Concentration-dose Ratio Research Articles

Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study.

Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM). This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC). The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018). There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome.

Relationship between clinical efficacy and plasma concentration-dose ratio of risperidone in patients with schizophrenia.

This study aimed to retrospectively explore the relationship between clinical efficacy and plasma concentration-dose ratio of risperidone (RIS) in 252 patients with schizophrenia taking RIS orally. After the same dose of RIS treatment, the plasma concentration of RIS/9-hydroxyrisperidone (9-OH-RIS), the total plasma concentration of RIS, and the ratio of the steady-state plasma concentration to the daily dose of the total active product (C/D) showed individual difference. The RIS plasma concentration was significantly higher in patients taking high doses than those taking lower doses ( P = 0.003). There was a statistically significant difference in C/D ratio between males and females ( P = 0.003). There were significant differences in ratio of C/D and the total plasma concentration of RIS between patients under 60 years and over 60 years ( P = 0.016; P = 0.005). Logistic regression analysis showed that the therapeutic effect and adverse reactions of RIS were correlated with the ratio of C/D in patients with schizophrenia ( P = 0.038; P < 0.001). It has been suggested that the importance of monitoring of the plasma concentration of RIS in patients with schizophrenia and the ratio of C/D may be used as the reference for RIS personalized treatment.

Pharmacogenetics and phenoconversion: the influence on side effects experienced by psychiatric patients.

Introduction: Preventing side effects is important to ensure optimal psychopharmacotherapy and therapeutic adherence among psychiatric patients. Obtaining the pharmacogenetic profile of CYP2C19 and CYP2D6 can play an important role in this. When the genotype-predicted phenotype shifts because of the use of co-medication, this is called phenoconversion. The aim was to study the influence of the pharmacogenetic (PGx) profile and phenoconversion on side effects experienced by psychiatric patients. Methods: A retrospective cohort study was performed using data from 117 patients from a psychiatric outpatient clinic. Patients were genotyped with a psychiatric PGx panel and side effects were evaluated using the Udvalg for Kliniske Undersølgelser side effects rating scale (UKU). Results: Of all patients, 10.3% and 9.4% underwent phenoconversion (any shift in predicted phenotype) for CYP2C19 and CYP2D6 respectively. No significant associations were found between the phenotype and UKU-score. 75% of the patients with an Intermediate metabolizer (IM) or Poor metabolizer (PM) phenoconverted phenotype of CYP2C19 experienced nausea and vomiting compared to 9.1% of the Normal metabolizer (NM) and Ultrarapid metabolizer (UM) patients (p = 0.033). 64% of the patients with an IM or PM phenoconverted phenotype of CYP2D6 experienced the side effect depression compared to 30.4% NMs and UMs (p = 0.020). CYP2D6 IM and PM patients had a higher concentration-dose ratio than NM patients (p < 0.05). Discussion: This study underlines the importance to consider phenoconversion when looking at a patient's genotype. This is important for a better prediction of the phenotype and preventing possible side effects under a specific psychopharmacotherapy.

Belumosudil Impacts Immunosuppression Pharmacokinetics in Patients with Chronic Graft-versus-Host Disease

Belumosudil (BEL) is a novel Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor approved for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have failed 2 or more prior lines of systemic therapy. Although the pharmacokinetic effects of BEL on other immunosuppressive (IS) agents have not been clinically evaluated, in vitro data indicate that BEL may have possible interactions with drugs with a narrow therapeutic index used to treat cGVHD, such as tacrolimus, sirolimus, and cyclosporine, through cytochrome P450 (CYP3A) and p-glycoprotein interactions. Further evaluation of these potential interactions is warranted to optimize the safety and effectiveness of these medications when combined with BEL. In this study, we investigated the potential effects of BEL on sirolimus and tacrolimus levels when used concurrently by assessing changes in IS levels after the addition of BEL. This retrospective single-center study of patients who started BEL while on tacrolimus and/or sirolimus between February 1, 2019, to February 1, 2023, included patients who had IS levels measured at baseline prior to starting BEL and at least 1 subsequent IS measurement to assess changes over time. The primary endpoint was the concentration-dose (C/D) ratio analyzed before and after the addition of BEL. Secondary endpoints included the incidence of IS levels outside of the therapeutic range (subtherapeutic or supratherapeutic) and mean dosage changes over time. Thirty-seven patients met our eligibility criteria and were included in this analysis. Patients taking sirolimus (n = 30) or tacrolimus (n = 16) concurrently with BEL had a statistically significant increase in the C/D ratio (sirolimus recipients, 160% [P < .001]; tacrolimus recipients, 113% [P = .013]) between the pre-BEL and final post-BEL assessments. The C/D ratios for both tacrolimus and sirolimus recipients continued to increase at several time points after initiation of BEL, indicating that multiple drug dosage adjustments may be required. After BEL initiation, 19% of tacrolimus levels and 57% of sirolimus levels were supratherapeutic. Despite dosage adjustments, 27% of tacrolimus levels were supratherapeutic at both the second and third assessments after starting BEL, and 28% and 30% of sirolimus levels were supratherapeutic at these 2 time points, respectively. All 12 of the patients who discontinued BEL during the study period (100%) showed a return to their baseline C/D ratio, confirming that the C/D ratio change can be attributed to BEL. The impact of BEL on IS levels is clinically significant, warranting dosage adjustments of concurrent medications. A significant number of patients taking sirolimus with BEL had levels >15 ng/mL during the study period, indicating a potential risk for toxicity if this interaction is unmonitored. We recommend empiric dose reductions of 25% for tacrolimus and 25% to 50% for sirolimus when adding BEL, as well as close monitoring of IS levels during the initial weeks of BEL therapy. Future studies are warranted to better describe the impact of BEL on patients taking CYP3A inhibitors.

Determination of valproic acid and its six metabolites in human serum using LC-MS/MS and application to interaction with carbapenems in epileptic patients.

Valproic acid (VPA) is a classic medication for several types of epilepsy and mood disorders, and some of its effectiveness and toxicity is associated with metabolites. Although many reports have reported the drug-drug interactions of VPA, no study has focused on the influence of carbapenems (CBPMs) on VPA's active metabolites. An LC-MS/MS method for determining VPA and its six metabolites (3-hydroxy valproic acid, 4-hydroxy valproic acid, 2-propyl-2-pentenoic acid, 2-propyl-4-pentenoic acid, 3-keto valproic acid, and 2-propylglutaric acid) in human serum was established and applied to evaluate the drug-drug interaction with CBPMs in epileptic patients. The stable isotope valproic acid-d6 was used as an internal standard. Analytes in serum samples (50 μl) were isolated using a Kinetex C18 column (3× 100 mm, 2.6μm) and detected via negative electrospray ionization after protein precipitation. It was linear (r> 0.99) over the calibration range for different analytes. The accuracy was 91.44-110.92%, and the precision was less than 9.98%. The matrix effect, recovery, and stability met the acceptance criteria. According to the data collected from 150 epileptic patients, the concentration-dose ratio for VPA and its metabolites decreased with CBPM polytherapy. This method is simple and rapid with great accuracy and precision. It is suitable for routine clinical analysis of VPA and its metabolites in human serum.

GRWR Correlates with the Metabolism of Tacrolimus after Pediatric Living Donor Liver Transplantation According to Donor CYP3A5 Polymorphism.

Tacrolimus is characterized by high pharmacokinetic variability in combination with a narrow therapeutic range. However, influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio (GRWR) on tacrolimus' pharmacokinetics after pediatric living donor liver transplantation (LDLT) remains unclear. A total of 174 LDLT recipients (<6 y) were grouped according to donor CYP3A5 genotypes (nonexpressor (NEX) or expressor (EX)) and GRWR (<3.0% (SS, small-size) or ≥3.0% (LS, large-size)): SS/NEX (n = 40), SS/EX (n = 38), LS/NEX (n = 48), and LS/EX (n = 48). Pharmacokinetics of tacrolimus and clinical outcomes were analyzed. The relationships between the concentration-dose ratio and donor CYP3A5 genotypes and graft size were examined 3, 7, 14, and 30 days after the transplantation. Tacrolimus C0 levels varied greatly among groups, although recipients started with the same initial dosage. LS/EX recipients had significantly lower C0 levels in comparison with those of other groups. The use of CYP3A5-EX-grafts and a greater GRWR both resulted in significantly higher TAC dose requirements and lower C/D ratios. However, the significance of GRWR no longer exists 3 months after transplantation. The multivariate generalized linear mixed model analysis showed that donor CYP3A5 genotypes (F = 11.876; P = 0.01) and GRWR (F = 4.631; P = 0.033) were independent impact factors for C/D ratios 3, 7, 14, and 30 days after transplantation. Donor CYP3A5-EX genotype was associated with significantly increasing risks of infectious complications and significantly lower Cylex ATP values. However, no significant difference was observed in acute rejections among 4 groups. Monitoring of C0 levels alone is not reliable to guide tacrolimus administration. Donor CYP3A5 and GRWR both significantly affect tacrolimus pharmacokinetics after pediatric LDLT. The use of Cylex ATP tests would be helpful to avoid overimmunosuppression.

Analysis of influencing factors on monohydroxylated derivative of oxcarbazepine plasma concentration in children with epilepsy.

This study aimed to investigate the factors affecting the plasma concentration of monohydroxylated derivative (MHD) of oxcarbazepine (OXC) in children with epilepsy. We recruited 125 children with epilepsy who received OXC monotherapy. Among them, 16 single nucleotide polymorphisms were detected by MassARRAY genotyping technology to evaluate the influence of related factors on the plasma concentration of OXC monotherapy. MHD is the main active metabolite of OXC, and its plasma concentration was measured by high-performance liquid chromatography (HPLC). Bivariate correlation analysis revealed that concentration-dose ratio (CDR) increased with weight, and the corresponding maintenance dose decreased with weight (r=0.317, P=0.001 for CDR; r=-0.285, P=0.000 for OXC maintenance dose). The duration of seizure was found to be associated with CDR (0.90 ± 0.36 vs 0.74 ± 0.26 μg·kg/mg/mL for ≥6 years vs <1 year, P=0.028; 0.90 ± 0.36 vs 0.64 ± 0.21 μg·kg/mg/mL for ≥6 years vs 1-3 years, P=0.004; 0.90 ± 0.36 vs 0.69 ± 0.18 μg·kg/mg/mL for ≥6 years vs 3-6 years, P=0.031). The CDR of patients with ABCB1 rs1045642 mutation homozygous GG type is higher than heterozygous AG type (0.79 ± 0.30 vs 0.68 ± 0.20 μg·kg/mg/mL for AG vs GG, P=0.032). This study clarified the association of weight, duration of seizure, and gene polymorphisms of ABCB1 rs1045642 with MHD plasma concentration in children with epilepsy.

Reducing the Pill Burden: Immunosuppressant Adherence and Safety after Conversion from a Twice-Daily (IR-Tac) to a Novel Once-Daily (LCP-Tac) Tacrolimus Formulation in 161 Liver Transplant Patients.

Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus (IR-Tac) to a novel once-daily life cycle pharma Tacrolimus (LCP-Tac) formulation. We converted a total of 161 LT patients at baseline, collecting Tacrolimus trough levels, laboratories, physical examination data and the BAASIS© questionnaire for self-reported adherence to immunosuppression at regular intervals. With 134 participants completing the study period (17% dropouts), the overall adherence to the BAASIS© increased by 57% until month 24 compared to baseline (51% vs. 80%). Patients who required only a morning dose of their concomitant medications reported the largest improvement in adherence after conversion. The intra-patient variability (IPV) of consecutive Tacrolimus trough levels after conversion did not change significantly compared to pre-conversion levels. Despite reducing the daily dose by 30% at baseline as recommended by the manufacturer, Tac-trough levels remained stable, reflected by an increase in the concentration-dose (C/D) ratio. No episodes of graft rejection or loss occurred. Our data suggest that the use of LCP-Tac in liver transplant patients is safe and can increase adherence to immunosuppression compared to conventional IR-Tac.

Progression of Interstitial Fibrosis and Tubular Atrophy in Low Immunological Risk Renal Transplants Monitored by Sequential Surveillance Biopsies: The Influence of TAC Exposure and Metabolism.

The combination of tacrolimus (TAC) and mycophenolate is the most widely employed maintenance immunosuppression in renal transplants. Different surrogates of tacrolimus exposure or metabolism such as tacrolimus trough levels (TAC-C0), coefficient of variation of tacrolimus (CV-TAC-C0), time in therapeutic range (TTR), and tacrolimus concentration dose ratio (C/D) have been associated with graft outcomes. We explore in a cohort of low immunological risk renal transplants (n = 85) treated with TAC, mycophenolate mofetil (MMF), and steroids and then monitored by paired surveillance biopsies the association between histological lesions and TAC-C0 at the time of biopsy as well as CV-TAC-C0, TTR, and C/D during follow up. Interstitial inflammation (i-Banff score ≥ 1) in the first surveillance biopsy was associated with TAC-C0 (odds ratio (OR): 0.69, 95% confidence interval (CI): 0.50–0.96; p = 0.027). In the second surveillance biopsy, inflammation was associated with time below the therapeutic range (OR: 1.05 and 95% CI: 1.01–1.10; p = 0.023). Interstitial inflammation in scarred areas (i-IFTA score ≥ 1) was not associated with surrogates of TAC exposure/metabolism. Progression of interstitial fibrosis/tubular atrophy (IF/TA) was observed in 35 cases (41.2%). Multivariate regression logistic analysis showed that mean C/D (OR: 0.48; 95% CI: 0.25–0.92; p = 0.026) and IF/TA in the first biopsy (OR: 0.43, 95% CI: 0.24–0.77, p = 0.005) were associated with IF/TA progression between biopsies. A low C/D ratio is associated with IF/TA progression, suggesting that TAC nephrotoxicity may contribute to fibrosis progression in well immunosuppressed patients. Our data support that TAC exposure is associated with inflammation in healthy kidney areas but not in scarred tissue.

Effects of atorvastatin and aspirin on post-stroke epilepsy and usage of levetiracetam.

Objective:Atorvastatin and aspirin have been used in treating different forms of epilepsy. However, their effect on post-stroke epilepsy (PSE) still needs to be validated by large-scale clinical studies. In addition, their impact on the use of the antiepileptic drug levetiracetam for post-stroke epilepsy remains to be explored. Thus, the aim of this study was to further evaluate the effect of atorvastatin and aspirin on PSE and their effect on the usage of the antiepileptic drug levetiracetam in PSE patients.Methods:Patients, aged 65 to 85 years, with newly diagnosed post-ischemic stroke epilepsy from August 30, 2014 to August 30, 2018 were included in the study, with the exclusion of those with coexisting conditions.Results:Initially, 1321 patients were included, and 780 remained in the study at the 1-year follow-up. During the study, atorvastatin treatment with or without aspirin reduced the number of clinical epileptic episodes in PSE patients. It also reduced the dosage of levetiracetam and achieved better control of epilepsy compared to levetiracetam mono-treatment. Aspirin co-treatment with levetiracetam did not result in a significant improvement. However, the combination of aspirin with atorvastatin significantly reduced the number of seizures compared to atorvastatin treatment alone.Conclusion:Atorvastatin and aspirin co-treatment with levetiracetam can reduce epilepsy in PSE patients and reduce the dosage of levetiracetam required for effective control of PSE.

Changes in serum perampanel concentration profile after discontinuation of carbamazepine.

To evaluate changes in the pharmacokinetics of perampanel after discontinuation of carbamazepine. We enrolled 13 patients receiving perampanel who discontinued carbamazepine therapy between June 2016 and December 2018. Data on serum concentrations were obtained from the therapeutic drug monitoring database of the National Epilepsy Center (Shizuoka, Japan). To compare the pharmacokinetics of perampanel before and after discontinuation of carbamazepine, we determined the concentration/dose (CD) ratio of perampanel (serum level [ng/mL] divided by the dose [mg/kg]). The follow-up period was set to eight weeks following the discontinuation of carbamazepine therapy. The mean baseline CD ratio of perampanel was 1,247ng/mL/mg/kg which increased markedly over time after discontinuation of carbamazepine, with a mean CD ratio at Weeks 1-2, Weeks 3-4, and Weeks 5-8 of 2,683, 3,914, and 4,220, respectively. At eight weeks, the mean CD ratio of perampanel had increased by 276%. Eleven patients developed adverse events, including dizziness, somnolence, irritability, and ataxia. Five of these 11 patients required perampanel dose reduction within eight weeks after discontinuation of carbamazepine. Two patients achieved seizure-free status at Weeks 5-8. The serum perampanel concentration began to increase from one week after discontinuation of carbamazepine, and continued to rise for eight weeks. Based on these findings, we recommend frequent monitoring of serum perampanel concentration for at least eight weeks after stopping carbamazepine therapy. Monitoring is required as a guide for dose adjustment in order to achieve a safe and effective therapeutic dose of perampanel.

The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival.

Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS). We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate). Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041). C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

Impact of CYP2C19 Phenotypes on Clinical Efficacy of Stiripentol in Japanese Patients With Dravet Syndrome.

Stiripentol is a strong inhibitor of CYP2C19 and CYP3A4. This study compared the effect of stiripentol on the pharmacokinetics of clobazam and N-desmethyl-clobazam (NCLB; an active metabolite of clobazam) between different CYP2C19 phenotypes. We also evaluated the clinical impact of CYP2C19 phenotypes in Japanese patients with Dravet syndrome receiving a combination of valproic acid, clobazam, and stiripentol. We retrospectively reviewed 241 blood samples from 64 patients (aged 1-40 years) and calculated the concentration/dose (CD) ratio [serum level (ng/mL) divided by dose (mg/kg)] for clobazam and NCLB. Based on their CYP2C19 genotypes, patients were classified as extensive metabolizers (EM group: CYP2C19*1/*1, *1/*2, or *1/*3) or poor metabolizers (PM group: CYP2C19*2/*2, *3/*3, or *2/*3). We also reviewed the clinical records of 56 patients who commenced stiripentol therapy and calculated the retention rate for stiripentol therapy over an observation period of 208 weeks. Concomitant administration of stiripentol led to a marked increase in the CD ratio of clobazam (1.8-fold in the EM group and 1.5-fold in the PM group). In addition, stiripentol increased the CD ratio of NCLB by 6.6-fold in the EM group, but decreased it by 0.7-fold in the PM group. The estimated retention rate with stiripentol therapy was higher, and the duration of retention was longer in the EM group than in the PM group (1378 versus 933 days, P < 0.001). In patients with the PM phenotype, the adjusted hazard ratio for ceasing stiripentol therapy was 6.7 (95% confidence interval: 1.8-24.7, P < 0.005). The effect of stiripentol on the pharmacokinetics of NCLB was significantly different between patients with the EM and PM phenotypes, which could influence the clinical response of Japanese patients with Dravet syndrome receiving the combination of valproic acid, clobazam, and stiripentol.

Effect of cytochrome P450 3A5 polymorphism on the pharmacokinetics of tacrolimus in renal transplant recipients.

BackgroundRenal transplant is an effective treatment option for end-stage kidney disease and tacrolimus is one of the most commonly used immunosuppressant drugs in renal transplant patients. Tacrolimus is a substrate of cytochrome P450 3A5 (CYP3A5), and a narrow therapeutic index and large inter-individual variability. The objective of this study was to determine the frequency of CYP3A5*3 polymorphism and its effect on the pharmacokinetics of tacrolimus in post-renal transplant patients at Mandalay General Hospital.MethodsThree different genotypes of CYP3A5 were determined by polymerase chain reaction-restriction fragment length polymorphism in 54 post-renal transplant recipients. Tacrolimus trough concentrations (Ctrough) were measured by enzyme multiplied immunoassay technique following method validation. The apparent clearance (CL/F) was calculated from measured Ctrough.ResultsThe frequency of CYP3A5*1 allele was 0.24 and that of CYP3A5*3 allele was 0.76 in the study sample. There were a total of 33 CYP3A5 non-expressors (patients with CYP3A5*3/*3 genotype) and 21 CYP3A5 expressors (patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotype), respectively. CL/F was significantly lower in the non-expressor group than in the expressor group (mean±standard deviation, 12.53±5.28 vs. 21.22±5.95 L/hr; P<0.001). The mean Ctrough and concentration dose ratio (C/D) for tacrolimus in CYP3A5 non-expressors were significantly higher than those in CYP3A5 expressors (Ctrough, 7.14±2.56 vs. 5.92±1.76 ng/mL; C/D, 6.92±4.11 vs. 2.89±1.85 ng/mL/mg), respectively (P<0.05).ConclusionsIn this study, 76% of the Myanmar renal transplant recipients carried the CYP3A5*3 allele that was associated with lower functional activity of the CYP3A5 enzyme a lower CL/F of tacrolimus in these Thus, CYP3A5 polymorphism influences the pharmacokinetics of tacrolimus, which may affect the pharmacological response to tacrolimus

CYP3A5 gene polymorphisms and their impact on dosage and trough concentration of tacrolimus among kidney transplant patients: a systematic review and meta-analysis.

Tacrolimus is an immunosuppressive drug widely used in kidney transplantation. Cytochrome P450 3A5 (CYP3A5) protein is involved in tacrolimus metabolism. Single nucleotide polymorphism in the CYP3A5 gene (6986A>G) results in alteration in metabolic activity of CYP3A5 protein which eventually affects the tacrolimus concentration. Patients with CYP3A5 expresser genotypes (A/A *1/*1 and A/G *1/*3) metabolize tacrolimus more rapidly than CYP3A5 nonexpressers (G/G *3/*3). We performed meta-analysis to estimate the effect of CYP3A5 polymorphism on the trough concentration-dose ratio (Co/D) and risk of renal allograft rejection with similar post-transplant periods and Asian vs. European populations. Our results showed that the tacrolimus Co/D ratio is significantly lower in CYP3A5 expresser group as compared with nonexpresser in Asian as well as in European populations at any post-transplant period (p < 0.00001). No significant association was found with renal allograft rejection episodes between expressers and nonexpressers in European populations (OR: 1.12; p = 0.47). Interestingly, Asian population (with expresser genotypes) and patients after 3 years post-transplantation (with expresser genotypes) have a higher risk of rejection (OR: 1.62; p < 0.05), (OR: 1.68; p < 0.05), respectively. This could be due to high prevalence of expresser genotypes in Asian population. Few tacrolimus-based studies are identified with long-term graft survival. There is a need to have more studies looking for long-term graft survival in expresser as well as no-expresser groups especially in Asian populations who have high frequency of CYP3A5 functional genotype.

Lack of association between ACE I/D, NOS3 VNTR polymorphisms and drug toxicity of tacrolimus treated post-renal transplantation patients

Introduction: Tacrolimus is the most commonly used calcineurin inhibitor for renal transplant individuals. Genetic factors play a major role in allografts by affecting blood pressure regulation, vascular proliferation and inflammatory responses. Objectives: The aim of this study was to evaluate a possible role of the ACE I/D and NOS3 VNTR polymorphisms in kidney transplantation patients treated with tacrolimus in the south Indian population. Patients and Methods: This study included 50 kidney transplant individuals and 100 unrelated healthy individuals from the general population as control. The genotyping was performed by polymerase chain reaction and electrophoresis. Genotypes were compared among cases and controls applying χ2 test. The difference in C/D ratios was compared using Mann–Whitney U test or Kruskal-Wallis test. Results: The ACE ID polymorphisms in different models [genetic (P=0.723), dominant (P=0.148) and recessive (P=0.652)] or allele model (P=0.455) did not differ significantly between the groups. Similarly, there was no significant difference for the NOS3 VNTR genotypes in genetic model (bb vs ba P=0.118; bb vs aa P=0.446), dominant model (bb vs ba+aa P=0.099) and allelic model (b vs a P=0.103). No significant difference was observed for ACE ID and NOS3 VNTR genotypes between the toxicity and non-toxicity groups. Furthermore, no significant association was observed for daily dose and concentration dose ratio for the studied polymorphisms. Conclusion: The present study revealed no significant association between cases and controls as well as toxicity and non-toxicity groups. Furthermore, there was no association between genotypes and daily dose and dose concentration.

Correlation of Tacrolimus Levels and Metabolizer Status Based on CYP3A5 Polymorphism in Indian Lung Transplant Recipients

Purpose Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Methods Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes Results 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Conclusion Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations. Tacrolimus (Tac) variable pharmacokinetics influences its efficacy and toxicity. CYP3A5 gene polymorphism leads to marked differences in metabolism of Tac. Aim is to assess the impact of CYP3A5 polymorphism on Tac. dose. Retrospective analysis of 3 months post-op, weekly Tac. levels, on lung transplant recipients between 01/2018 to 09/2018. Tac levels monitored every 3 days, aiming therapeutic range of 8 to 12 ng/mL. Monitoring continued twice weekly for 4 weeks, then weekly till 12 weeks. Genomic DNA was extracted from 0.1 ml of blood by silica column based protocol. A few ng of the DNA sample was subjected to AS-rtPCR-MPA in duplicates, thus yielding a total of 2 replicates. CYP3A5 polymorphisms was detected from each of the 2 replicates, thus dividing the patients into poor, intermediate or extensive metabolizer phenotypes 18 patients were divided into 3 groups - poor, intermediate, and rapid metabolizers, n = 5, 10, 3 respectively. As shown in Graph 1, most variation in weekly mean Tac dose was noted in rapid metabolizers. C/D ratio (Concentration Dose ratio) was calculated using the formula: C/D ratio = blood Tacrolimus trough level / daily Tac. dose, and plotted over time, displaying significant variation in the rapid metabolizers. Results suggest CYP3A5 genetic polymorphism significantly influences Tac. pharmacokinetics. This can help plan Tac. dose, obtain therapeutic levels, & minimize toxicity. Larger studies are required to establish the clinical correlation across age, sex and ethnic variations.

Graft-to-Recipient Weight Ratio Associated With Tacrolimus Metabolism Following Pediatric Living Donor Liver Transplantations.

Tacrolimus (TAC) is an important immunosuppressant in liver transplantation. Since TAC is mainly metabolized by the liver enzymes CYP3A4 and 5, liver function is crucial for its pharmacokinetics (PK). Liver function is dynamic after liver transplantation; hence the PK of TAC metabolism after pediatric liver transplantation is not well understood. We aimed to investigate the time-dependent changes in TAC metabolism and to find factors influencing TAC PK after pediatric liver transplantation. We retrospectively reviewed the characteristics of the donors and recipients in pediatric living donor liver transplantation and used the TAC concentration-dose (CD) ratio as a surrogate marker of TAC metabolism. Included were 326 patients with a median age of 13 months. After the liver transplantation, the CD ratio gradually decreased, then plateaued around day 21 to 28. A linear regression analysis demonstrated that a lower graft-to-recipient weight ratio (GRWR) and higher prothrombin time-international normalized ratio (PT-INR) were independently associated with a higher CD ratio in the early period after liver transplantation. However, association between GRWR and TAC CD ratio disappeared around 6 to 12 months after a liver transplantation possibly owing to graft regeneration. Tacrolimus metabolism improved within the first month after liver transplantation, and the small graft size was associated with lower TAC metabolism in the early period after pediatric living donor liver transplantation.

Clozapine Metabolism in East Asians and Caucasians: A Pilot Exploration of the Prevalence of Poor Metabolizers and a Systematic Review.

In clozapine therapeutic drug monitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor metabolizers (PMs) requires stratification by ethnicity, smoking, and sex. After sex and smoking stratification in 129 Chinese inpatients (mean, 8.8 TDM samples per patient), we explored the association between the total concentration-dose (C/D) ratio and CYP1A2 (*1C, *1F, and *7) and CYP2C19 alleles (*2 and *3). A systematic literature review identified 22 clozapine TDM prior studies (13 in Caucasians and 7 in East Asians). In our Chinese sample, the mean total clozapine C/D ratio (ng/mL per mg/d) was 1.96 for 22 male smokers, 2.07 for 5 female smokers, 2.47 for 36 male nonsmokers, and 2.95 for 66 female nonsmokers. CYP1A2 *1C had no significant effects, and CYP1A2 *1F had small effects. Five clozapine PMs (4%) needed low clozapine doses of 75 to 115 mg/d to get therapeutic concentrations. Using the same methodology in a published Italian sample, we found 5 PMs (3.3% of 152). In the systematic review, the clozapine C/D ratio (ng/mL per mg/d) was higher when comparing: (1) weighted mean values of 1.57 in 876 East Asians versus 1.07 in 1147 Caucasians and (2) ranks of 8 East Asians versus 13 Caucasian samples (P < 0.001). Future TDM studies need to further explore the frequency of clozapine PMs after sex and smoking stratification in East Asian and Caucasian patients. Compared with Caucasians, East Asians appear to have a clinically relevant decrease in clozapine clearance.

Результаты проведения терапевтического лекарственного мониторинга галоперидола у пациентов с алкогольными психозами и шизофренией

The purpose of the study: was to conduct therapeutic drug monitoring in two groups of patients with different nosology (schizophrenia and alcoholic psychosis) taking haloperidol (HAL) in different drug forms, evaluate the distribution of HAL concentrations relative to the therapeutic range, compare the concentration-dose ratio data and make recommendations for personalized pharmacotherapy patients of these groups. Material and methods: Dur ing this study, clinical , pathological and psychometr ic approaches were used. The concentration of haloperidol was determined by high-performance liquid chromatography in combination with mass-spectrometry. Group A — male patients whose age were 30,02 ± 6,9 years; group B also included male patients whose age were 40,54 ± 9,34 years. Group B was divided into subgroups, where some patients took tablet form of GAL, whereas others received therapy in the form of infusions. The exclusion criterion was overweight and the presence of infectious diseases (HIV, hepatitis, liver disease). Inclusion criteria were a signed voluntary informed consent, clinical diagnosis and the absence of somatic diseases. Concomitant therapy in groupsA and B was different. Results: In group A, indicators of measured concentrations were in the subtherapeutic range — 18,2%, therapeutic — 54,5%, conditionally toxic range — 27,3%. In group B — for the infusion form of HAL in the subtherapeutic range were 51,6% of the measured concentrations, in the therapeutic range — 48,4%, in the conditionally toxic — 0,0%; for the tablet form, the distri-bution was as follows — 69,2% in the subtherapeutic range, 30,8% in the therapeutic range, in the conditionally toxic range no concentration indicators were recorded. Conclusion: This study has shown a significant difference between normalized concentrations when comparing indicators from the group of patients with schizophrenia to the patients from the group B, who took the tablet form. That observation allows usto conclude that significant effect on the biotransformation of GAL can have a comedic effect from inducer of the C3A4 isoform of the cytochrome R450 — carbamazepine, while the concomitant therapy in the group A included atypical antipsychotics that did not affect this enzyme.