Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates. RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%. CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Less Is More: Backing off Sliding Scale Insulin for Hospitalized Patients.

In hospitalized patients with type 2 diabetes (T2DM), a less aggressive supplemental insulin regimen is noninferior to a standard, more aggressive, supplemental regimen.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk.

SOURCE CITATION: Bajaj HS, Aberle J, Davies M, et al. Once-weekly insulin icodec with dosing guide app versus once-daily basal insulin analogues in insulin-naive type 2 diabetes (ONWARDS 5): a randomized trial. Ann Intern Med. 2023;176:1476-1485. 37748181.

Interim analyses of the multinational real-world prospective cohort HEM-POWR study evaluating the effectiveness and safety of damoctocog alfa pegol in patients with hemophilia A.

OBJECTIVES: To assess effectiveness and safety of damoctocog alfa pegol in interim analyses of the ongoing real-world hemophilia A HEM-POWR study. METHODS: HEM-POWR (NCT03932201) is a multinational Phase 4 prospective observational study. The primary objective was annualized bleeding rate (ABR) in previously treated patients (PTPs) with hemophilia A. Secondary objectives included adverse events and number of affected joints. RESULTS: At data cut-off (August 17, 2022), the safety analysis set included 268 patients and the full analysis set (FAS) included 161 patients. The most common dosing regimen during observation period was prophylaxis (FAS = 158/161, 98.1%) every 3-4 days (twice weekly; FAS = 78/158, 49.4%) and a median (min, max) infusion dose of 37.5 (10, 72) IU/kg. PTPs receiving prophylactic damoctocog alfa pegol have fewer infusions compared with prior treatment. Median total ABR (Q1, Q3) was 0.0 (0.0, 1.8) and mean total ABR (SD) was 2.4 (8.2). The proportion of patients with no affected joints increased between initial visit and follow-up. No FVIII inhibitors, treatment-related adverse events, or deaths were reported. CONCLUSIONS: Damoctocog alfa pegol shows effectiveness and acceptable safety, as well as consistent utilization, in real-world PTPs with hemophilia A, including in patients with non-severe hemophilia and those with a history of inhibitors. Please see video for a summary of this study.

Position Statement: Range Orders in the Management of Pain.

American Society for Pain Management Nursing (ASPMN) supports safe medication practices and the appropriate use of pro re nata (PRN) range orders for analgesics in the management of pain within the scope of nursing practice. Although range orders may apply to many medications prescribed as PRN, the focus of this ASPMN position statement is on PRN analgesic medication. PRN range orders are commonly used to provide flexibility in dosing to meet the analgesic requirements of an individual patient. There are many patient-specific factors that require professional clinical assessment when administering medications to patients. Unfortunately, several myths persist regarding The Joint Commission's (TJC) standard around the implementation of range orders leading many to assume that range orders are not supported or safe. On the contrary, if utilized in a consistent and appropriate manner, PRN range orders can allow nurses to provide optimal pain management while still providing safe administration (Paquette et al., 2022).

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer.

BACKGROUND: Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP. METHODS: Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues. RESULTS: Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid-derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP. CONCLUSION: LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

Managing delayed or missed pregabalin doses in patients with focal epilepsy: a Monte Carlo simulation study.

BACKGROUND: Delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the United States Food and Drug Administration (FDA) for non-adherence are generic and lack clinical evidence. AIM: To assess remedial strategies for delayed or missed pregabalin doses in patients with epilepsy using Monte Carlo simulations. METHOD: Monte Carlo simulations were performed using a published population pharmacokinetic model for pregabalin. The applicability of five proposed remedial regimens as well as FDA recommendations was evaluated by simulating various poor adherence scenarios in eight populations, including those with renal dysfunction. RESULTS: All proposed remedial strategies were associated with delay duration and renal function. When delays are relatively short, an immediate regular dose is advised. The cut-off time points for taking the regular dose as a remedial regimen were 1, 2, 4, and 12 h for patients with mild renal impairment and normal renal function, moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively. However, when delay aligns closely with a dosing interval, a regular dose combined with a partial dose proves effective. Generally, supplementing 1.3-fold the regular dose at the next scheduled time adequately compensates for the missed dose. CONCLUSION: Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses.

Extended-release tacrolimus dosing and outcomes in pediatric and young adult transplant recipients - A single-center experience.

BACKGROUND: Published data on LCP-tacrolimus (LCPT) in the pediatric population are limited. METHODS: This single-center, retrospective, observational study describes LCPT doses needed to reach therapeutic ranges in pediatric and young adult kidney and liver transplant recipients in both de novo usage and conversion from immediate-release tacrolimus (IR-Tac). Adverse outcomes up to 12 months after LCPT initiation were also evaluated. RESULTS: Forty-one transplant recipients (30 kidney, 11 liver) were included. The median initial doses of LCPT were 0.034 mg/kg (IQR 0.019) de novo and 0.09 mg/kg (IQR = 0.076) converted. The median doses at first therapeutic level were 0.086 mg/kg (IQR 0.028) de novo and 0.1 mg/kg (IQR 0.066) converted. The median LCPT:IR-Tac conversion ratio initially was 0.7 and 0.75 at therapeutic levels. The rate of AKI per 100 days of exposure to IR-Tac was 0.546 and 0.439 on LCPT. The percentage of patients with rejection was not different before and after conversion (clinical rejection 8.6% [n = 3] vs 11.4% [n = 4], p = .6; biopsy-proven rejection 2.9% [n = 1] vs 11.4% [n = 4], p = .11). One patient had graft loss unrelated to rejection, and the graft was explanted. CONCLUSION: In this study, pediatric and young adult abdominal transplant recipients had therapeutic tacrolimus levels at LCPT doses below the adult-labeled dose; the conversion ratio from IR-Tac to LCPT at therapeutic level was similar. There were no identified safety concerns in de novo or converted LCPT use in pediatric and young adult patients.

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PK of nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

Medication adherence of bisphosphonate weekly or monthly regimens in patients with osteoporosis using a nationwide large claims database.

Bisphosphonate (BPN) therapy, which mainly targets osteoporosis, evolves rapidly, leaving patients and physicians with a substantial collection of BPN regimen options. In this study, we aimed to clarify BPN medication adherence between weekly and monthly regimens using a nationwide claims database in Japan. We analyzed 5,016 patients with a screening period of 3 months and a 12 month observation period who started using BPN. We used propensity score matching with baseline patient background after dividing the patients into two groups: weekly and monthly BPN users. Medication adherence was calculated using proportion days cover (PDC). A PDC of > 80% was 55.9% and 52.5% in monthly and weekly formulas, respectively, during the 12 months after initiating BPN treatment. PDC-based BPN medication adherence was higher in monthly regimens than in weekly regimens (66.3±34.0 vs. 64.1±36.8%). No differences were found in the proportion of patients with > 80% medication adherence between the monthly and weekly regimens after stratifying patient background using propensity score matching. Our clinical findings highlight the importance of closely monitoring BPN medication adherence, particularly during the initial year of therapy. Notably, half of the patients with osteoporosis exhibited low medication adherence. Therefore, prioritizing monthly regimens over weekly regimens is crucial to promote BPN adherence and ensure optimal treatment outcomes.

Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.

BACKGROUND: Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy. METHODS: In this randomised, phase 2, open-label, dose-optimisation study we enrolled adult patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy, and with Eastern Cooperative Oncology Group scores of 0-2, from 40 hospitals and centres across seven countries. In part one of the trial, participants were randomly allocated 1:1 to 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17, combined with subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles. The primary efficacy outcome was the rate of complete remission in the intention-to-treat group. The two dose cohorts were evaluated independently without between-cohort statistical comparison. Safety analyses were performed in all patients who received one dose of study drug. Part two of the trial was planned to be a single-arm expansion to evaluate cusatuzumab plus azacitidine at the cusatuzumab dose level selected in part one (primary hypothesis ≥35% rate of complete remission vs null hypothesis of 20%); however, changes in the acute myeloid leukaemia treatment landscape during this trial made it unlikely that enrolment to part two of the study would be clinically feasible, so the study stopped at the end of part one. The trial was registered at ClinicalTrials.gov, NCT04023526. FINDINGS: 103 patients were enrolled between Aug 30, 2019, and Feb 25, 2020, and randomly assigned to either cusatuzumab 10 mg/kg (n=51) or 20 mg/kg (n=52). Median follow-up was 7·2 months (IQR 10·7 months). 57 of 103 (55%) patients were male and 46 (45%) patients were female, 78 (76%) were White, one (1%) was Asian, and 24 (23%) did not report their race. In the 10 mg/kg group, complete remission rate was 12% (six of 51 patients; 95% CI 6-23) and in the 20 mg/kg group was 27% (14 of 52; 17-40). Grade 3 or worse treatment-emergent adverse events (TEAEs) were similar between the cusatuzumab 10 mg/kg (n=51) and 20 mg/kg (n=51) cohorts and included thrombocytopenia (24 patients [47%] vs 29 [57%]), anaemia (24 [47%] vs 17 [33%]), and neutropenia (20 [39%] in both cohorts). Serious TEAEs were also similar in the two cohorts (44 [86%] vs 40 [78%]). Treatment-related TEAEs leading to death were reported in both groups (three patients [6%] in the 10 mg/kg group vs one patient [2%] in the 20 mg/kg group); the reported causes of death were pneumonia (n=2) and septic shock (n=2). INTERPRETATION: Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887). FUNDING: Janssen Research & Development and argenx.

Impact of obesity on the conversion of immediate-release tacrolimus to extended-release tacrolimus in kidney transplant recipients.

Outcomes analyzing conversion from IR-tacrolimus (IR) to LCP-tacrolimus (LCP) in obesity are limited. This was a retrospective longitudinal cohort study of patients converted from IR to LCP from June 2019 to October 2020. Primary outcomes were conversion ratios for weight-based dose at a steady-state therapeutic level and identification of appropriate dosing weight. Other outcomes included tacrolimus coefficient of variation (CV), time in therapeutic range (TITR), adverse events, infections, donor specific antibodies (DSAs), and acute rejection. A total of 292 patients were included; 156 and 136 patients with a BMI < 30 and BMI ≥ 30 kg/m2 , respectively. Baseline characteristics were similar, except for pancreas transplant, diabetes, and HLA mismatch. IR to LCP conversion ratio ranged from .73 to .79. Mean LCP dose was similar (.08 vs. .07 mg/kg/day for BMI < 30 and BMI ≥ 30 kg/m2 , respectively); there was a significant difference in IR and LCP mg/kg dosing at steady state with TBW (.11 mg/kg vs.09 mg/kg and .08 mg/kg vs. .06 mg/kg, respectively). The most appropriate dosing weight was adjusted body weight (AdjBW), consistent across IR and LCP steady-state doses, and might yield more accurate steady-state dosing requirements. In multivariable modeling, BMI was a significant predictor of steady state mg/kg dosing at therapeutic goal for total body weight (TBW), but not ideal body weight (IBW) or AdjBW.

Comparison of amoxicillin administered twice and three times daily in children with acute otitis media.

To compare the effectiveness of amoxicillin administered in regimens of two or three daily doses in children with acute otitis media (AOM). As a secondary aim, we measured and compared treatment adherence between the two groups.A prospective observational study was conducted in the emergency department of a children's hospital.We recruited a total of 353 patients having a median age of 1.58 years. Twice-daily dosing was prescribed to 58%, while 42% received three doses per day. The clinical course of AOM was favourable in 92% of the patients who received two doses of amoxicillin and in 95% of those who received three doses (p = 0.25). Four patients (1%) had persistent symptoms beyond day 7. None developed intracranial complications. In the group receiving three doses daily, 31% reported difficulties with the dosing schedule, and 9.6% faced challenges when administering the medication at the specified volume, compared with 5.8% and 25% of those who received the two-dose regimen, respectively.  Conclusion: Twice-daily amoxicillin has similar efficacy to a three-dose daily regimen and can offer advantages for caregivers in terms of administration schedule. What is Known: • Amoxicillin given in two daily doses is as effective as a three doses regimen in the treatment of acute otitis media in children. • The lower the number of daily doses, the higher the adherence to a drug treatment. What is New: • Administration of amoxicillin in twice-daily doses may improve adherence, as it is less frequently associated with family-perceived problems with dosing schedules.

Dose Changes for Long-term Opioid Patients Following a State Opioid Prescribing Policy.

BACKGROUND: In 2018, Nevada implemented opioid prescribing legislation (AB474) to support the uptake of CDC pain care guidelines. We studied the law's association with doses over threshold levels of morphine milligram equivalents (MMEs) and with time to dose increases and decreases, among long-term opioid patients. METHODS: A difference-in-difference study examined dosing changes across opioid prescription episodes (ie, prescriptions within 30 day and within the same dosing threshold). Patients with at least 120 days supply over 6 months in Nevada and Colorado Medicaid pharmacy claims were included. Using a logistic regression model, we compare the predicted probabilities that opioid episodes exceeded 50 MME before and after implementation of the law, in both states. Adjusted hazard ratios (aHR) from a gap time survival model estimated time to escalate above 50 MME among low-dose episodes (<50 MME), and time to de-escalate below 50 MME among high-dose episodes (≥50 MME). RESULTS: Among 453,577 episodes (74,292 patients), the Nevada law was associated with a 2.9% reduction in prescriptions over 50 MME (95% CI: -3.5, -2.3) compared with Colorado. While the law was also associated with slower escalation (Nevada: aHR = 0.75; 95% CI: 0.72, 0.77, Colorado: aHR = 1.04; 95% CI: 1.01, 1.06), it was also associated with slower de-escalation (Nevada: aHR = 0.87; 95% CI: 0.84, 0.89, Colorado: aHR = 0.97; 95% CI: 0.96, 0.99). CONCLUSIONS: Slower dose escalations, rather than faster dose de-escalation, likely explain post-law reductions in doses over 50 MME. Slower dose de-escalations may be due to longer days supply post-policy.

Effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplant recipients: The PRETHI study.

Data comparing long-term effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplantation are scarce. We compared the effectiveness, pharmacokinetic profile, and safety of LCPT (Envarsus) and PR-Tac (Advagraf) for up to 12 months post-transplant. Adult de novo liver transplant recipients who started IR-Tac (Prograf) and were converted to LCPT or PR-Tac 3-5 days post-transplant were included. Data from 163 patients were analyzed, 87 treated with LCPT and 76 with PR-Tac. The incidence of treatment failure was 30.5% in the LCPT group versus 23.0% in the PR-Tac group (p = .291). Biopsy-proven acute rejection (BPAR) was reported in 26.8% of patients in the LCPT group and 17.6% in the PR-Tac group (p = .166). Graft loss was experienced in one patient (1.2%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p = .346). Death was registered in three patients (3.7%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p > .999). Patients in the LCPT group showed 45.7% higher relative bioavailability (Cmin /total daily dose [TDD]; p < .01) with similar Cmin and 33.3% lower TDD versus PR-Tac (p < .01). The evolution of renal function, safety profile, and the incidence of post-transplant renal failure, dyslipidemia, obesity, hypertension, and diabetes mellitus were similar in patients treated with LCPT and PR-Tac. In de novo liver transplant patients, LCPT and PR-Tac showed comparable effectiveness with higher relative bioavailability, similar Cmin and lower TDD in the LCPT group. Renal function, safety, and post-transplant complications were comparable in LCPT and PR-Tac groups.

Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. METHODS: In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. RESULTS: Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. CONCLUSION: Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.Trial Registration: NCT03700320.

Hepatocyte proliferation activity in untreated rats, measured by immunohistochemical detection of Ki-67: The effect of age on the repeated-dose liver micronucleus assay.

The repeated-dose liver micronucleus (RDLMN) assay is a widely accepted method for detecting genotoxic substances. We investigated the effect of animal age on this assay. Proliferation activity in the liver tissue of untreated rats at age = 3.5, 6, 8, 10, or 12 weeks was measured via immunohistochemical expression of Ki-67 protein. The percentage of Ki-67-positive hepatocytes decreased markedly with age, reaching very low levels after 10 weeks, indicating decline with age of proliferative capacities in the liver. We calculated the area under the curve (AUC) of the approximate curve generated from the percentage of Ki-67-positive cells, to estimate the hepatocyte proliferation activity over the dosing period in the two regimens of the 4-week RDLMN assay: dosing initiated at age = 6 or 8 weeks. Hepatocyte proliferation activity of the former regimen was approximately double that of the latter. We also calculated the AUC for the juvenile-rat method, in which rats are treated for two days at age = 3.5 weeks. The AUC calculated for that method was approximately half of that for the 4-week repeated-dosing regimen initiated at 6 weeks of age. These findings suggest that the 4-week RDLMN assay with dosing initiated at age = 6 weeks could be approximately twice as sensitive as the other two methods.

Retrospective evaluation of LCP-tacrolimus (Envarsus XR) dosing in de novo kidney transplant.

INTRODUCTION: Tacrolimus is known to exhibit significant inter- and intra-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability regarding therapeutic response. LCP-tacrolimus (LCPT-Envarsus XR) was approved in 2018 for use as a de novo immunosuppressive agent in kidney transplants, but there is limited evidence to guide de novo dosing of LCPT in patients with obesity. The primary objective of this study was to evaluate the impact of different calculated weight-based de novo LCPT dosing on early transplant outcomes. METHODS: This was a retrospective study of patients with obesity (BMI ≥ 30 kg/m2 ) who received a kidney transplant at the University of Illinois Hospital and Health System (UIH), between March 2019 and March 2021. Subjects were included if were age 18 years or older and received de novo LCPT throughout index hospitalization. The primary endpoint of this study was to compare correlations between the first tacrolimus trough level and dosing weight strategy (e.g., TBW, AdjBW, IBW). RESULTS: There was a statistically significant, though modest, correlation between all three dosing strategies and the first tacrolimus trough level (TBW correlation coefficient = .431, p < .001; AdjBW correlation coefficient = .455, p < .001; IBW correlation coefficient = .465; p < .001). In regression modeling for supratherapeutic levels each additional .01 mg/kg increase in dose by TBW, AdjBW, and IBW increased the odds of a supratherapeutic level by 1.46, 1.34, and 1.24, respectively (p < .001). CONCLUSIONS: The use of LCPT in kidney transplant recipients with obesity dosed using TBW demonstrated the strongest correlation with initial supratherapeutic tacrolimus levels. Larger prospective studies are needed to investigate the further impact of body weight on dosing regimens in the obese population.

Comparison of the Prolonged- and Immediate-Release Tacrolimus Capsule Formulation: The Patient's View and Medication Satisfaction of Patients After Pediatric Heart Transplantation.

BACKGROUND: Medication adherence is essential for long-term success after pediatric organ transplantation. Causes of reduced adherence should be detected early to improve the consequent medication intake. We describe the influence of switching from tacrolimus twice daily (tacrolimus-BID) to tacrolimus once daily (tacrolimus-QD) on medication satisfaction and medication adherence in patients after pediatric heart transplantation. METHODS: A retrospective analysis was conducted regarding patient satisfaction and adherence to the immunosuppressant tacrolimus after pediatric heart transplantation, before and after conversion from tacrolimus-BID to tacrolimus-QD, using questionnaires. RESULTS: Thirty-eight patients were enrolled (tacrolimus-BID: n = 35, mean age 15.7 ± 5.2 years; tacrolimus-QD: n = 38, mean age 16.2 ± 5.6 years). The amount of unadministered medication in the last 3 months did not differ between the 2 pharmaceutical forms. However, 17% (n = 6) reported unstable tacrolimus trough levels when taking tacrolimus-BID, vs 8% (n = 3) under tacrolimus-QD (P = .453). However, there was no statistically significant difference in the stability of the last 6 trough levels of each patient (P = .074). A total of 57% (n = 20) of patients had subjective side effects before conversion, compared to only 29% (n = 11) after conversion (P = .013). Regarding the intensity of the side effects, 6 patients reported strong/very strong side effects when taking tacrolimus-BID vs 1 patient when taking tacrolimus-QD (P = .250). In addition, the overall satisfaction with the immunosuppressant was higher under tacrolimus-QD (92% vs 83%; P = .508). However, this improvement was statistically not significant and may not be clinically relevant. CONCLUSIONS: The amount of forgotten medication was not reduced after conversion from tacrolimus-BID to tacrolimus-QD. However, subjective side effects as well as patient satisfaction improved under tacrolimus-QD.