Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

679 Pharmacokinetics of direct oral anticoagulants in patient with atrial fibrillation and extreme obesity

Aims Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity. Methods and results We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range. A total of 58 patients [mean (SD) age, 70.93 (8.73) years; 40% female] with extreme obesity [mean (SD) body mass index, 44.43 (3.54) kg/m2] and AF while undergoing DOAC treatment was included in the present study. In nine patients (15.5%), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs. 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs. 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges. Conclusions Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.

Validated Simple HPLC-UV Method for Mycophenolic Acid (MPA) Monitoring in Human Plasma. Internal Standardization: Is It Necessary?

The aim of the work was to prepare a simple but reliable HPLC-UV method for the routine monitoring of mycophenolic acid (MPA). Sample preparation was based on plasma protein precipitation with acetonitrile. The isocratic separation of MPA and internal standard (IS) fenbufen was made on Supelcosil LC-CN column (150 × 4.6 mm, 5 µm) using a mobile phase: CH3CN:H2O:0.5M KH2PO4:H3PO4 (260:700:40:0.4, v/v). UV detection was set at 305 nm. The calibration covered the MPA concentration range: 0.1–40 µg/mL. The precision was satisfactory with RSD of 0.97–7.06% for intra-assay and of 1.92–5.15% for inter-assay. The inaccuracy was found between −5.72% and +2.96% (+15.40% at LLOQ) and between −8.82% and +5.31% (+19.00% at LLOQ) for intra- and inter-assay, respectively, fulfilling acceptance criteria. After a two-year period of successful application, the presented method has been retrospectively calibrated using the raw data disregarding the IS in the calculations. The validation and stability parameters were similar for both calculation methods. MPA concentrations were recalculated and compared in 1187 consecutive routine therapeutic drug monitoring (TDM) trough plasma samples from mycophenolate-treated patients. A high agreement (r2 = 0.9931, p < 0.0001) of the results was found. A Bland–Altman test revealed a mean bias of −0.011 μg/mL (95% CI: −0.017; −0.005) comprising −0.14% (95% Cl: −0.39; +0.11), whereas the Passing–Bablok regression was y = 0.986x + 0.014. The presented method can be recommended as an attractive analytical tool for medical (hospital) laboratories equipped with solely basic HPLC apparatus. The procedure can be further simplified by disapplying an internal standard while maintaining appropriate precision and accuracy of measurements.

Influence of CYP2D6 and CYP3A5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Bisoprolol in Hypertensive Chinese Patients

Purpose: This study was performed to investigate the effects of common polymorphisms in CYP2D6 and CYP3A5 on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients.Methods: One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism were genotyped by TaqMan® assay.Results: After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg (P &lt; 0.01) and 6.3 ± 7.6 BPM (P &lt; 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight (P &lt; 0.001) but there was no significant effect of the CYP2D6 and CYP3A5 polymorphisms on these or the trough plasma concentrations. There was no significant association of the CYP2D6 and CYP3A5 polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol.Conclusion: Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in CYP2D6 that were examined and the CYP3A5*3 polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.

Dose-dependent Pharmacological Response to Rituximab in the Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculiti

Objective Rituximab (RTX) is effective in induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV. Methods A prospective cohort of AAV patients (n=28) with either GPA (n=23) or MPA (n=5) receiving maintenance RTX therapy were followed in a single tertiary care academic medical center over a 2-year period. Patient demographics, RTX dosing information, and trough plasma RTX levels were collected along with laboratory measures of pharmacologic response, including B-cell counts and ANCA titers. Results RTX dosing information from 94 infusions with 59 trough samples were collected with a mean±SD dose of 640±221 mg, dosing interval of 210±88 days, and trough plasma RTX concentration of 622±548 ng/mL. RTX trough concentrations were associated with RTX dose (ρ=0.60, p<0.0001) and dosing interval (ρ=-0.55, p<0.0001). RTX dosing intensity (mg/d) was associated with RTX trough concentrations (ρ=0.57, p<0.0001). Higher dosing intensities were associated with undetectable B-cell repopulation (p<0.0001), but not negative ANCA titers (p=0.6). Stratification of dosing intensities based on the standard dosing regimen of 500 mg every six months (2.4 to 3.3 mg/d) demonstrated that this regimen was associated with B-cell repopulation in 8 of 17 doses (47%) compared to 0 of 23 doses (0%) with the high-dose regimen (>3.3 mg/d) (p<0.0001). Conclusion RTX maintenance dosing of 500 mg every six months may be inadequate to maintain B-cell depletion in the treatment of AAV.

High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox–Gastaut syndrome (LGS).Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose.Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p &lt; 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p &lt; 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p &lt; 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders.Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.

Impact of Letermovir Prophylaxis on Voriconazole Exposure in Allogeneic Hematopoietic Cell Transplant Recipients

Introduction: Letermovir is a terminase complex inhibitor that was recently approved for prevention of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (HCT). Its favorable side effect profile makes it an attractive alternative to other anti-CMV agents. Nevertheless, its use may present other challenges secondary to enzyme induction, leading to clinically significant drug-drug interactions. Voriconazole is widely used for prophylaxis against invasive fungal infections in the setting of HCT. By virtue of its hepatic metabolism mediated by CYP2C19, the package insert recommends close monitoring of voriconazole trough concentration when given concomitantly with letermovir. The objective of this study was to characterize the extent of interaction between voriconazole and letermovir in allogeneic HCT recipients. The study was approved by the institutional review board. Methods: Patient selection and data collection: An institutional database was queried to identify patients who underwent allogeneic HCT and received antifungal prophylaxis with voriconazole from November 2018 through July 2020. Per the institutional standard operating procedure (SOP), patients initially received intravenous micafungin 50 mg daily which was switched to voriconazole when oral drug administration became feasible. The voriconazole prophylactic dose was guided by CYP2C19 phenotype. Rapid metabolizers (harboring the gain of function variantCYP2C19*17) received 300 mg twice daily whereas others received 200 mg twice daily. Further dose adjustment was warranted if trough concentration, measured at least 5 days after starting voriconazole, did not fall within target range of 1 to 5.5 mg/L. Patients at risk for CMV reactivation who underwent HCT after SOP revision (November 2019) received prophylaxis with letermovir 480 mg daily on day +6 post HCT. After a retrospective review of electronic medical records, HCT recipients were divided into two cohorts;cohort 1included patients who received letermovir prophylaxis whereascohort 2comprised those who did not. Data extracted from medical records included: demographics, hematological disorder, voriconazole dose and trough concentration, and date of letermovir initiation. Statistical analysis: The Student's t-test was used to compare mean voriconazole trough plasma concentration between cohorts 1 and 2. The chi-squared/Fisher's exact test was used to compare rate of subtherapeutic voriconazole trough concentration. Multivariate logistic regression analysis was performed to determine the association between letermovir use and subtherapeutic voriconazole concentration after adjusting for age, gender, race, weight and voriconazole dose. All statistical analyses were performed in SAS (version 9.4) Results: 64 patients were identified (23 in cohort 1 and 41 in cohort 2). Baseline characteristics were comparable except for age (62.0±8.7 years in cohort 1 vs. 58.0±12.2 years, p=0.01); 39% of patients in cohort 1 and 30% in cohort 2 received voriconazole 300 mg twice daily upfront for prophylaxis due to the rapid CYP2C19 metabolizer phenotype whereas the rest received voriconazole 200 mg twice daily (p=0.6). There was no significant difference in mean voriconazole trough plasma concentration (p=0.5) or frequency of subtherapeutic trough (p=0.16) between cohorts 1 and 2 (Figure 1). Multivariate logistic regression analysis indicated that letermovir prophylaxis had no impact on subtherapeutic voriconazole concentration (OR: 0.4, 95% CI: 0.1-1.4, p=0.1). In the subgroup of patients who received voriconazole at 300 mg twice daily, the rate of subtherapeutic concentration did not differ significantly between cohorts 1 and 2 (p=1.0), whereas a non-significant trend in rate of subtherapeutic voriconazole concentration was noted in subgroup of patients who received the 200 mg dose (p=0.1,Figure 2) Conclusions: Our single center experience suggests there may not be a significant interaction between voriconazole and letermovir. Notably, patients receiving the 300 mg dose upfront may not require an additional dose increase to achieve a voriconazole trough within the recommended range despite the concomitant use of letermovir. Our group is collaborating with other centers to corroborate these findings, particularly in patients receiving the standard voriconazole prophylactic dose of 200 mg. Disclosures Grunwald: Forma Therapeutics:Research Funding;Agios:Consultancy;Abbvie:Consultancy;Trovagene:Consultancy;Daiichi Sankyo:Consultancy;Astellas:Consultancy;Daiichi Sankyo:Consultancy;Trovagene:Consultancy;Trovagene:Consultancy;Premier:Consultancy;Astellas:Consultancy;Astellas:Consultancy;Genentech/Roche:Research Funding;Premier:Consultancy;Genentech/Roche:Research Funding;Genentech/Roche:Research Funding;Premier:Consultancy;Janssen:Research Funding;Merck:Consultancy;Forma Therapeutics:Research Funding;Incyte:Consultancy, Research Funding;Celgene:Consultancy;Incyte:Consultancy, Research Funding;Incyte:Consultancy, Research Funding;Pfizer:Consultancy;Celgene:Consultancy;Celgene:Consultancy;Cardinal Health:Consultancy;Merck:Research Funding;Daiichi Sankyo:Consultancy;Agios:Consultancy;Abbvie:Consultancy;Merck:Consultancy;Amgen:Consultancy;Merck:Consultancy;Amgen:Consultancy;Abbvie:Consultancy;Pfizer:Consultancy;Amgen:Consultancy;Pfizer:Consultancy;Agios:Consultancy;Cardinal Health:Consultancy;Forma Therapeutics:Research Funding;Cardinal Health:Consultancy;Janssen:Research Funding.Ai:Incyte:Speakers Bureau;Celgene:Speakers Bureau.Knight:Foundation for Financial Planning:Research Funding.Chojecki:Incyte:Research Funding;Novartis:Other: Investigator Meeting Attendance.Avalos:Juno:Membership on an entity's Board of Directors or advisory committees;Best Practice-Br Med J:Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia.Copelan:Amgen:Membership on an entity's Board of Directors or advisory committees.

Low Tenofovir Plasma Exposure in HIV Oral Pre-exposure Prophylaxis Recipients with Gastrointestinal Disorders

ABSTRACTFour pre-exposure prophylaxis (PrEP) users with gastrointestinal disorders (sleeve gastrectomy, terminal ileitis, celiac disease, or chronic diarrhea) and receiving oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) were included. Despite self-reported high adherence, trough plasma tenofovir concentrations (after supervised intake) were significantly lower in these patients than in PrEP recipients without gastrointestinal disorders (21 ± 9.1 versus 138 ± 85 ng/ml). PrEP users with gastrointestinal disorders may need increased TDF doses or alternative prophylactic measures.