Comparison of the Impact of Pharmacogenetic Variability on the PK of Slow Release and Immediate Release Tacrolimus Formulations.

Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected.

Psychotropic drug concentrations and clinical outcomes in children and adolescents: a systematic review.

INTRODUCTION: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. AREAS COVERED: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated. EXPERT OPINION: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159.

Detection of a rare CYP3A4 variant in a transplant patient characterized by a tacrolimus poor metabolizer phenotype.

A validated CYP3A genotype classification system allows clustering patients into poor, intermediate and extensive metabolizer phenotypes. However, substantial overlap exists between the clusters. A rare CYP3A4 allele, named CYP3A4*20 (rs67666821), has been specifically described in the Spanish population. The authors investigated the relevance of CYP3A4*20 testing to see if the above-mentioned metabolic CYP3A classification system can be improved. In a cohort of 204 kidney transplant recipients, one male patient carrying a CYP3A4*20 allele was detected. This patient was receiving very low doses of tacrolimus to maintain therapeutic levels from day 7 onward when compared with the majority of the patients. These data suggest that this patient should be regarded as a CYP3A-poor metabolizer.

SLCO1B1 rs4149056 genetic polymorphism predicting methotrexate toxicity in Chinese patients with non-Hodgkin lymphoma.

AIM: To investigate the impact of polymorphisms in the FPGS, GGH and SLCO1B1 genes on high dose methotrexate (HD-MTX) related toxicity in Chinese patients with non-Hodgkin lymphoma (NHL). MATERIALS & METHODS: We analyzed FPGS (rs10106), GGH (rs719235, rs10464903, rs12681874), SLCO1B1 (rs4149056) genetic polymorphisms in 105 Chinese patients with NHL treated with HD-MTX. RESULTS: There was a statistically significant impact of the SLCO1B1 rs4149056 polymorphism on hepatotoxicity. Patients with TC and CC genotype had more hepatotoxicity than TT genotype (60 vs 32.94%, p = 0.025). After adjusting for disease stage, dosage, infusion time and therapy method, SLCO1B1 rs4149056 genotype remained significantly associated with hepatotoxicity (p = 0.028). CONCLUSION: SLCO1B1 rs4149056 genetic variants can affect the HD-MTX-related toxicity in Chinese patients with NHL.

Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation.

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, the need for more accurate drug dosing has become evident. Personalized immunosuppressive therapy requires better strategies for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed the clinical usefulness of therapeutic drug monitoring (TDM) of MPA in solid organ transplantation in a prospective way, and they have produced opposing results. To provide clinicians with an objective and balanced clinical interpretation of the current scientific evidence on TDM of MPA, a consensus meeting involving 47 experts from around the world was commissioned by The Transplantation Society and held in Rome on November 20 to 21, 2008. The goal of this consensus meeting was to offer information to transplant practitioners on clinically relevant pharmacokinetic characteristics of MPA, to rationalize the basis for currently advised target exposure ranges for MPA in various types of organ transplantation, and to summarize available methods for application of MPA TDM in clinical practice. Although this consensus report does not evaluate the final role of MPA TDM in transplantation, it seeks to examine the current scientific evidence for concentration-controlled dosing of MPA.

A controlled trial comparing two doses of cyclosporine in conjunction with mycophenolate mofetil and corticosteroids.

It is unknown whether the addition of mycophenolate mofetil (MMF) to cyclosporine (CsA) and prednisone after renal transplantation (RTx) allows for a reduced dose of CsA, to minimize the incidence of CsA-related side effects and to reduce costs. Therefore, 313 renal allograft recipients were randomized for treatment with MMF (1000 mg twice a day), prednisone, and either conventional- or low-dose CsA during the first 3 mo after RTx. The target trough levels were 300 and 150 ng/ml, respectively, during the first 3 mo and 150 ng/ml in both groups thereafter. A total of 313 patients were included: 161 patients received a conventional dose and 152 received a low dose of CsA. During the first 6 mo after RTx, graft failure or patient death occurred in 19 of 161 patients (12%) in the conventional-dose group and in 11 of 152 patients (7%) in the low-dose group (not significant). Biopsy-proven acute rejection occurred in 36 of 161 patients (22%) in the conventional-dose group and in 29 of 152 patients (19%) in the low-dose group (not significant). The incidence of delayed graft function was similar in both groups (31 of 161 [19%] versus 28 of 152 [18%]; not significant). Serum creatinine did not differ between the conventional- and the low-dose groups: 151 +/- 56 micromol/L versus 142 +/- 49 micromol/L at 3 mo and 141 +/- 60 micromol/L versus 136 +/- 49 micromol/L at 6 mo. There were no differences between the groups regarding BP, lipid metabolism, and infectious complications. In the low-dose group, an estimated $500 per patient was saved on the costs of CsA. In conclusion, the addition of MMF to CsA and prednisone after RTx allows the use of a lower-than-conventional dose of CsA, without increasing the risk of rejection.