Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.

The Tacrolimus Metabolism Rate and Dyslipidemia after Kidney Transplantation

Fast tacrolimus (Tac) metabolism is associated with reduced survival rates after renal transplantation (RTx), mainly due to cardiovascular events. Because dyslipidemia is a leading cause of cardiovascular death, we hypothesized that most RTx patients do not achieve recommended target low-density lipoprotein cholesterol (LDL-C) levels (European cardiology society guidelines) and that fast Tac metabolizers have higher dyslipidemia rates. This study included RTx recipients who received initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, and prednisolone. Patients were grouped according to their Tac concentration-to-dose ratio (C/D ratio) 3 months after RTx. Dyslipidemia parameters were analyzed at RTx, 3 months, and 12 months after RTx. Statin use and renal function were documented in a 12-month follow-up, and death was documented in a 60-month follow-up. Ninety-six RTx recipients were divided into two groups: 31 fast Tac metabolizers (C/D ratio < 1.05 ng/mL·1/mg) and 65 slow metabolizers (C/D ratio ≥ 1.05 ng/mL·1/mg). There were no differences in triglyceride or cholesterol levels between groups at RTx, 3, and 12 months after RTx. A total of 93.5% of fast and 95.4% of slow metabolizers did not achieve target LDL-C levels (p = 0.657). Fast metabolizers developed lower renal function compared to slow metabolizers 12 months after RTx (p = 0.009). Fast metabolizers showed a 60 month survival rate of 96.8% compared to 94.7% in the slow metabolizer group (p = 0.811). As most RTx recipients do not reach recommended target LDL-C levels, individualized nutritional counseling and lipid-lowering therapy must be intensified. Fast Tac metabolism is associated with lower renal function after RTx, but does not play a significant role in dyslipidemia.

Real-World Administration of Once-Daily MeltDose® Prolonged-Release Tacrolimus (LCPT) Allows for Dose Reduction of Tacrolimus and Stabilizes Graft Function Following Liver Transplantation

The calcineurin inhibitor tacrolimus is included in most immunosuppressive protocols after liver transplantation. This retrospective, observational 24-month study investigated the tolerability of once-daily MeltDose® prolonged-release tacrolimus (LCPT) after switching from twice-daily immediate-release tacrolimus (IR-Tac) in a real-world cohort of 150 patients with previous liver transplantation. No graft rejection or new safety signals were observed. Only 7.3% of patients discontinued LCPT due to side effects. In the overall patient population, median liver transaminases, total cholesterol, triglycerides, glucose, and HbA1c remained constant after switching to LCPT. Total cholesterol significantly decreased (p ≤ 0.002) in patients with initially elevated levels (>200 mg/dL). A total of 71.8% of 96 patients maintained a glomerular filtration rate > 60 mL/min/1.73 m2 throughout the study, while 44.7% of patients were classified as fast metabolizers and 55.3% as slow metabolizers. Median daily tacrolimus dose could be reduced by 50% in fast metabolizers and by 30% in slow metabolizers, while trough levels were maintained in the target range (4–6 ng/mL). In conclusion, our observational study confirmed previous evidence of good overall tolerability and a favorable outcome for the patients after switching from IR-Tac to LCPT after liver transplantation.

Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor–Containing Regimens

Background Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. Methods We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. Results In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Hexobarbital Sleep Test for Predicting the Susceptibility or Resistance to Experimental Posttraumatic Stress Disorder

Hexobarbital sleep test (HST) was performed in male Wistar rats (hexobarbital 60 mg/kg, i.p.) 30 days prior to stress exposure. Based on the duration of hexobarbital-induced sleep, rats were divided into two groups, animals with high intensity (fast metabolizers (FM), sleep duration <15 min) or low intensity of hexobarbital metabolism (slow metabolizers (SM), sleep duration ≥15 min). The SM and FM groups were then divided into two subgroups: unstressed and stressed groups. The stressed subgroups were exposed to predator scent stress for 10 days followed by 15 days of rest. SM and FM rats from the unstressed group exhibited different behavioral and endocrinological patterns. SM showed greater anxiety and higher corticosterone levels. In stressed animals, anxiety-like posttraumatic stress disorder (PTSD) behavior was aggravated only in SM. Corticosterone levels in the stressed FM, PTSD-resistant rats, were lower than in unstressed SM. Thus, HST was able to predict the susceptibility or resistance to experimental PTSD, which was consistent with the changes in glucocorticoid metabolism.

Implications of Efavirenz Pharmacogenetics When Switching From Efavirenz- to Dolutegravir-containing Antiretroviral Regimens

Many patients switch from efavirenz- to dolutegravir-based regimens. In a phase 1 dolutegravir-efavirenz interaction study, mean dolutegravir minimum concentration decreased by 60% and 85% among CYP2B6 normal and slow/intermediate metabolizers, respectively. Mean efavirenz half-life was 2.7 times greater in slow vs normal metabolizers. Slow metabolizers will experience more prolonged subtherapeutic dolutegravir concentrations.

Differences in MDR1 (C3435T), CYP2D6, and CYP1A2 Genotype Frequencies between Patients with Treatment Failure to Antipsychotics and Healthy Russian Population

Background: Personalized approach is one of the options to overcome treatment failure in psychiatry and increase the efficacy of antipsychotic treatment for an individual patient by using genetic tests. Objective: The aim of this study was to investigate the frequency of MDR1 (C3435T), CYP2D6, CYP2C19, and CYP1A2 genotypes in psychiatric patients with treatment failure to antipsychotics to compare the results with those published for the Russian population. Methods: A total number of 52 patients attending a psychiatry outpatient clinic were included in the study. All patients required changing the therapy with antipsychotics due to treatment failure. Results: We revealed the higher frequency of Т/Т MDR1 (C3435T) homozygotes among study patients as compared with the Russian healthy population. For CYP1A2, the higher frequency of normal metabolizers (*1A/*1A) and lower frequency of slow metabolizers (*1F/*1F) were observed. No difference was found for intermediate metabolizers (*1A/*1F) and one patient had *1A/*1C genotype with decreased activity. For the majority of CYP2D6 genotypes, the observed frequencies were similar to those reported for the Russian healthy population except for CYP2D6 *3/*4 (slow metabolizers), for which higher frequency among study patients was found. The frequencies of CYP2С19 genotypes were comparable to the Russian population, however, no slow metabolizers (*2/*2, *2/*3, *3/*3 genotypes) were identified. Conclusion: Psychiatric patients with treatment failure to antipsychotics demonstrated a high frequency of T/T MDR1 (C3435T) and CYP2D6 *3/*4 genotypes coding inactive proteins. The frequency of CYP1A2 wild type genotype *A/*A was higher with a simultaneous decrease in the frequency of *F/*F genotype compared with the healthy Russian population. Further studies of MDR1 (C3435T) genotype as well as CYP2D6, CYP2C19, and CYP1A2 genotypes frequency should be conducted in patients with treatment failure to antipsychotics.

ВИЗНАЧЕННЯ ГЕНЕТИЧНОГО ПОЛІМОРФІЗМУ CYP2C9 НА ТЛІ ПРИЗНАЧЕННЯ ВАРФАРИНУ У ПАЦІЄНТІВ НА ІШЕМІЧНУ ХВОРОБУ СЕРЦЯ, УСКЛАДНЕНУ ПОСТІЙНОЮ ФОРМОЮ ФІБРИЛЯЦІЇ ПЕРЕДСЕРДЬ

This article describes the results of a genetic study of the spread of CYP2C9 polymorphic variants in patients in the Podilskyi region of Ukraine. In different ethnic groups, the frequency of cytochrome polymorphic isoenzymes can vary significantly. The presence of genetic mutations of this cytochrome (Arg144Cys, Ile359Leu) is associated with an increased concentration of warfarin in the blood, which can lead to excessive hypocoagulation and risk of bleeding. Particular attention should be paid to patients with a detected mutation in homozygous form, as both alleles of the gene are mutant (their carriers are "slow metabolizers" and therefore require more careful dose selection). Patients are advised to undergo individual genotyping, which will help to predict the risk of each individual patient.

Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers after Renal Transplantation

Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio <1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio <1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.

Effects of Nicotine Metabolic Rate on Cigarette Reinforcement

Introduction The rate of nicotine metabolism, estimated by the nicotine metabolite ratio (NMR), is an important determinant of tobacco dependence. This study investigated the effect of NMR on smoking behavior due to nicotine reinforcement during ad libitum smoking. Aims and Methods As part of a larger study, participants were stratified based on saliva NMR as fast and slow metabolizers. After smoking a cigarette and measuring nicotine blood concentrations, participants smoked as desired over a 90-minute period. Analysis included time to first cigarette, total number of cigarettes, total number of puffs, and weight of tobacco consumed. Results Sixty-one (48%) participants were fast metabolizers and 66 (52%) slow metabolizers by NMR. No significant differences were found regarding the smoking topography variables by NMR. Normal metabolizers by genotype (n = 79) had a shorter time to first cigarette than reduced metabolizers (n = 39; p = .032). Blacks smoked fewer cigarettes (p = .008) and took fewer total puffs (p = .002) compared with Whites. Among Whites, fast metabolizers by NMR had a shorter time to first cigarette compared with slow metabolizers (p = .014). Among fast metabolizers, Whites had, compared with Blacks, shorter latency to first cigarette (p = .003) and higher number of total puffs (p = .014) and cigarettes smoked (p = .014). Baseline cigarettes per day and nicotine elimination half-life significantly predicted topography outcomes. Conclusions Saliva NMR did not predict cigarette reinforcement during a relatively brief period of ad libitum smoking. Differences were seen by race, with White fast metabolizers by NMR having shorter time to first cigarettes compared with slow metabolizers. Implications After a 90-minute period of nicotine abstinence, NMR was not significantly associated with smoking reinforcement. Slow and fast metabolizers had similar time to first cigarette, number of cigarettes smoked, total number of puffs, and tobacco consumed; however, within-race differences show that within Whites, fast metabolizers had a faster time to first cigarette than slow metabolizers.