. When compared with high-volume postdilution olHDF (convective volume of 26.02 ± 1.8 L/session), HD + SHF + HP provided comparable values of percentage reduction ratio of IS (52.0 ± 11.7 vs. 56.3 ± 7.5%, p = 0.14) and ß2 M (83.7 ± 4.9 vs. 84.0 ± 4.3%, p = 0.37) and slightly lower urea reduction ratio. Despite greater dialysate albumin loss (p = 0.008), there was no significant change in serum albumin level in HD + SHF + HP group. CONCLUSIONS: HD + SHF + HP could not provide superior efficacy in removing uremic toxins to high-volume postdilution olHDF. The use of low BFR of 200 ml/min during the first 2 h of HD + SHF + HP session, according to the instruction of manufacturer, might impair the efficacy of the HD + SHF part in removing uremic toxins.

Comparative Effectiveness between Expanded Hemodialysis (Hemodialysis Using a Medium Cut-Off Dialyzer) and Mixed-Dilution Online Hemodiafiltration Using a High-Flux Dialyzer in Removing Middle-Molecule Uremic Toxins.

INTRODUCTION: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed. METHOD: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment. RESULTS: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower ß2M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α1M (p < 0.001) and λFLC (p < 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups. CONCLUSION: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α1M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF.

Safety and Pharmacokinetics of Standardized Extract of Centella asiatica (ECa 233) Capsules in Healthy Thai Volunteers: A Phase 1 Clinical Study.

The aim of this study was to investigate the safety and pharmacokinetic profiles of a newly developed, standardized extract of Centella asiatica (ECa 233) capsule in healthy Thai volunteers. This study was designed as an open-labeled, 2-sequence dosage, single- and repeated-dose study investigated under fasting conditions. Plasma concentrations of the parent compounds and their relative acid metabolites were measured and pharmacokinetic parameters were calculated using noncompartmental analysis. Tolerability was assessed based on physical examinations, monitoring of vital signs, clinical laboratory tests, and any observed adverse events. A key finding of this study was that the pharmacokinetics of ECa 233 in healthy volunteers did not correspond with its pharmacokinetics in animal studies. As indicated in human pharmacokinetic parameters, maximum plasma concentration and area under the curve of the parent compounds (madecassoside and asiaticoside) were very low, while their respective metabolites (madecassic acid and asiatic acid) demonstrated higher values. Based on the pharmacokinetic results observed in the dose comparison, accumulation of active metabolites after repeated dose is highly suggestive. In addition, the asiatic acid profile showed 2-fold increase in Cmax and AUC(0-t) after increasing dose from 250 to 500 mg of ECa 233. Lastly, the safety and tolerability evaluation illustrated that single and multiple doses in both 250 and 500 mg oral administration of ECa 233 were well tolerated, and none of the volunteers discontinued their participation due to adverse effects during the study.

The prominent impairment of liver/intestinal cytochrome P450 and intestinal drug transporters in sepsis-induced acute kidney injury over acute and chronic renal ischemia, a mouse model comparison.

Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1→3)-ß-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.

The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity.

BACKGROUND: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes. METHODS: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode. RESULTS: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient's genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005). CONCLUSION: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity.

Bioequivalence and pharmacokinetic/pharmacodynamic correlation of clopidogrel in healthy Thai subjects
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Clopidogrel is an antiplatelet drug, selectively binding to the platelet P2Y12 receptor of adenosine diphosphate. Clopidogrel is a prodrug modified through active metabolite in the liver by two steps of CYP enzyme. The active metabolite is responsible for inhibiting platelet aggregation. OBJECTIVE: The study aimed to assess the bioequivalence of clopidogrel 75 mg generic and reference drugs and to investigate the correlation between pharmacokinetics of active metabolites and its antiplatelet activities. MATERIALS AND METHODS: Determination of clopidogrel, carboxylic acid form, and active metabolite were done by liquid chromatography tandem mass spectrometry, and evaluation of platelet function was also investigated by light transmission aggregometer. 20 subjects were randomized and assigned in a crossover design to take a single 75-mg oral dose of clopidogrel generic and reference drugs in two periods with washout. Pharmacokinetic parameters Cmax, AUC0-t, and AUC0-inf of clopidogrel, carboxylic acid form, and active metabolite were analyzed. RESULTS: Bioequivalence could be shown when testing parameters with ANOVA, as 90% confidence intervals were found to be within the acceptance range of 80 - 125%. For the maximum of platelet aggregation after administration of both products, no significant differences were found. Significant correlation of Cmax of clopidogrel active metabolite and maximum platelet aggregation was found after receiving 0 - 6 hours of both formulations. CONCLUSION: The study found bioequivalence of clopidogrel generic and reference drugs. There were also significant correlations between Cmax of clopidogrel active metabolite and maximum platelet aggregation.
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Pharmacokinetics and bioequivalence of a pregabalin 150-mg capsule in healthy Thai subjects.

OBJECTIVE: The purpose of the study was to evaluate the pharmacokinetics and bioequivalence of pregabalin following administration of a 150-mg capsule of test and reference products. METHOD: The study was designed as a randomized, two-treatment, two-period, two-sequence, single-dose crossover with 1-week washout period between period I and period II dosing. 20 healthy male and female Thai subjects were enrolled in the study. Each subject was in fasted state for ~ 10 hours prior to receiving a single oral 150-mg pregabalin capsule. Serial blood samples were collected at pre-dose until 32 hours after drug administration. Plasma samples were extracted by protein precipitation and derivatized with 4-chloro-7-nitrobenzofurazan. Pregabalin plasma concentrations were determined by HPLC method, and pharmacokinetic parameters were calculated. For bioequivalence assessment, the differences of Cmax, AUC0-t, and AUC0-inf means based on ln-transformed data were assessed by the 90% confidence interval (CI). RESULTS: Pharmacokinetic parameters were determined that test and reference products showed 0.96 ± 0.35 and 1.04 ± 0.96 hours for tmax, 4,594.217 ± 834.195 and 4,568.68 ± 573.963 ng/mL for Cmax, 30,048.150 ± 2,998.920 and 29,315.722 ± 2,747.396 ng×h/mL for AUC0-t, 30,594.210 ± 2,872.317 and 29,831.454 ± 2,688.020 ng×h/mL for AUC0-inf, respectively. The 90% CIs of Cmax, AUC0-t, and AUC0-inf for test and reference products were assessed at 95.356 - 104.630%, 99.303 - 105.751%, and 99.373 - 105.788%, respectively. The results were within the acceptance criteria of 80 - 125%. CONCLUSION: Pharmacokinetic parameters of a single oral 150-mg pregabalin capsule in healthy Thai subjects were evaluated and showed rapid absorption. 90% CI for the differences of Cmax, AUC0-t, and AUC0-inf were within the acceptable range of the criteria so that bioequivalence of the test and reference products of pregabalin 150-mg capsule could be concluded.
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Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease.

This study compared the molecular lipidomic profile of LDL in patients with nondiabetic advanced renal disease and no evidence of CVD to that of age-matched controls, with the hypothesis that it would reveal proatherogenic lipid alterations. LDL was isolated from 10 normocholesterolemic patients with stage 4/5 renal disease and 10 controls, and lipids were analyzed by accurate mass LC/MS. Top-down lipidomics analysis and manual examination of the data identified 352 lipid species, and automated comparative analysis demonstrated alterations in lipid profile in disease. The total lipid and cholesterol content was unchanged, but levels of triacylglycerides and N-acyltaurines were significantly increased, while phosphatidylcholines, plasmenyl ethanolamines, sulfatides, ceramides, and cholesterol sulfate were significantly decreased in chronic kidney disease (CKD) patients. Chemometric analysis of individual lipid species showed very good discrimination of control and disease sample despite the small cohorts and identified individual unsaturated phospholipids and triglycerides mainly responsible for the discrimination. These findings illustrate the point that although the clinical biochemistry parameters may not appear abnormal, there may be important underlying lipidomic changes that contribute to disease pathology. The lipidomic profile of CKD LDL offers potential for new biomarkers and novel insights into lipid metabolism and cardiovascular risk in this disease.

A reduction of asymmetric dimethylarginine in renal transplant recipients receiving sirolimus-based regimen.

OBJECTIVE: Sirolimus may be of benefit in terms ofa reduction of cardiovascular disease in renal transplant recipients. The aim of the present study was to investigate cardiovascular risk markers in renal transplant recipients receiving calcineurin inhibitors (CNI-based regimen), as compared to those receiving sirolimus (SRL-based regimen). MATERIAL AND METHOD: 42 patients were recruited (21 patients for each regimen). Plasma concentrations of cardiovascular risk markers, including asymmetric dimethylarginine (ADMA), nitric oxide (NO), homocysteine (Hcy), and total antioxidant status (TAOS) were measured. RESULTS: Plasma ADMA concentrations were lower in patients with SRL-based regimen, as compared to those with CNI-based regimen (0.52 ± 0.02 and 0.60 ± 0.02 µmol/L, p = 0.027). There were no statistically significant differences seen in NO, Hcy, and TAOS between the two treatments. CONCLUSION: As compared to CNI-based regimen, cardiovascular risk marker (ADMA) levels are lower in patients with SRL-based regimen.

Pharmacokinetics and bioequivalence study of irbesartan tablets after a single oral dose of 300 mg in healthy Thai volunteers.

OBJECTIVE: Pharmacokinetics and bioequivalence of 300 mg irbesartan tablets were studied in 26 healthy Thai male volunteers. METHODS: A single oral dose of one 300 mg tablet of the test product and the reference product was given to each volunteer according to a randomized two-way crossover design with 1-week wash out period. Blood samples were collected at predetermined time intervals until 72 hours post dose and irbesartan concentration was quantified with a validated HPLC method. Individual plasma irbesartan concentration-time profile was analyzed for pharmacokinetic parameters. RESULTS: Maximum plasma concentrations (Cmax) of 3,617.19 and 3,295.77 ng/mL for test and reference, respectively, were achieved. Areas under the plasma concentration-time curve; AUC0-t and AUC0-∞ were 15,304.65 and 15,638.90 ng×h/mL for test and 15,389.21 and 15,730.34 ng×h/mL for reference. The median tmax was 1.50 hours and 1.25 hours for test and reference, respectively. Plasma elimination half-lives (t1/2) were 7.35 hours and 8.09 hours for test and reference, respectively. Primary pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ were tested parametrically by analysis of variance (ANOVA), and it revealed no statistically significant difference (defined as p < 0.05) between the corresponding Cmax, AUC0-t, and AUC0-∞ with respect to sequence, volunteers, period and formulation. The 90% confidence intervals for the ratio of test and reference product of the parameters Cmax, AUC0-t, and AUC0-∞ were within 80 - 125% (100.13 - 121.40% for Cmax, 90.83 - 106.86% for AUC0-t and 91.11 - 106.55% for AUC0-∞). CONCLUSION: The two products were bioequivalent in terms of both rate and extent of drug absorption into systemic circulation.

An increase in urinary primaquine and a reduction in urinary primaquine-5,6-orthoquinone in the Thai population with CYP2D6 reduced enzyme function.

Objectives: Primaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of CYP2D6 polymorphisms with the pharmacokinetics of primaquine and POQ were reported in the Thai population. Methods: We evaluated the genetic distribution of CYP2D6 in 345 Thai army populations together with the pharmacokinetic profiles of primaquine and POQ in plasma and urine (n = 44, descriptive data are presented in median (range)). All dose-related pharmacokinetic parameters were normalized by primaquine dose per body weight before statistical analysis. Results: CYP2D6*10 was the allele observed with the highest frequency (56.62%) corresponding to CYP2D6*10/*10 (32.94%) and CYP2D6*1/*10 (27.94%) genotypes. CYP2D6 intermediate metabolizers (CYP2D6 IM) were found in 44.41% of the cohort and had an increase in the cumulative amount of primaquine excreted (CAE) in urine compared to normal metabolizers of CYP2D6 (CYP2D6 NM); (CYP2D6 IM vs. CYP2D6 NM: 2444 (1697-3564) vs. 1757 (1092-2185) µg/mg/kg, p = 0.039), a reduction in urine CAE of POQ (CYP2D6 IM vs CYP2D6 NM: 115 (46-297) vs. 318 (92-498) µg/mg/kg, p = 0.047) and a reduction in the POQ/primaquine CAE ratio in urine (CYP2D6 IM vs. CYP2D6 NM: 0.06 (0.01-0.11) vs. 0.16 (0.06-0.26), p = 0.009). No significant differences were found in the pharmacokinetic profiles of plasma primaquine and POQ. Conclusions: The CYP2D6 polymorphisms influenced the changes in primaquine and POQ that were noticeable in the urine, supporting the role of the CYP2D6 gene testing before drug administration.

Therapeutic drug monitoring of mycophenolic acid and clinical outcomes of lupus nephritis: a systematic review and meta-analysis.

INTRODUCTION: Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment. METHODS: A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics. RESULTS: A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events. CONCLUSION: This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.

Genetic polymorphisms and clinical parameters associated with renal toxicity in Thai hematologic malignancy patients receiving high dose methotrexate.

High-dose methotrexate (HD-MTX) is a widely used chemotherapy regimen for hematologic malignancies such as lymphomas and acute lymphoblastic leukemia, but its use can lead to adverse effects, including acute kidney injury (AKI), impaired liver function, and mucositis, causing extended hospital stays and delayed subsequent chemotherapy. Our study aimed to investigate the predictive factors for renal toxicities associated with HD-MTX in Thai patients undergoing treatment for hematologic malignancies. We enrolled 80 patients who underwent MTX-containing regimens, analyzing 132 chemotherapy cycles. The most common disease was primary central nervous system lymphoma (33%). Genetic polymorphisms were examined using the MassARRAY® system, identifying 42 polymorphisms in 25 genes. Serum creatinine and MTX levels were measured 24 and 48 h after MTX administration. For the primary outcome, we found that the allele A of MTRR rs1801394 was significantly related to renal toxicity (odds ratio 2.084 (1.001-4.301), p-value 0.047). Patients who exceeded the MTX threshold levels at 24 h after the dose had a significantly higher risk of renal toxicity (OR (95%CI) = 6.818 (2.350-19.782), p < 0.001). Multivariate logistic regression analysis with a generalized estimated equation revealed hypertension and age as independent predictors of increased MTX levels at 24 h after the given dose.

Efficacy and mechanisms of cannabis oil for alleviating side effects of breast cancer chemotherapy (CBC2): protocol for randomized controlled trial.

BACKGROUND: In a pilot study using both cannabidiol (CBD) and tetrahydrocannabinol (THC) as single agents in advanced cancer patients undergoing palliative care in Thailand, the doses were generally well tolerated, and the outcome measure of total symptom distress scores showed overall symptom benefit. The current study aims to determine the intensity of the symptoms experienced by breast cancer patients, to explore the microbiome profile, cytokines, and bacterial metabolites before and after the treatment with cannabis oil or no cannabis oil, and to study the pharmacokinetics parameters and pharmacogenetics profile of the doses. METHODS: A randomized, double-blinded, placebo-controlled trial will be conducted on the breast cancer cases who were diagnosed with breast cancer and currently receiving chemotherapy at King Chulalongkorn Memorial Hospital (KCMH), Bangkok, Thailand. Block randomization will be used to allocate the patients into three groups: Ganja Oil (THC 2 mg/ml; THC 0.08 mg/drop, and CBD 0.02 mg/drop), Metta Osot (THC 81 mg/ml; THC 3 mg/drop), and placebo oil. The Edmonton Symptom Assessment System (ESAS), Food Frequency Questionnaires (FFQ), microbiome profile, cytokines, and bacterial metabolites will be assessed before and after the interventions, along with pharmacokinetic and pharmacogenetic profile of the treatment during the intervention. TRIAL REGISTRATION: TCTR20220809001.

The In Vitro Efficacy of Activated Charcoal in Fecal Ceftriaxone Adsorption among Patients Who Received Intravenous Ceftriaxone.

Broad-spectrum antibiotics can kill both pathogens and gut microbiota. Reducing exposure to excess intestinal antibiotics could theoretically protect gut microbiota homeostasis. Recently, engineered charcoals, gel microparticles, and resin beads have demonstrated efficacy in intestinal antibiotic adsorption in animal studies. We report the first in vitro study evaluating human fecal antibiotic adsorption efficacy of conventional activated charcoal (AC). We collected fecal samples from eight patients who received intravenous (IV) ceftriaxone after admission to King Chulalongkorn Memorial Hospital, Thailand, during January−March 2020. Fecal ceftriaxone was measured by indirect competitive enzyme-linked immunoassays. Three different doses of AC were mixed with fecal samples under a specified protocol. The geometric mean reduction in fecal ceftriaxone concentration when mixed with AC 30 mg/g feces was 0.53 (95% CI 0.33−0.85, p-value < 0.001), meaning 47% adsorption efficacy. Increased adsorption was found with higher doses, 71% and 87% for AC 150 and 500 mg/g feces, respectively. In conclusion, the usual food-poisoning-care dose of conventional AC, 30 mg/g feces, demonstrated dose-dependent and significant fecal ceftriaxone adsorption. Conventional oral AC might be a pragmatic and inexpensive option for the protection of gut microbiota in patients receiving IV ceftriaxone. However, in vivo studies and microbiome analysis are needed for further evidence.

HLA-B*46:01:01:01 and HLA-DRB1*09:01:02:01 are associated with anti-rHuEPO-induced pure red cell aplasia.

Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case-control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55-13.51), 0.006; 4.63 (1.56-13.75), 0.006; 5.72 (1.67-19.67), 0.006; and 5.81 (1.68-20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28-12.49), 0.017, 4.50 (1.32-15.40), 0.016, 3.42 (1.09-10.74), 0.035, and 3.75 (1.08-13.07), 0.038, in Models 1-4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.

Pharmacokinetics and pharmacodynamics profiles of enteric-coated mycophenolate sodium in female patients with difficult-to-treat lupus nephritis.

Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC0-12h ) ≥45 µg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [Cmax ], time to Cmax , and MPA-AUC0-12h ) and PD (activity of inosine-5'-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC0-12h ≥45 µg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r2  = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC0-12h ≥45 µg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 µg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted.

A simple LC-MS/MS method for pharmacokinetic study of carvedilol and 4/-hydroxyphenyl carvedilol at a low dose.

Background and purpose: The study was aimed at validating a simple, rapid, and low-cost LC-MS/MS method for carvedilol and 4/-hydroxyphenyl carvedilol assay in human plasma. The validated method was applied to investigate the pharmacokinetics after a low dose of 6.25 mg. carvedilol. Experimental approach: In this study, the plasma was extracted by liquid-liquid extraction and evaporated the organic layer to dryness, then both analytes in the residue were reconstituted and detected by LC- MS/MS. The method was validated following the guideline on bioanalytical method validation. Thirty-one healthy volunteers participated in the pharmacokinetic study. After 10 h of fasting, each volunteer received one tablet of 6.25 mg carvedilol orally. Blood samples were collected at 16 prescheduled time points. The plasma samples were analyzed for pharmacokinetics. Findings/Results: The method was linear over a range of 0.050-50.049 ng/mL for carvedilol and 0.050- 10.017 ng/mL for 4/-hydroxyphenyl carvedilol. Crucial validated results reached the requirements of selectivity, accuracy, precision, and stability. Pharmacokinetics of carvedilol and 4/-hydroxyphenyl carvedilol were evaluated which showed Cmax at 21.26 ± 9.23 and 2.42 ± 2.07 ng/mL; AUC0-t 66.95 ± 29.45 and 5.93 ± 3.51 ng.h/mL; AUC0-inf 68.54 ± 30.11 and 6.78 ± 3.49 ng.h/mL; and T1/2 6.30 ± 1.95 and 6.31 ± 6.45 h, respectively. Conclusion and implications: The validated method was able to detect and quantify both analytes in plasma samples and can be applied to the pharmacokinetic study of carvedilol and 4/-hydroxyphenyl carvedilol after receiving carvedilol at 6.25 mg orally.