A Case Report of Drug Interactions Between Nirmatrelvir/Ritonavir and Tacrolimus in a Patient With Systemic Lupus Erythematosus.

Nirmatrelvir/ritonavir is a treatment for COVID-19 consisting of nirmatrelvir, which has anti-SARS-CoV-2 activity, and ritonavir, a booster to maintain blood levels. Ritonavir is known to be a potent inhibitor of cytochrome P450 3A (CYP3A), and interactions with CYP3A-metabolized drugs, such as the immunosuppressant tacrolimus, can be problematic. Ritonavir's inhibition of CYP3A is irreversible due to covalent binding, and its inhibitory effects are expected to persist until replaced by new CYP3A. Here, we report a case where the combination of nirmatrelvir/ritonavir and tacrolimus resulted in toxic tacrolimus blood levels. A patient on tacrolimus for systemic lupus erythematosus (SLE) developed COVID-19 and was prescribed nirmatrelvir/ritonavir. After starting the combination of nirmatrelvir/ritonavir and tacrolimus, the patient's tacrolimus blood levels became abnormally high, leading to the discontinuation of these drugs due to symptoms of tacrolimus toxicity. Even after ritonavir blood levels had fallen below the detection limit, the decline in tacrolimus blood levels was delayed. The CYP3A inhibition of ritonavir persists even when its blood concentration decreases, emphasizing the need for careful consideration of concomitant medications before starting nirmatrelvir/ritonavir therapy. Adjustments or discontinuation may be necessary.

[Significant Changes Associated with the Transition from Outsourcing to In-hospital Therapeutic Drug Monitoring of Novel Antiepileptics].

For many of the novel antiepileptics, immunoassays, used for routine therapeutic drug monitoring (TDM), cannot be used. We could monitor eight novel antiepileptics using an LC/MS method since July 2017. The purpose of this study was to evaluate the significant changes associated with the transition from outsourcing to in-hospital monitoring of novel antiepileptics. The number of measurements of novel antiepileptics was significantly increased during the first (p<0.01) and second (p<0.001) years of in-hospital monitoring as compared to that one year prior to in-hospital monitoring which was outsourced. The proportion of measurements of novel antiepileptics to all antiepileptics was 19.7%, 31.1%, and 38.4% during outsourcing, and first, and second years of in-hospital monitoring, respectively. The measurement cost was significantly reduced during the first (p<0.001) and second (p<0.001) years of in-hospital monitoring as compared to that during outsourcing. In addition, the revenue from TDM of antiepileptic drugs was significantly increased during the first (p<0.05) and second (p<0.01) years of in-hospital monitoring as compared with that during outsourcing. In conclusion, the switch from outsourcing to in-hospital monitoring led to an increase in the number of orders, a reduction in the measurement-related expenses of novel antiepileptics, and an increase in the revenue from TDM of antiepileptic drugs, which could promote the proper use of novel antiepileptics through TDM.

Comparison of 4 Commercial Immunoassays Used in Measuring the Concentration of Tacrolimus in Blood and Their Cross-Reactivity to Its Metabolites.

BACKGROUND: Therapeutic drug monitoring of tacrolimus is necessary for appropriate dose adjustment for a successful immunosuppressive therapy. Several commercial immunoassays are available for tacrolimus measurements. This study aimed at simultaneously evaluating the analytical performances of 4 such immunoassays, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a standard. For the first time, cross-reactivity to tacrolimus metabolites was assessed at concentrations frequently observed in clinical settings, as opposed to the higher concentrations tested by assay manufacturers. METHODS: An affinity column-mediated immunoassay (ACMIA), using upgraded flex reagents; released in 2015, a chemiluminescence immunoassay (CLIA), an electrochemiluminescence immunoassay (ECLIA), and a latex agglutination turbidimetric immunoassay (LTIA) were evaluated using frozen whole blood samples collected from transplantation patients. Cross-reactivities to 3 major tacrolimus metabolites (13-O-demethyl-tacrolimus [M-I], 31-O-demethyl-tacrolimus [M-II], and 15-O-demethyl-tacrolimus [M-III]) were evaluated. RESULTS: Each immunoassay correlated well with LC-MS/MS, and the Pearson's correlation coefficients (R) were 0.974, 0.977, 0.978, and 0.902 for ACMIA, CLIA, ECLIA, and LTIA, respectively. Using Bland-Altman difference plots to compare the immunoassays with LC-MS/MS, the calculated average biases were -6.73%, 6.07%, 7.46%, and 12.27% for ACMIA, CLIA, ECLIA, and LTIA, respectively. The cross-reactivities of ACMIA to the tacrolimus metabolites M-II and M-III were 81% and 78%, respectively, when blood was spiked at 2 ng/mL, and 94% and 68%, respectively, when it was spiked at 5 ng/mL. CONCLUSIONS: Each immunoassay was useful, but had its own characteristics. ACMIA cross-reactivities to M-II and M-III were much higher than the respective 18% and 15% reported on its package insert, suggesting that cross-reactivity should be examined at clinically relevant concentrations.

Clinical prospects of biomarkers for the early detection and/or prediction of organ injury associated with pharmacotherapy.

Several biomarkers are used to monitor organ damage caused by drug toxicity. Traditional markers of kidney function, such as serum creatinine and blood urea nitrogen are commonly used to estimate glomerular filtration rate. However, these markers have several limitations including poor specificity and sensitivity. A number of serum and urine biomarkers have recently been described to detect kidney damage caused by drugs such as cisplatin, gentamicin, vancomycin, and tacrolimus. Neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and cystatin C have been identified as biomarkers for early kidney damage. Hy's Law is widely used as to predict a high risk of severe drug-induced liver injury caused by drugs such as acetaminophen. Recent reports have indicated that glutamate dehydrogenase (GLDH), high-mobility group box 1 (HMGB-1), Keratin-18 (k18), MicroRNA-122 and ornithine carbamoyltransferase (OCT) are more sensitive markers of hepatotoxicity compared to the traditional markers including the blood levels of amiotransferases and total bilirubin. Additionally, the rapid development of proteomic technologies in biofluids and tissue provides a new multi-marker panel, leading to the discovery of more sensitive biomarkers. In this review, an update topics of biomarkers for the detection of kidney or liver injury associated with pharmacotherapy.

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2-3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.