CYP3A5 Genotype Research Articles

CYP3A5 genotype-based model to predict tacrolimus dosage in the early postoperative period after living donor liver transplantation.

PurposeLiver transplantation is the treatment of choice for patients with end-stage liver disease. Due to the between- and within-individual pharmacokinetic variability in tacrolimus, used to prevent rejection after transplantation, it is difficult to predict the dose needed achieve the target levels in the blood. This study aimed to construct a population pharmacokinetic model of tacrolimus dosage prediction for therapeutic drug monitoring in clinical settings for Korean adult patients receiving living donor liver transplantation (LDLT).MethodsA total of 58 Korean adult patients receiving LDLT with tacrolimus administration were enrolled. Demographic, clinical, and CYP3A5*1/*3 polymorphism data were collected. Population pharmacokinetic modeling of tacrolimus during the first 14 days after transplantation was performed using NONMEM program. Parameters were estimated by the first-order conditional estimation with interaction method. The internal validation of the final model was assessed by the bootstrap and visual predictive check methods using 500 samples from the original data.ResultsOne-compartmental model was selected as a base model. After the stepwise covariate model building process, postoperative day (POD) and combinational CYP3A5 genotype of the recipient and donor were incorporated into clearance (CL/F). The estimated typical values of CL/F and volume of distribution (V/F) were 6.33 L/h and 465 L, respectively. The final model was CL/F =6.33× POD0.257×2.314 (if CYP3A5 expresser recipient grafted from CYP3A5 expresser donor) ×1.523 (if CYP3A5 expresser recipient grafted from CYP3A5 nonexpresser donor) and V/F =465× POD0.322.ConclusionA population pharmacokinetic model for tacrolimus was established successfully in Korean adult patients receiving LDLT. This model is expected to contribute to improving patient outcomes by optimizing tacrolimus dose adjustment for liver transplant patients.

Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes.

This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes. Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes. The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration-time curve (AUC0-12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole. The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0-12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole.

Correlations between CYP3A4 polymorphism and susceptibility to breast cancer in Chinese Han population.

CYP3A4 is a major enzyme catalyzing the metabolism of endogenous steroids that play an important role in the etiology of carcinogenesis. This study was designed to investigate the contribution of CYP3A4 polymorphism to breast cancer in Chinese Han female population. To examine whether variants of CYP3A4 contribute to breast cancer, 5 single-nucleotide polymorphisms (SNPs) of CYP3A4 were genotyped by Sequenom MassARRAY in 267 breast cancer patients and 302 healthy controls. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age. We found that the TT genotype of CYP3A4*1G (rs2242480) polymorphism was associated with increased risk of breast cancer using the fixed effects model (recessive model: OR = 2.34, p = 0.018). Stratified according to age, CYP3A4*1G increased the risk of breast cancer especially in less than 50-year-old group (codominant model OR = 3.68, p = 0.041; recessive model: OR = 3.55, p = 0.012). Furthermore, TT genotype of rs2242480 was associated with Cerb-B2 positive (recessive model: OR = 2.47, p = 0.025) and stage I/II (recessive model: OR = 2.32, p = 0.041). However, no statistically significant associations in other polymorphisms and haploview analysis were observed. This study provides an evidence for polymorphism of CYP3A4 gene associated with the development of breast cancer, also a new insight into etiology of breast cancer. However, the underlying mechanism of the CYP3A4 gene in breast cancer is necessary for further study.

Pharmacogenetic impact of docetaxel on neoadjuvant treatment of breast cancer patients.

This study aimed to investigate the effect of CYP3A4 and CYP3A5 genotypes on clinical outcomes of docetaxel treatment. In the PROMIX trial, 150 breast cancer patients received docetaxel preoperatively. CYP3A4 and CYP3A5 genotype combinations were transformed into total CYP 3A phenotypes. Seven patients were characterized as poor metabolizer (PM), 22 patients as extensive metabolizer and 121 patients as intermediate metabolizer.The frequency of grade 3/grade 4 adverse events was higher in the PM group (p=0.002). One PM subject who basically lacked enzyme activity died from typhlitis. Total45recurrences were reported after a median of 5-year follow-up; none of these was PM. The allelic variants CYP3A4*22 and CYP3A5*3 contribute to the interpatient variations of docetaxel.

A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation.

Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied. To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations. Single hospital-based transplant center. This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6years) and randomized (2:1) after transplant to receive genotype-guided (n=35) or standard (n=18) starting dose of tacrolimus for 36-48hours and were followed for 30days. Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6)days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P=0.049), and had fewer out-of-range concentrations [OR (95% CI)=0.60 (0.44, 0.83), P=0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups. CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations.

Relationship between In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Systemic Tacrolimus Metabolite/Parent Drug Ratio in Renal Transplant Recipients and Healthy Volunteers.

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; P < 0.001]. There was, however, no relationship between CYP3A4 activity and tacrolimus metabolite/parent ratios. Additional analyses in 16 healthy volunteers showed that dual pharmacological inhibition of CYP3A4 and P-glycoprotein using itraconazole resulted in increased tacrolimus metabolite/parent ratios (+65%, +112%, and 25% for 13-, 15-, and 31-DMT, respectively; P < 0.01). This finding was confirmed in a cohort of nine renal transplant recipients who underwent tacrolimus pharmacokinetic assessments before and during CYP3A4 inhibition (58% increase in overall metabolite/tacrolimus ratio; P = 0.017).

Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations

In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel.

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P=0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24hours after ticagrelor ingestion than the controls (43% vs. 21%; P=0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.

Abstract B048: Androgen metabolism and incidence of prostate cancer in Nigeria

Abstract The risk of prostate cancer among blacks, especially of Nigerian descent, is higher than other races. This could be attributed to biologic and genetic variability. The role of androgen metabolism in prognosis of prostate cancer has been delineated and reported. One of the enzymes involved in androgen metabolism is CYP3A4, which has not been studied in Nigerian men afflicted with prostate cancer. Racial differences in this functional gene may contribute to variations in incidence of prostate cancer across ethnic divides. Therefore, identifying a diagnostic and prognostic biomarker such as CYP3A4 polymorphism for prostate cancer in black men will improve the treatment and management of the disease. In this study, we investigated the genotypes of CYP3A4 of prostate cancer patients from Nigeria for possible correlation to the high incidence of the disease in Nigerian men. The results obtained showed a preponderance of the GG genotypes, which indicates a possible correlation between this genotype of CYP3A4 and higher risk of prostate cancer among Nigerian men. Citation Format: Solomon Rotimi, Chidiebere Ogo, Olubanke Ogunlana, Shalom Chinedu, Emeka Iweala. Androgen metabolism and incidence of prostate cancer in Nigeria [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B048.

Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects

ObjectivesStatins are the most commonly prescribed medications for the treatment of atherosclerotic cardiovascular disease. Statin-associated adverse effects occur in ∼10% of patients and are associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. In the present study, we examine the association between cytochrome P450 3A5*3 (CYP3A5*3) T>C (rs776746), COQ G>C (rs4693075), and SLCO1B1 T>C (rs4149056) genetic variants with the risk of myopathy in South Indian patients on statin therapy. MethodsA total of 202 patients on atorvastatin or rosuvastatin therapy for 12 years were recruited in the study. Genotyping of drug metabolic CYP3A5*3 gene variant and drug transporter genes COQ G>C (rs4693075) and SLCO1B1 T>C (rs4149056) was analyzed by Sanger's sequencing. ResultsIn our study subjects, the percentage of patients diagnosed to have statin-induced myopathy was 18%. The majority of the patients were on 10 mg/day dose of either atorvastatin or rosuvastatin. The homozygous nonexpressors genotype CYP3A5*3/3 frequency of the CYP3A5 polymorphism was higher in patients with myopathy. But we could not find association of CYP3A5, COQ, and SLCO1B1 gene polymorphisms with either rosuvastatin or atorvastatin. ConclusionOur results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group. We did not find significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes.

Many studies have examined the effect of caffeine on exercise performance, but findings have not always been consistent. The objective of this study was to determine whether variation in the CYP1A2 gene, which affects caffeine metabolism, modifies the ergogenic effects of caffeine in a 10-km cycling time trial. Competitive male athletes (n = 101; age = 25 ± 4 yr) completed the time trial under three conditions: 0, 2, or 4 mg of caffeine per kilogram body mass, using a split-plot randomized, double-blinded, placebo-controlled design. DNA was isolated from saliva and genotyped for the -163A > C polymorphism in the CYP1A2 gene (rs762551). Overall, 4 mg·kg caffeine decreased cycling time by 3% (mean ± SEM) versus placebo (17.6 ± 0.1 vs 18.1 ± 0.1 min, P = 0.01). However, a significant (P <0.0001) caffeine-gene interaction was observed. Among those with the AA genotype, cycling time decreased by 4.8% at 2 mg·kg (17.0 ± 0.3 vs 17.8 ± 0.4 min, P = 0.0005) and by 6.8% at 4 mg·kg (16.6 ± 0.3 vs 17.8 ± 0.4 min, P < 0.0001). In those with the CC genotype, 4 mg·kg increased cycling time by 13.7% versus placebo (20.8 ± 0.8 vs 18.3 ± 0.5 min, P = 0.04). No effects were observed among those with the AC genotype. Our findings show that both 2 and 4 mg·kg caffeine improve 10-km cycling time, but only in those with the AA genotype. Caffeine had no effect in those with the AC genotype and diminished performance at 4 mg·kg in those with the CC genotype. CYP1A2 genotype should be considered when deciding whether an athlete should use caffeine for enhancing endurance performance.

Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients.

Clinical responses to oral tramadol show a large variation in cancer patients. This study aimed to evaluate the impacts of cytochrome P450 (CYP) genotype and serum inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients. The predose plasma concentrations of tramadol and its demethylated metabolites were determined at day 4 or later in 70 Japanese cancer patients treated with oral tramadol. The CYP genotypes, serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the duration of tramadol treatment were evaluated. The CYP2D6 genotype did not affect the plasma tramadol concentration. The plasma concentration of O-desmethyltramadol and its ratio to tramadol were lower in the CYP2D6 intermediate and poor metabolizer (IM + PM) group than in the normal metabolizer (NM) group (P = 0.002 and P = 0.023). The plasma concentration of N-desmethyltramadol and its ratio to tramadol were higher in the CYP2D6 IM + PM group than in the NM group (P = 0.001 and P = 0.001). The CYP2B6*6 and CYP3A5*3 alleles had no effect on the plasma concentrations of tramadol and its demethylated metabolites. The serum IL-6 and CRP levels were inversely correlated with the plasma concentration ratios of N-desmethyltramadol to tramadol and of N,O-didesmethyltramadol to O-desmethyltramadol. The serum IL-6 level was associated with the treatment duration of oral tramadol. The CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.

Effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its active metabolites.

CYP3A4, CYP2C19, and CYP3A5 are primarily involved in the metabolism of cilostazol. We investigated the effects of CYP2C19 and CYP3A5 genetic polymorphisms on the pharmacokinetics of cilostazol and its two active metabolites. Thirty-three healthy Korean volunteers were administered a single 100-mg oral dose of cilostazol. The concentrations of cilostazol and its active metabolites (OPC-13015 and OPC-13213) in the plasma were determined by HPLC-MS/MS. Although the pharmacokinetic parameters for cilostazol were similar in different CYP2C19 and CYP3A5 genotypes, CYP2C19PM subjects showed significantly higher AUC0-∞ for OPC-13015 and lower for OPC-13213 compared to those in CYP2C19EM subjects (P < 0.01 and P < 0.001, respectively). Pharmacokinetic differences in OPC-13015 between CYP3A5 non-expressors and expressors were significant only within CYP2C19PM subjects. The amount of cilostazol potency-adjusted total active moiety was the greatest in subjects with CYP2C19PM-CYP3A5 non-expressor genotype. These results suggest that CYP2C19 and CYP3A5 genetic polymorphisms affect the plasma exposure of cilostazol total active moiety. CYP2C19 plays a crucial role in the biotransformation of cilostazol.

Tacrolimus population pharmacokinetic models according to CYP3A5/CYP3A4/POR genotypes in Chinese Han renal transplant patients.

To develop a population pharmacokinetic (PK) model of tacrolimus in Chinese Han renal transplant population and establish the influence of different covariates (especially different CYP3A5/3A4/POR genotype) on PK properties. Trough tacrolimus concentrations, clinical characteristics and CYP3A5/CYP3A4/POR genotypes were collected from 141 adult renal transplant recipients after transplantation. The population PK analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 3.4.2. Tacrolimus PK profiles exhibited high interpatient variability. A two compartment model with first-order input and elimination described the tacrolimus PK profiles in the studied population. Among the genotypes, only CYP3A5 genotype was confirmed to have clinical significance. Our final model confirmed that CYP3A5*3 plays a more significant role in tacrolimus PK and could affect the blood concentrations and CL/F (clearance rate/bioavailbility). This model is expected to help to improve individualized tacrolimus dosing.

Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 Polymorphisms Using HRMA in Psychiatry Patients with Schizophrenia and Bipolar Disease for Personalized Medicine.

The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs. CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms were characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine. Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation. The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant were 0.092 and 0.096 in schizophrenia and bipolar groups, respectively. The knowledge in pharmacogenomic and also the developments in molecular genetics are growing rapidly. In future, this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients.

Genotype and Allele Frequency of CYP3A4 -392A>G in Turkish Patients with Major Depressive Disorder.

Genetic polymorphisms may help for individualized drug dosing and improved therapeutics. CYP3A4 is responsible for the metabolism of more than 50% of the commonly used drugs and metabolizes typical antipsychotic medications and antidepressant drugs. The objective of the study was to assess the genotype and allele frequencies of CYP3A4 -392A>G in Turkish patients with major depressive disorder receiving any SSRIs and to compare these results with the frequencies of other ethnic groups. Genotyping analyses of CYP3A4 -392A>G was conducted on 84 Turkish patients using the PCR-RFLP technique. The allele frequencies were found as 0.982 (A) and 0.018 (G) for CYP3A4 -392A>G. The genotype frequencies were determined as 0.976 (AA), 0.012 (AG), and 0.012 (GG). The genotype frequencies were consistent with the Hardy-Weinberg equilibrium. The genotype and allele frequencies of CYP3A4 -392A>G were determined to be low in Turkish patients with major depressive disorder receiving SSRIs. Furthermore, the results of the study were compared with those of other ethnic groups and they displayed pronounced differences among other ethnic groups, especially black subjects.

Evaluating tacrolimus pharmacokinetic models in adult renal transplant recipients with different CYP3A5 genotypes.

Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus. A literature search of the PubMed and Web of Science databases ultimately led to the inclusion of eight one-compartment models in our analysis. We collected a total of 1715 trough concentrations from 174 patients. Predictive performance was assessed based on visual and numerical comparison bias and imprecision and by the use of simulation-based diagnostics and Bayesian forecasting. Of the eight one-compartment models assessed, seven showed better predictive performance in CYP3A5 extensive metabolizers in terms of bias and imprecision. Results of the simulation-based diagnostics also supported the findings. The model based on a Chinese population in 2013 (model 3) showed the best and most stable predictive performance in all the tests and was more informative in CYP3A5 extensive metabolizers. As expected, Bayesian forecasting improved model predictability. Diversity among models and between different CYP3A5 genotypes of the same model was also narrowed by Bayesian forecasting. Based on our results, we recommend using model 3 in CYP3A5 extensive metabolizers in clinical practice. All models had a poor predictive performance in CYP3A5 poor metabolizers, and they should be used with caution in this patient population. However, Bayesian forecasting improved the predictability and reduced differences, and thus the models could be applied in this latter patient population for the design of maintenance dose.

Neuropsychiatric manifestations among HIV-1 infected African patients receiving efavirenz-based cART with or without tuberculosis treatment containing rifampicin

PurposeEfavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti-tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations.MethodsProspective cohort study of cART naïve HIV patients with or without tuberculosis (HIV-TB) co-infection treated with efavirenz-based cART. Rifampicin-based anti-tuberculosis therapy was initiated 4 weeks prior to efavirenz-based cART in HIV-TB patients. Data on demographic, clinical, laboratory, and a 29-item questionnaire on neuropsychiatric manifestations were collected for 16 weeks after cART initiation. Genotyping for CYP2B6, CYP3A5, SLCO1B1, and ABCB1 and quantification of efavirenz plasma concentration were done on the 4th and 16th week.ResultsData from 458 patients (243 HIV-only and 215 HIV-TB) were analyzed. Overall incidence of neuropsychiatric manifestations was 57.6% being higher in HIV-only (66.7%) compared to HIV-TB patients (47.4%) (p < 0.01). HIV-only patients were more symptomatic, with proportionately higher grades of manifestations compared to HIV-TB patients. Median time to manifestations was 1 week after cART initiation in HIV-only and 6 weeks after anti-TB (i.e., 2 weeks after cART initiation) in HIV-TB patients. HIV-only patients had significantly higher efavirenz plasma concentrations at 4 weeks after cART compared to HIV-TB patients. No association of sex or genotype was seen in relation to neuropsychiatric manifestations. Risk for neuropsychiatric manifestations was three times more in HIV-only patients compared to HIV-TB (p < 0.01).ConclusionsIncidence of neuropsychiatric manifestations during early initiation of efavirenz-based cART is high in Tanzanian HIV patients. Risk of neuropsychiatric manifestations is lower in HIV patients co-treated with rifampicin containing anti-TB compared to those treated with efavirenz-based cART only.

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1±1.6days for CYP3A extensive metabolizers (EM, P<0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2±0.5days less (P=0.01) and EM spent 2.1±0.5days less (P<0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P<0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P=0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P=0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.