Target Trough Research Articles

Early acute kidney injury after tacrolimus administration in heart transplant recipients receiving basiliximab induction therapy.

In this study, we aimed to analyze the association among the timing of tacrolimus initiation, time required to reach the target blood concentration, and early acute kidney injury (AKI) after tacrolimus administration in heart transplant recipients who received basiliximab induction therapy. 88 patients treated with tacrolimus-based immunosuppressive therapy were retrospectively reviewed. Induction therapy was administered to 52 patients. AKI was evaluated within 7 days of tacrolimus administration. The rate of increase in tacrolimus trough concentration to the target trough concentration of 10 µg/mL early after its administration was set to be similar in the basiliximab induction and non-induction group; 8 and 2 patients developed AKI in the induction and non-induction group, respectively. In the induction group, there was no significant difference in the timing of tacrolimus initiation and the time required to reach the target concentration between patients who developed and did not develop AKI. In contrast, the cumulative incidence of AKI was significantly different between patients with an estimated glomerular filtration rate below and those with an estimated glomerular filtration rate above 43 mL/min/1.73m2 at the start of tacrolimus administration (37.5% and 11.4%, respectively; p=0.045). In patients receiving basiliximab induction therapy, the timing of tacrolimus initiation and the time to reach the target concentration are unlikely to be associated with early AKI after tacrolimus administration. However, the recovery of sufficient renal function after heart transplantation is important for determining the start time of tacrolimus.

Nuclear Magnetic Resonance-Based Glomerular Filtration Rate Estimation Is More Closely Associated with Serum Vancomycin Target Trough Achievement vs. Serum Creatinine-Based Equations

Nuclear Magnetic Resonance-Based Glomerular Filtration Rate Estimation Is More Closely Associated with Serum Vancomycin Target Trough Achievement vs. Serum Creatinine-Based Equations

Population pharmacokinetic study in children with vascular anomalies: body weight as a key variable in predicting the initial dose and dosing frequency of sirolimus.

The main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus. A PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (C trough) of 5-15ng/mL. In total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16kg, were 4.06L/h (4% relative standard error, RSE) and 155L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08mg/kg/day for BW of <10, 10-20, 20-40, and ≥40kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09mg/kg/day for BW of <10, 10-30, 30-50, and ≥50kg, respectively. Notably, sirolimus C trough could be maintained between 5-15ng/mL across various dosing frequencies based on the recommended dosing regimen. We established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus' guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.

Pharmacokinetic model-based assessment of factor IX prophylaxis treatment regimens in severe hemophilia B

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product’s optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences.

Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study.

The optimal infliximabdose intensification strategy to address loss of response associated with subtherapeutic infliximabtrough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. This pharmacokineticsimulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (<3.00mg/L) trough levels after 30weeks of standard (5mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis >7.50 mg/L, Crohn's disease >9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease >10.10 mg/L) and clinical improvement (ulcerative colitis >3.70 mg/L, Crohn's disease >7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) and intensive (>10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) dosing strategies defined, respectively. The median pre-intensification infliximab trough level was 0.91mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p<0.01). When controlling for cumulative (mg/kg) infliximab dose over 32weeks, strategies that concurrently dose increased and interval shortened achieved the highestinfliximab trough levels (all p<0.01). This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.

Pharmacokinetic/pharmacodynamic analysis of vancomycin in patients with Enterococcus faecium bacteraemia: a retrospective cohort study

ObjectivesThe trough concentration of vancomycin and the area under the concentration–time curve (AUC)/minimum inhibitory concentration (MIC) ratio are crucial in determining vancomycin efficacy against methicillin-resistant Staphylococcus aureus. However, the use...

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). TDM reduced the proportion of patients with subtherapeutic exposure levels by ~50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

O-227 First successful ovary allotransplants to Turner’s syndrome patients requiring immunosuppression

Abstract Study question To determine whether we can safely and successfully transplant an ovary tissue allograft from a non-identical donor to her Turner’s syndrome sister. Summary answer We report the first successful cases (with pregnancy) of ovarian tissue allotransplantation to Turners syndrome women using a safe immunosuppression protocol. What is known already Young women with Turner’s have been unable to have children without the use of donor egg IVF, but many Turner’s women would like to have normal hormonal function and to become pregnant naturally. Frozen ovarian cortex tissue can be successfully auto-transplanted back to women with ovarian failure and result in normal pregnancy and live birth with a success rate of 41-76%. This has never been accomplished between a non-identical donor to her Turner syndrome sister. Added benefits are hormonal function obviates the need for hormone replacement, and pregnancy can occur naturally rather than with donor egg IVF. Study design, size, duration 1.) 20 year-old woman with non-mosaic XO Turner’s, no menses, and AMH (Anti-Mullerian hormone) of 0.015 ng/mL, whose 22 year-old sister had two children, normal menses, and an AMH of 4.97. They were HLA identical but ABO incompatible. 2.) A 21 year-old woman with non-mosaic XO Turner’s, no menses and AMH of 0.015 whose 28 year old sister had 2 children, normal menses, and AMH of 2.92. They were ABO compatible, but one HLA mismatch. Participants/materials, setting, methods The left ovary of the donor was removed and dissected. One third of the cortex was transplanted to the right streak ovary of the recipient and the remaining two-thirds were cryopreserved. The immunosuppression protocol consisted of methylprednisolone the morning of surgery along with anti- thymocyte globulin, and for maintenance, tacrolimus 3 mg orally BID with a target trough of 5-10 ng/mL, azathioprine 100 mg orally, and prednisone only 5 mg po daily. Main results and the role of chance By 168 days post-op the first Turner’s recipient was menstruating and ovulating normally with no sign of rejection. Her AMH began to rise at 168 days from 0.05 to 0.35ng/mL by 223 days, typical for a successful ovary cortical graft, and her FSH varied from 4.5 to 8.5 mIU/mL. By one year her uterus grew from infantile to that of a normal adult and she became spontaneously pregnant 10 months later and delivered a healthy baby. The donor FSH was 6.8 mIU/mL, unchanged from pre-op, she continued menstruating normally, and became spontaneously pregnant with her third child (despite having an IUD in place) by six months post op. The second Turner’s syndrome began menstruating monthly at 4 months post-op, and her AMH rose to 0.25 mg/mL as her FSH dropped to 5.3 mIU/mL. At the time of this writing she is 6.5 months post-op and continues to menstruate and ovulate normally. Limitations, reasons for caution There are only the first two cases and therefore at this stage, the conclusions are only a proof of concept. Wider implications of the findings We have demonstrated successful ovarian tissue transplantation with spontaneous pregnancy to Turner’s syndrome females using a safe immunosuppression protocol. The fact that ABO incompatibility did not cause rejection indicates that an ovary tissue graft can survive on diffusion alone. Furthermore, HLA mismatch does not preclude success with this immunosuppression protocol. Trial registration number not applicable

Association between prolonged vancomycin infusion and trough concentrations in children. Retrospective study.

Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort study included pediatric patients who received vancomycin from June 2017 to June 2020 at a tertiary referral hospital. The patients were divided into two groups according to infusion strategy, the SII (standard intermittent infusion) group and the PI (prolonged infusion) group. Demographic details, infusion period, serum creatinine, duration of vancomycin therapy, trough concentration of vancomycin, and pediatric intensive care unit stay were reviewed. Differences of the concentrations were measured. Results: Sixty-eight patients were included: 31 in the SII group and 37 in the PI group. The trough concentration of vancomycin was significantly higher in the PI group than in SII group (11.2 mg/L [5.9-13.7] vs. 7 mg/L [3.5- 9.3]; p = 0.02). The target attainment rate was higher in the PI group than in the SII group (59.4% and 19.3%, respectively; p = 0.001). There were no significant differences between the SII and PI groups regarding the peak concentrations of vancomycin, final creatinine and peak creatinine. There were no differences between the SII and PI groups regarding the failure events, PICU stay and duration of vancomycin therapy. The multivariable analysis showed that PI was significantly associated with higher trough serum concentrations of vancomycin (OR = 2.27; p = 0.005). Conclusion: Compared to the SII strategy, the PI strategy may be an optimized option to children with severe infection, as it can achieve higher trough concentrations and target concentration attainment.

Evaluation of the appropriateness of vancomycin therapeutic drug monitoring in the intensive care unit with a clinical pharmacy approach, a cross-sectional study

ObjectivesVancomycin, a glycopeptide antibiotic has antibacterial activity against Gram-positive bacteria and is frequently used in the intensive care unit (ICU). Inappropriate therapeutic drug monitoring (TDM) of vancomycin is a common...

Individualized Closed-Loop Acoustic Stimulation Suggests an Alpha Phase Dependence of Sound Evoked and Induced Brain Activity Measured with EEG Recordings.

Following repetitive visual stimulation, post hoc phase analysis finds that visually evoked response magnitudes vary with the cortical alpha oscillation phase that temporally coincides with sensory stimulus. This approach has not successfully revealed an alpha phase dependence for auditory evoked or induced responses. Here, we test the feasibility of tracking alpha with scalp electroencephalogram (EEG) recordings and play sounds phase-locked to individualized alpha phases in real-time using a novel end-point corrected Hilbert transform (ecHT) algorithm implemented on a research device. Based on prior work, we hypothesize that sound-evoked and induced responses vary with the alpha phase at sound onset and the alpha phase that coincides with the early sound-evoked response potential (ERP) measured with EEG. Thus, we use each subject's individualized alpha frequency (IAF) and individual auditory ERP latency to define target trough and peak alpha phases that allow an early component of the auditory ERP to align to the estimated poststimulus peak and trough phases, respectively. With this closed-loop and individualized approach, we find opposing alpha phase-dependent effects on the auditory ERP and alpha oscillations that follow stimulus onset. Trough and peak phase-locked sounds result in distinct evoked and induced post-stimulus alpha level and frequency modulations. Though additional studies are needed to localize the sources underlying these phase-dependent effects, these results suggest a general principle for alpha phase-dependence of sensory processing that includes the auditory system. Moreover, this study demonstrates the feasibility of using individualized neurophysiological indices to deliver automated, closed-loop, phase-locked auditory stimulation.

Treatment of thrombotic cardiovascular diseases in people with haemophilia: A Japanese consensus study.

Cardiovascular diseases (CVD) that require long-term anticoagulant and antiplatelet therapy presents a problem in people with haemophilia (PWH) who receive factor replacement therapy to reduce bleeding risk. Currently, there are no Japanese guidelines for the management of PWH with CVD. To develop expert guidance on managing CVD in PWH in Japan. A steering committee of four experts (two haemophilia specialists, one thrombosis specialist, one cardiologist) identified 44 statements related to five key themes. An online questionnaire was produced comprising a mix of 4-point Likert scale and multiple-choice questions that was sent to specialists in the management of PWH with CVD in Japan. Consensus was defined as high or very high if a respective ≥75% or ≥90% of respondents agreed with a statement. Of 16 potential respondents, responses were received from 15 specialists. Of the Likert scale questions, 71% (29/41) achieved ≥90% agreement (very strong agreement), 17% (7/41) achieved 75%-89% agreement (strong agreement) and 15% (6/41) did not achieve consensus agreement. The three multiple-choice questions failed to identify a strong preference. Agreement on specific target trough clotting factor levels for managing certain clinical situations, such as when in the presence of non-valvular atrial fibrillation or myocardial infarction, was also achieved. The results of this consensus study provide a framework for cardiologists and haematologists to manage PWH who are at risk of, or who have, CVD. Implementation of the recommendations provided herein may improve outcomes for PWH with CVD.

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P &amp;lt; 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

Early Therapeutic Drug Monitoring Optimizes Teicoplanin Use in Febrile Neutropenic Patients with Hematological Malignancies.

A target trough concentration (Cmin) of teicoplanin ≥ 15-20mg/L between the fourth and sixth day has been suggested for severe infections or management of febrile neutropenia (FN). Owing to no reports discussing the impact of early target attainment on treatment outcomes, this study aimed to evaluate the dose-Cmin relationship and clinical outcome and estimate the optimal early target Cmin for FN in patients with hematological malignancies. This single-center, prospective study enrolled patients with hematological malignancies who were treated with teicoplanin either as an empirical antibiotic for FN or as targeted treatment for Gram-positive bacteria. Blood samples were collected on day three (48h) post-loading doses, day5 (96h), and day8 (when applicable) and determined by ultrahigh-pressure liquid chromatography-triple quadruple mass spectrometry. A total of 117 samples from 47 patients with FN (27 men, 20 women) were consecutively analyzed. A two-tailed αvalue of 0.05 was considered statistically significant. The mean Cmin values at 48h, 96h, and on day8 were 23.4, 21.4, and 27.8mg/L, respectively. The patients achieving Cmin ≥ 20mg/L at 48h had a higher likelihood of treatment success. The areas under the receiver operating characteristic curves were 0.71 for clinical efficacy and the cutoff value of Cmin at 48h was 18.85mg/L (95% confidence interval 0.55-0.87; P = 0.018). The Cmin of teicoplanin after completion of loading doses could predict the treatment response, with a target concentration ≥ 18.85mg/L.

Relationships between bronchiectasis and time to achieving target trough immunoglobulin G levels in patients with common variable immunodeficiency.

Background: The main treatment of common variable immunodeficiency (CVID) is to maintain immunoglobulin G (IgG) levels within the target range. However, trough IgG levels differ among patients with similar body mass index (BMI) and those receiving the same dose of immunoglobulin replacement therapy (IGRT). A crucial factor that underlies these differences is the presence of extensive bronchiectasis, which is associated with the immunoglobulin salvage pathway. Objective: We compared trough IgG levels in patients with CVID and with and in those without bronchiectasis who had received the same dose of IGRT for 2 years to determine the association of IgG level with infection frequency. Method: This retrospective cohort study included 61 patients with CVID, of whom 21 had bronchiectasis. We reviewed the electronic records for demographic variables, baseline immunoglobulin levels, mean trough IgG levels over 2 years, efficacy levels (trough IgG level - baseline IgG level), the time interval from treatment initiation to achieving the target trough IgG level (700 mg/dL), and the number of infections. Results: The median age of the patients was 39 years (IQR, 27-51), and 29 were women (47.5%). There were no significant differences between the groups in terms of age, age at diagnosis, delay in diagnosis, sex, BMI, IGRT type (subcutaneous or intravenous), and baseline immunoglobulin levels. Trough IgG and efficacy levels were lower (P < 0.001 and P = 0.016, respectively), the time required to achieve the target IgG level was longer in patients with bronchiectasis than in those without bronchiectasis, and this time interval was significantly associated with the infection frequency. Trough IgG and albumin levels were correlated (p = 0.007), with minor differences between the groups (p = 0.04). Conclusion: Bronchiectasis was significantly associated with a longer time to achieve the target IgG levels. These long-term differences between the patients with and those without bronchiectasis have significant clinical implications.

Population Pharmacokinetics of Lamotrigine and Its N2-Glucuronide Metabolite in Chinese Patients With Epilepsy.

Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy. A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L). For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration. Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens.

Prospective validation of a model-informed precision dosing tool for vancomycin treatment in neonates.

We recruited 48 neonates (50 vancomycin treatment episodes) in a prospective study to validate a model-informed precision dosing (MIPD) software. The initial vancomycin dose was based on a population pharmacokinetic model and adjusted every 36-48 h. Compared with a historical control group of 53 neonates (65 episodes), the achievement of a target trough concentration of 10-15 mg/L improved from 37% in the study to 62% in the MIPD group (P = 0.01), with no difference in side effects.

Therapeutic drug monitoring of vancomycin in surgical patients using a validated HPLC method.

Vancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin. A selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88 : 12 v/v. The separation was carried on C18 column (125 × 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose. The developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by using this method showed that 39 (60%) samples were within the target trough concentration range (TTCR), i.e. 10 - 20 mg/L, while 23 samples (35.4%) were below the TTCR, and 3 samples (4.6%) were above this range. The developed method is sensitive and cost effective for quantification of vancomycin in human plasma. The results of sample analysis shows that the developed method can be used reliably for TDM of vancomycin.

المراقبة الدوائية العلاجية للإنفلاكسيماب في المرضى العراقيين المصابين بمرض كرون

Background: Inflammatory bowel disease (IBD) is a collection of chronic, recurrent inflammatory illnesses of the gastrointestinal system, including Crohn's disease (CD). Infliximab is one of the biological medications used to treat CD. Therapeutic drug monitoring has evolved as a treatment in IBD, aiming to optimize benefit while meeting more demanding, objective end criteria. Objective: To determine the achievement of target trough level (TL), develop anti-drug antibodies (ADAs) to infliximab, assess response to therapy, and study TL relations with different variables. Methods: The present study was cross-sectional and conducted from May 2022 to November 2022. It included 40 CD patients allotted into 2 groups: group 1 patients achieved the TL target, and group 2 patients did not achieve the TL target. Results: Twenty-two patients achieved target TL, while 18 patients did not. Dose escalation is recommended for 11 patients, switching therapy for 15 patients, and continuing the same dosage regimen for 14 patients. In addition, erythrocyte sedimentation rate, C-reactive protein, serum calprotectin and ADAs were significantly lower in patients who achieved target infliximab TL. Only serum calprotectin can be used to predict the achievement of the target TL of infliximab. Conclusions: Therapeutic drug monitoring of infliximab to determine the TL and ADAs can help to explain why some patients do not respond to this drug. Serum calprotectin may be used as a novel marker to predict the TL and response to infliximab.

Abstract 7162: Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients

Abstract Atezolizumab is an anti-PDL1 approved for treating small cell lung cancer and non-small cell lung cancers. A threshold of 6 µg/ml in plasma has been associated with target engagement with Atezolizumab. The extent to which patients could be overexposed with the standard 1200 mg Q3W flat-dosing remains unknown, but several in silico studies have suggested that flat-dosing with immune checkpoint inhibitors could lead to plasma concentrations far above the necessary levels to be efficacious. Here, we monitored Atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels of Atezolizumab. No patient displayed plasma levels below 6 µg/ml. The results showed that the mean trough level after the first course was 78.3 ± 17 µg/ml, i.e., 13 times above the target concentration associated with target engagement. The overall response rate was 55.5%. Low-grade IRAEs was observed in 37% of patients. No severe immune-related toxicities was observed. On univariate analysis, no relationship was found between exposure metrics of Atezolizumab (i.e., Cmin, Cmax, AUC at the first cycle or during the forthcoming courses) and pharmacodynamic endpoints (i.e., efficacy, toxicity). First-line Atezolizumab treatment and treatment for NSCLC were both significantly associated with efficacy on univariate analysis (p=0.0067 and p=0.0497, respectively), but further multivariate analysis did not confirm this relationship (p=0.2465 and p=0.9981). Smoking status was moderately associated with toxicities on univariate analysis (p=0.03), but this effect was not confirmed on further multivariate analysis (p=0.99). None of the other covariates (i.e., age, sex, NLR, number of metastatic sites, associated chemotherapy) were associated with efficacy or toxicity. Further simulations suggested that the dosing interval could be extended from the standard 21 days (i.e., Q3W) to 49 up to 136 days (mean: 85.7 days, i.e., Q12W dosing), while ensuring plasma levels always above the 6 µg/ml target threshold. This observational, real-world study confirms for the first time in real-world patients that the standard 1200 mg Q3W fixed-dose regimen of Atezolizumab results in significant overexposure in plasma. Of note, this overexposure was not associated with increased side-effects. As plasma levels always exceed pharmacologically active concentrations, the inter-individual variability we observed in PK parameters did not impact efficacy and could not explain differences in response. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy, thus lowering drug-cost in the future. Citation Format: Sophie Marolleau, Alice Mogenet, Mourad Hamimed, Clara Boeri, Laurent Greillier, Joseph Ciccolini. Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7162.