ABSTRACT
Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10-15 ng/mL in the first 4 weeks and 7-10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03-8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre-transplant CYP3A5 testing at our institution.
Subject(s)
Kidney Transplantation , Tacrolimus , Humans , Child , Cytochrome P-450 CYP3A/genetics , Fluconazole , Kidney Transplantation/adverse effects , Immunosuppressive Agents , Genotype , Dose-Response Relationship, Drug , Polymorphism, Single NucleotideABSTRACT
Evidence for the extrapulmonary benefits of (CFTR) modulators is rapidly expanding. The use of CFTR modulators in CF patients who have undergone lung transplantation is not clear without guidance published in the medical literature to assist clinicians in the care of these patients. We discuss the potential benefits of CFTR modulators and provide insight into their use based on our experience in a small cohort of CF LTx recipients. We present pros and cons of CFTR modulator therapy for LTx recipients with CF. CFTR modulators should be considered in CF patients after lung transplantation for the time being until further research defines how to best use these therapies in transplant recipients.
Subject(s)
Aminophenols/therapeutic use , Benzodioxoles/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/drug therapy , Cystic Fibrosis/surgery , Indoles/therapeutic use , Lung Transplantation , Postoperative Care/methods , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinolines/therapeutic use , Quinolones/therapeutic use , Adolescent , Biomarkers/metabolism , Combined Modality Therapy , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Combinations , Humans , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To compare the occurrence of hypotension following administration of intermittent intravenous (IV) and enteral sildenafil for treatment of pulmonary hypertension (PH) in infants. We hypothesized there may be more adverse effects associated with intermittent IV sildenafil compared with enteral sildenafil. METHODS: This was a retrospective matched-cohort study conducted in a tertiary care children's hospital. Patients were included if they were less than 1 year of age and received intermittent sildenafil for PH. Exclusion criteria consisted of concurrent extracorporeal membrane oxygenation during the initiation of sildenafil, the utilization of sildenafil as a one-time dose, continuation of home-dosing regimen, or inclusion in the other cohort. A total of 40 patients were matched 1:1 based on postmenstrual age and primary diagnosis. RESULTS: There was no statistically significant difference in the primary outcome, as 30% (6/20) of patients receiving IV sildenafil required a hypotension intervention compared with 10% (2/20) in the enteral cohort (P = 0.24). The majority of interventions occurred within 24 hr of the initiation of sildenafil with 4/6 patients (67%) in the IV group and 2/2 patients (100%) in the enteral group, respectively. Baseline mean arterial pressure was significantly lower in the IV patients that required an intervention compared with those that did not (44 ± 6.3 vs. 65 ± 13.4 mmHg, P = 0.0024). CONCLUSIONS: There were no statistically significant differences in safety outcomes between intermittent IV and enteral sildenafil in infants with PH. Hemodynamic parameters should be monitored closely upon sildenafil initiation. Limitations include the retrospective nature and small sample size. Pediatr Pulmonol. 2017;52:232-237. © 2016 Wiley Periodicals, Inc.
