Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity.

BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Current Status and Issues of Collaboration Between Physicians and Pharmacists in Fertility Preservation.

Purpose: This study addresses the critical issue of fertility preservation among young patients with cancer in Japan, recognizing the brief decision-making window and the need for comprehensive support. Pharmacists, well-versed in the side effects of anticancer drugs, can play a vital role in this support process. However, the extent of pharmacists' involvement in fertility preservation remains unclear. We aimed to investigate pharmacists' roles in addressing cancer treatment-induced fertility concerns and their collaboration with physicians, offering insights into enhancing pharmacist participation in fertility preservation. Methods: A survey conducted between April and July 2022 targeted doctors and pharmacists at cancer treatment hospitals, along with pharmacists affiliated with the Japanese Society of Pharmaceutical Health Care and Sciences. Results: Our findings indicated that although pharmacists had limited knowledge about gonadotoxicity and fertility, they expressed readiness to conduct research and provide information when consulted. Approximately 10%-20% of the pharmacists participated in explaining the primary disease at diagnosis. Pharmacists played a more prominent role after establishing chemotherapy regimens, with less involvement in its formulation. Notably, treatment decision case conferences emerged as crucial forums for gathering patient data, confirming treatment plans, and identifying those in need for fertility preservation information. Roughly half of the pharmacists attended these conferences, suggesting a need for increased participation. Conclusion: Enhancing physician-pharmacist collaboration could be pivotal for effective fertility preservation. This requires augmenting the knowledge and awareness of both professions and encouraging greater participation in case conferences to create a conducive environment for addressing this critical aspect of cancer care.

Investigation on the Usefulness of Sulfamethoxazole Trimethoprim Combination Small Tablets in Pediatric Pharmacotherapy: A Single Center Observational Study Using a Questionnaire.

Sulfamethoxazole trimethoprim (ST) combinations are used to prevent infection in immunocompromised patients. In pediatric patients, conventional ST combination tablets (cTab) are large and granules are not preferred due to their rough and bitter taste in the mouth. Since a new formulation of smaller tablets (sTab, 1 cTab = 1-gram granules = 4 sTab) was approved, a study regarding the usability of sTab in pediatric patients was conducted. Children who started taking sTab of the ST combination at our hospital between August 2021 and August 2022 were included. Using an anonymous questionnaire, the dosage of ST combinations, the child's response (3-point visual scale: positive, neutral, or negative), preparation and administration time, and method of taking the drug were asked. Twenty-two patients (median age: 11.0 years) receiving cTab. Median (range) number of tablets per dose was 1 (0.5-1.5) tablet, and was 4 tablets (1.0-4.0) after switching to sTab. Twenty patients (median age: 5.0 years) receiving granules. Median (range) single dose was 0.75 (0.2-2.0) gram, and was 2.0 (1.0-4.0) tablets after switching to sTab. Post-dose reactions were positive in 5, neutral in 7, and negative in 10 cases for cTab, and positive in 1, neutral in 7, and negative in 12 cases for granules. After switching to sTab, 9, 13 and 0 cases, and 10, 9 and 1 cases were positive, neutral, and negative, respectively. Median preparation and administration times were decreased after switching to sTab in both cTab and granules groups. The frequency of dosage manipulations was also decreased. The switch to sTab improved acceptability, and decreased burden of administration, suggesting that sTab is a user-friendly formulation in pediatric medications.

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance.

6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

Two-point blood sampling is sufficient and necessary to estimate the area under the concentration-time curve for intravenous busulfan in infants and young children.

BACKGROUND: Therapeutic drug monitoring for busulfan is important to prevent adverse events and improve outcomes in stem cell transplantation. We investigated intravenous busulfan pharmacokinetics and evaluated the utility of limited sampling strategy (LSS) as a simple method to estimate the area under the concentration-time curve (AUC). PROCEDURE: The study comprised 87 busulfan measurements in 54 children who received intravenous busulfan between August 2015 and May 2020. AUCs were calculated from three to five blood sampling points in each patient, and the correlation between AUC and plasma concentrations (ng/mL) at 1, 2, 3, 4, and 6 h after initiating busulfan infusion (C1 , C2 , C3 , C4 , and C6 , respectively). RESULTS: By one-point sampling strategy, the most relevant predicted AUC was based on C6 (r2  = 0.789; precision, 11.0%) in all patients. The predicted AUC based on C6 was acceptable (r2  = 0.937; precision, 5.9%) for adolescent patients weighing >23 kg, but the correlation was poor in infants and young children weighing ≤ 23 kg (r2  = 0.782; precision, 11.4%). By two-point sampling strategy, the predicted AUC based on C3 and C6 showed the most relevant concentrations (r2  = 0.943; precision, 6.4%), even in infants and young children, whereas the predicted AUC based on C3 and C6 was acceptable (r2  = 0.963; precision, 5.7%). CONCLUSIONS: The AUC of busulfan can be predicted based on C6 in adolescent patients. However, there was substantial interindividual variation in busulfan pharmacokinetics in infants and young children, in whom two-point LSS was necessary for accurate AUC prediction.

Tacrolimus blood concentration increase depends on administration route when combined with voriconazole in pediatric stem cell transplant recipients.

BACKGROUND: Understanding of TAC pharmacokinetics is required to avoid both overdosing and underdosing. VRCZ is known to increase the TAC blood concentration by inhibiting CYP3A4; however, detailed, practical information on pediatric cases is still scarce. Herein, we investigated the association between the TAC blood concentration and dosage focusing on the administration route and concomitant use of VRCZ in children. METHODS: In total, 38 children who received TAC during stem cell transplantation at our hospital between January 2013 and April 2018 were included. The ratio of the TAC blood concentration (ng/mL) to dosage (mg/kg/day) (C/D) was calculated at the last continuous intravenous infusion (C/Div) and after switching to oral administration (C/Dpo). RESULTS: Patients with VRCZ (n = 14) showed a higher C/D regardless of administration route (median C/Div: with VRCZ/without VRCZ = 832/643, median C/Dpo: with VRCZ/without VRCZ = 339/45). Additionally, the (C/Div)/(C/Dpo) was about one-fourth in cases with VRCZ; the median (C/Div)/(C/Dpo) was 3.3 for cases with VRCZ and 13.5 for cases without VRCZ. Interestingly, the increase in the TAC blood concentration due to VRCZ was higher when TAC was administered orally, especially in adolescent patients. CONCLUSIONS: To obtain an optimal TAC blood concentration, dose adjustment based on multiple factors, such as administration route, concomitant use of VRCZ, and age, is required.

Comparison of clonazepam and levetiracetam in children for prevention of busulfan-induced seizure in hematopoietic stem cell transplantation.

Antiseizure prophylaxis is required during busulfan administration for hematopoietic stem cell transplantation. However, antiseizure agents such as benzodiazepines and phenytoin may produce adverse effects through interaction with other drugs. We retrospectively assessed the prophylactic efficacy and safety of levetiracetam and clonazepam against busulfan-induced seizures between 2013 and 2018. Thirty patients (after 2015) received levetiracetam, and 13 patients (before 2015) received clonazepam in this study. Levetiracetam was well-tolerated and had a significantly lower frequency of adverse effects, such as somnolence, compared with clonazepam, although two patients in the levetiracetam group experienced seizures. Levetiracetam is a feasible option for preventing busulfan-induced seizures.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children.

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 µmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.