CYP3A5 Genotype Research Articles

Dosing strategy of tacrolimus when co-administered with Wuzhi tablet in renal transplant recipients.

Tacrolimus (TAC) is a first-line immunosuppressant to prevent allograft rejection. Wuzhi tablet is widely used as a TAC-sparing agent in China that could significantly elevate TAC exposure. However, insufficient data support the dose recommendation of TAC when co-administered with Wuzhi. A total of 305 adult renal transplant patients with 2,541 TAC trough concentrations (C0) were enrolled for population pharmacokinetic (PPK) modeling. CYP3A5 polymorphism was genotyped, and corresponding clinical factors were recorded. Nonlinear mixed-effects modeling and Monte Carlo simulation were used for dose recommendation. PK parameters were calculated based on one-compartment model with first-order absorption and elimination. The estimated total clearance (CL/F) and volume of distribution (Vd/F) of TAC were 23.84 L/h and 1,075.96 L, respectively. Wuzhi, CYP3A5 genotype, hematocrit (HCT), and weight were found to have a significant influence on CL/F. CL/F was significantly lower in the individuals who were CYP3A5 non-expressers and received TAC together with Wuzhi. CYP3A5 genotype (expressers or non-expressers), body weight (40-80 kg), and hematocrit (20 - 40%) were selected as the specific clinical scenarios, and the starting dose of TAC ranged from 1.5 to 4.5 mg when co-administered with Wuzhi. We establish a TAC PPK model comprising Wuzhi as a covariate in renal transplant recipients and recommend an initial dose of TAC when co-administered with Wuzhi, which could provide reference for the individualized regimens of TAC.

Bleeding Events Associated with Rivaroxaban Therapy in Naive Patients with Nonvalvular Atrial Fibrillation: A Longitudinal Study from a Genetic Perspective with INR Follow-Up.

Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.

Drug-drug interactions between letermovir and tacrolimus in Japanese renal transplant recipients simulated using a physiologically based pharmacokinetic model.

Letermovir (LET) is a novel antiviral agent recently approved for cytomegalovirus (CMV) prophylaxis of renal transplant patients in Japan. However, its interactions with tacrolimus (TAC), an important immunosuppressant, remain ambiguous, warranting careful evaluation considering the unique genetic and physiological characteristics of Japanese patients. Therefore, in this study, we aimed to investigate the drug-drug interactions between LET and extended-release TAC (ER-TAC) in Japanese renal transplant patients via physiologically based pharmacokinetic (PBPK) modeling. We developed PBPK models for LET and TAC, including a new model for ER-TAC, using the Simcyp simulator. We also created a virtual Japanese post-transplant population by incorporating physiological parameters specific to Japanese patients, including CYP3A5 genotypes. Our model accurately predicted the pharmacokinetics of both immediate-release and ER-TAC co-administered with LET. In the Japanese population, LET significantly increased ER-TAC exposure, with the effect varying by CYP3A5 genotype. For CYP3A5*1 carrier, the area under the curve ratio ranged from 2.33 to 2.53, while for CYP3A5*3/*3 carriers, it ranged from 2.82 to 2.86. The maximum concentration ratio was approximately 1.50 across all groups. Our findings suggest reducing the ER-TAC dose by approximately 57-60% for CYP3A5*1 carrier and 65% for CYP3A5*3/*3 carriers when co-administered with LET for Japanese renal transplant patients. Moreover, the developed model incorporating population-specific factors, such as hematocrit values and CYP3A5 genotype frequencies, is a valuable tool to evaluate complex drug interactions and guide the dosing strategies for LET and TAC in Japanese patients. Overall, this study expands the application of PBPK modeling in transplant pharmacology, contributing to the development of effective immunosuppressive strategies for Japanese renal transplant patients.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

B-269 Development and CYP3A4 Characterization of a Population-based Urinary Buprenorphine and Norbuprenorphine Nomogram

Abstract Background Buprenorphine (Bup), routinely prescribed for opioid use disorder, metabolizes to norbuprenorphine (NBup) primarily via cytochrome P450 (CYP) 3A4. Confirmation of urinary Bup and NBup helps monitor patient adherence to therapy and potential misuse. This study aims to develop and characterize a population-based urinary NBup/Bup nomogram using pharmacogenetics (PGx) to facilitate opioid result interpretations. Methods Adult urinary Bup and NBup results between 09/01/2022 and 09/30/2023 at UNC Health were retrieved from the EMR. Results outside the clinically reportable range (CRR; 5-25,000 ng/mL) were assigned the lower or upper CRR value, respectively. A scatterplot of Bup versus NBup/Bup on logarithmic scale was generated using Excel. Buffy coats from 14 EDTA whole blood samples were extracted and isolated using EasySep buffer (StemCell) with centrifugation at 8000rpm for 10 minutes without braking and stored at -80°C until shipment to DHMC. Genomic DNA was extracted using an EZ1 DNA procedure (Qiagen) and libraries (Agilent SureSelect) were prepared by hybridization capture of a custom PGx panel. Paired-end sequencing was performed on a MiSeq prior to diplotype-metabolizer function assignments in AUGMET. 22 CYP3A4 gene hotspots were detected by NGS and analyzed for gene-drug-variant relationships. Results 3593 results from 896 patients were retrieved. The NBup/Bup nomogram revealed 3 subgroups from this population (Figure). CYP3A4 genotyping showed 13 wildtype calls and 1 CYP3A4 *1/*22 star allele genotype, with reduced enzyme activity. Wildtype results corresponded with Bup/NBup in subgroups 1(n=1), 2 (n=11) and 3 (n=1); CYP3A4 *1/*22 result corresponded with subgroup 3. Conclusions We developed a novel NBup/Bup nomogram revealing 3 subgroups in our patient population. Overlap of wildtype CYP3A4 in subgroups 1, 2 and 3 as well as CYP3A4 *1/*22 genotype in subgroup 3 suggest the NBup/Bup subgroups are independent of CYP3A4 phenotype. The characterization of population-based urinary NBup/Bup nomogram shows promise for aiding in opioid result interpretations.

Effect of CYP3A5*3 genotype on exposure and efficacy of quetiapine: A retrospective, cohort study

BackgroundThe involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. MethodsPatient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. ResultBased on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype.The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and dealkylated quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 <0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. ConclusionThe results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to carefully monitor and potentially adjust the dosage for patients with this genotype to avoid adverse effects. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

Pharmacokinetics and pharmacogenomics of ribociclib in black patients with metastatic breast cancer the LEANORA study

Underrepresented populations’ participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve did not significantly differ between PMs (39,230 h*ng/mL) and IM/NMs (43,546 h*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.

Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes. This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [Emax], Emax, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment. The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid Emax model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin. These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

Drug-drug interaction between diltiazem and tacrolimus in relation to CYP3A5 genotype status in Chinese pediatric patients with nephrotic range proteinuria: a retrospective study.

Tacrolimus is widely used to treat pediatric nephrotic range proteinuria (NRP). Diltiazem, a CYP3A4/5 inhibitor, is often administered with tacrolimus, affecting its pharmacokinetic profile. The impact of this combination on tacrolimus exposure, particularly in CYP3A5*3 genetic polymorphism, remains unclear in pediatric NRP patients. This study aimed to evaluate the effects of diltiazem on tacrolimus pharmacokinetics, focusing on the CYP3A5*3 polymorphism. We conducted a retrospective clinical study involving pediatric NRP patients, divided into two groups: those receiving tacrolimus with diltiazem and those receiving tacrolimus alone. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. We compared daily dose-adjusted trough concentrations (C0/D) of tacrolimus in both the original and PSM cohorts. The influence of diltiazem on tacrolimus C0/D, stratified by CYP3A5*3 genetic polymorphism, was assessed in a self-controlled case series study. Before PSM, the tacrolimus C0/D in patients taking diltiazem was significantly higher compared to those with tacrolimus alone (75.84 vs. 56.86ng/mL per mg/kg, P = 0.034). This finding persisted after PSM (75.84 vs. 46.93ng/mL per mg/kg, P= 0.028). In the self-controlled case study, tacrolimus C0/D elevated about twofold (75.84 vs. 34.76ng/mL per mg/kg, P < 0.001) after diltiazem administration. CYP3A5 expressers (CYP3A5*1/*1 and *1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3) experienced a 1.8-fold and 1.3-fold increase in tacrolimus C0/D when combined with diltiazem, respectively. Diltiazem significantly increased tacrolimus C0/D, with CYP3A5*3 expressers showing higher elevations than non-expressers among pediatric NRP patients. These findings highlight the importance of personalized tacrolimus therapy based on CYP3A5*3 genotypes in pediatric patients taking diltiazem.

Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

305.7: Outcomes of standard versus CYP3A5 genotype adapted dosing of Tacrolimus in renal transplant recipients: A randomized control study.

305.7: Outcomes of standard versus CYP3A5 genotype adapted dosing of Tacrolimus in renal transplant recipients: A randomized control study.

Distribution of CYP3A4 and CYP3A5 Polymorphisms and Genotype Combination Implicated in Tacrolimus Metabolism.

Human cytochrome P450 (CYP), particularly CYP3A4 and CYP3A5 is mainly responsible for the metabolism of several drugs including tacrolimus. Significant interracial/interethnic variation in the expression and function of CYP3A5 and CYP3A4 is caused by Single Nucleotide Polymorphisms (SNPs) of genes encoding these proteins. The present study investigated the genetic polymorphisms CYP3A4*1B, CYP3A4*22, and CYP3A5*3 in the Tunisian population. We included in this study, Tunisian healthy subjects and renal transplant recipients receiving tacrolimus. CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). According to the genotypic combination of the three CYP polymorphisms, we have identified for the first time four metabolizers statuses: slow metabolizers (SM), intermediate metabolizers (IM), high metabolizers (HM), and extensive metabolizers (EM). A total of 101 renal transplant patients and 102 healthy subjects were included. Our results showed that the predominant alleles in the Tunisian population are a wild type of CYP3A4*1B (0.87), likewise CYP3A4*22 (0.975) and CYP3A5*3 (0.82). The genotype frequencies of CYP3A4*1B, CYP3A4*22, and CYP3A5*3 were found to be 3.9%, 0.0%, and 69.5%, respectively. Also, we found a significant linkage disequilibrium between CYP3A4*1B and CYP3A5*3. We approved that the IM is the predominant phenotype in our population with 124 patients followed by and EM with 41 patients, HM in 29 patients and SM in 9 patients. These results showed that Tunisians are most similar to Caucasians. The genetic background of these enzymes CYP3A4*1B, CYP3A4*22, and CYP3A5*3 in this study are important in the prescription of personalized medicine.

Impact of CYP1A2 Genotypes on the Ergogenic Effects and Subjective Mood States of Caffeine Ingestion in Resistance-Trained Women.

Caffeine's metabolism is determined by CYP1A2 genotypes: AC/CC (SLOW) and AA (FAST). This trial evaluated CYP1A2 genotypes' impact on exercise and cognitive effects in 36 resistance-trained females assessed under placebo (PL) and caffeine (6 mg/kg bw anhydrous caffeine-CAF) conditions, before ingestion and throughout the session. 23andMe® (San Francisco, CA, USA) determined genotypes using saliva. Data were analyzed using two-way RMANOVA and paired-samples t-tests (p < 0.05). A significant main effect for genotype existed for leg press repetitions to failure (RTF) for CAF (p = 0.038), with the FAST group performing more repetitions than the SLOW (p = 0.027). There was a significant condition x genotype interaction for the subjective outcome index score (p = 0.045), with significant differences for time (p < 0.01) and between genotype (p < 0.001). Follow-up analysis revealed a higher total score (p = 0.028) following CAF for the FAST group and a lower total score (p < 0.01) in the SLOW group. Dizziness was reported following CAF in the SLOW group (p = 0.014; Cohen's d = 0.725). Aside from leg press RTF, subjective outcome index score, and dizziness, the genotype groups experienced similar responses to resistance exercise performance and subjective mood states following caffeine ingestion.

Pharmacokinetics and Pharmacogenomics of Ribociclib in Black Patients with Metastatic Breast Cancer: The LEANORA study.

Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3 , *6 , and *7 ). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area-under-the-curve did not significantly differ between PMs (39,230 hr*ng/mL) and IM/NMs (43,546 hr*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.

Nicotine Gum in Thai Smokers with Different CYP2A6 Enzymes: A Population Pharmacokinetic Analysis

Objective: Despite the popularity of nicotine gum in Thailand, population pharmacokinetics of nicotine gum in the Thai population has not been investigated. This study aimed to develop a population pharmacokinetic (POPPK) model of nicotine and to quantify the effects of genetic and non-genetic factors to nicotine pharmacokinetics. Materials and Methods: Secondary data collected from a previous clinical trial assessing cytochrome P450 2A6 (CYP2A6) genotypes in Thai smokers was investigated. Eighteen participants who had received a single dose of 2 mg nicotine gum were included. Blood samples were collected before, at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4.5 and 6 hours after nicotine administration. POPPK analysis was performed using nonlinear mixed effect modelling. Results: One-compartment with 1st order elimination and absorption with 6-transit compartments best described the data. CYP2A6 enzyme activity was a significant covariate on the nicotine clearance. Apparent elimination clearance (CL/F) for a person with 100% CYP2A6 activity was 266.0 L/h. CL/F would be 36.0 L/h in a subject with 0% CYP2A6 activity. However, the impact of non-genetic factors (monthly alcohol consumption, Fagerstrom Test for Nicotine Dependence score and the number of cigarettes per day) on pharmacokinetics of nicotine were not found. Conclusion: This first report on population pharmacokinetics of nicotine gum in Thai smokers provided the pharmacokinetic model and quantified CL/F for smokers with different CYP2A6 genotypes. A markedly lower exposure to nicotine in the Thai population compared to others highlights the need for more studies to ensure the efficacy of nicotine gum in the Thai population.

Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.

To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767μg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

A descriptive study of the single-nucleotide polymorphisms known to affect the Tacrolimus trough concentration per dose, among a population of kidney failure patients in a tertiary hospital in Ghana

BackgroundThe burden of chronic kidney disease (CKD) and kidney failure in Ghana is on the ascendency, with the prevalence of CKD estimated at 13.3%. Patients with CKD who progress to kidney failure require life sustaining kidney replacement therapy (KRT) which is almost exclusively available in Ghana as haemodialysis. Kidney transplantation is considered the best KRT option for patients with irreversible kidney failure due to its relative cost efficiency as well as its superiority in terms of survival and quality of life. However, because transplants may trigger an immune response with potential organ rejection, immunosuppressants such as tacrolimus dosing are required.ObjectiveThis study sought to determine single nucleotide polymorphisms in CYP3A5, CYP3A4 and MDR1 genes that affect the pharmacokinetics of Tacrolimus in a population of Ghanaian patients with kidney failure.MethodThis cross-sectional study comprised of 82 kidney failure patients undergoing maintenance haemodialysis at the Renal and Dialysis unit of Korle-Bu Teaching Hospital (KBTH). Clinical and demographic data were collected and genomic DNA isolated. Samples were genotyped for specific SNPs using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).ResultsParticipants, 58/82 (70.73%) harbored the wildtype CYP3A5*1/*1 AA genotype, 20/82 (24.39%) carried the heterozygous CYP3A5*1/*3 AG genotype, and 4/82 (4.88%) had the homozygous mutant CYP3A5*3/*3 GG genotype. Also, 6/82 (7.32%) carried the wildtype AA genotype, 11/82 (13.41%) had the heterozygous AG genotype, and 65/82 (79.27%) harbored the homozygous mutant GG genotype of CYP3A4*1B (-290 A>G). For MDR1_Ex21 (2677 G>T), 81/82 (98.78%) carried the wildtype GG genotype, while 1/82 (1.22%) had the heterozygous GT genotype. For MDR1_Ex26 (3435 C>T), 63/82 (76.83%) had the wildtype CC genotype, while 18/82 (21.95%) carried the heterozygous CT genotype, and 1/82 (1.22%) harbored the mutant TT genotype.ConclusionSNPs in CYP3A4, CYP3A5, and MDR1 genes in a population of Ghanaian kidney failure patients were described. The varying SNPs of the featured genes suggest the need to consider the genetic status of Ghanaians kidney failure patients prior to transplantation and tacrolimus therapy.

Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes. Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively. Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.