Subtherapeutic Trough Research Articles

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.

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients.

Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.

Impact Of Pharmacist Led Therapeutic Drug Monitoring of Vancomycin in Pediatric Cancer Patients

Aim This study aimed to evaluate the dosing regimen and therapeutic drug monitoring of vancomycin in this patient population. Method The study included 100 pediatric patients (3 months to 15 years) with various gram-positive bacterial infections. All patients received the initial vancomycin dose of 15 mg/kg every 6 hours. The researchers evaluated the incidence of achieving desired trough levels with this dosing regimen. Results The results revealed that patients between 1.0 and 5.9 years of age were less likely to achieve the desired trough levels with the initial vancomycin dose. Consequently, dose adjustments were made for patients with sub-therapeutic trough levels. These adjustments involved a 25% increase in the vancomycin dose. Importantly, the study found that the higher vancomycin dosing did not have any harmful effects on kidney function in pediatric patients, and no significant adverse effects were observed. Conclusion The dosing regimen of 15 mg/kg every 6 hours was unlikely to achieve the desired trough concentrations in pediatric patients with complicated infections and oncological diseases. The study recommends dose adjustments for the treatment of different infections in this population to increase the likelihood of reaching therapeutic steady-state concentrations of vancomycin.

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(&amp;lt;3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD &amp;gt;9.7mg/L; UC &amp;gt;7.5mg/L) was the primary outcome, with clinical improvement (CD &amp;gt;7.0mg/L; UC &amp;gt;3.7mg/L) and perianal fistula healing (CD &amp;gt;10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (&amp;gt;10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p&amp;lt;0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p&amp;lt;0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

Implementation of vancomycin AUC/MIC dosing vs traditional trough dosing and incidence of acute kidney injury at a rural community hospital.

Vancomycin treats methicillin-resistant Staphylococcus aureus infections in hospitalized patients, yet nephrotoxicity is a major risk. Dosing based on the ratio of vancomycin 24-hour area under the curve to minimum inhibitory concentration (AUC/MIC) is preferred over a trough-only vancomycin dosing approach to minimize the risk of acute kidney injury (AKI). This study compares the safety of AUC/MIC-guided and trough-only vancomycin dosing at a 255-bed hospital. A retrospective cohort study of adult patients with stable renal function who received at least 3 days of intravenous vancomycin via either AUC/MIC or trough-only dosing was conducted. The primary outcome was AKI occurrence during treatment. Secondary outcomes included the frequencies of therapeutic, subtherapeutic, and supratherapeutic vancomycin troughs. Relative risk calculations were performed for all outcomes. 600 patients from the trough-only group and 561 patients from the AUC/MIC group were included. 121 patients from the trough-only group and 87 patients from the AUC/MIC group experienced AKI during treatment (relative risk [RR], 0.769; 95% CI, 0.599-0.988; P = 0.0397). Compared with the trough-only group, the AUC/MIC group was significantly less likely to have supratherapeutic troughs (RR, 0.703; 95% CI, 0.611-0.809; P < 0.0001) and significantly more likely to have therapeutic troughs (RR, 1.14; 95% CI, 1.069-1.211; P < 0.0001), with no significant between-group difference in subtherapeutic troughs (RR, 1.03; 95% CI, 0.854-1.25; P = 0.74). AUC/MIC dosing was associated with significantly lower risk of AKI, a lower risk of supratherapeutic trough levels, and a higher risk of therapeutic trough levels, with no significant difference in subtherapeutic troughs when compared to trough-only dosing. Limitations of this study included its retrospective nature and reliance on manual chart review.

P23 Benchmarking voriconazole therapeutic drug monitoring in adults and paediatrics

Abstract Background Voriconazole is the first-line agent for invasive aspergillosis and microbiology approved fungal infections. Voriconazole acts as both a substrate/inhibitor of several hepatic cytochrome P450 enzymes and demonstrates non-linear kinetics due to metabolism saturation. Inter-individual variability of voriconazole pharmacokinetics is high.1 Therapeutic drug monitoring (TDM) of trough plasma levels can mitigate treatment failure/toxicity. A therapeutic index between 1 and 5.5 mg/L is aimed for.1 An online protocol directs IV/oral dosing in line with British National Formulary guidance. An audit was conducted to benchmark protocol compliance. Standards Total compliance to the following standards was investigated for all voriconazole prescriptions: (i) suitable indication; (ii) documented stop or review date; (iii) protocol prescribed loading and maintenance dose; (iv) dose adjustment for non-therapeutic voriconazole trough level; and (v) trough sampling between 4 and 7 days since initiation. Methods Retrospective voriconazole dispensing data (April 2020–April 2022) was used to identify treated adult and paediatric patients. Correlating electronic prescribing and medicines administration (ePMA) system data was examined in line with standards. Patients receiving voriconazole prophylaxis or under 7 days total treatment were excluded from data collection. Descriptive statistics were used to describe patient characteristics and compliance with standards. Results In total, 47 patients (31 adults and 16 children) were identified. The IQR of age was 48 years. Total compliance was obtained to standard (ii) only. Overall, 94% of patients’ prescriptions possessed an appropriate indication and 6% were clinically appropriate with unclear documented indications. A total of 66% received protocol directed loading and maintenance doses, 6% were prescribed appropriate loading doses, without maintenance doses, and 28% received an inappropriate loading/maintenance dose. Within 4 to 7 days since treatment initiation, 55% had therapeutic trough levels; 27% had supratherapeutic levels, but only 33% of doses were reduced, whereas when subtherapeutic trough levels were encountered in 18% of cases, 75% of doses were increased. Overall, 47% had plasma trough levels taken within the recommended period; 30% did not have a trough level ordered, whilst the remaining 23% had sampling taken before 4 days or after 7 days. Conclusions Person and system interventions are required to improve pre-/post-prescription standards. Prescriber education focusing on indication documentation and recent patient body weight for dosing is required. Whereas an ePMA prescribing package incorporating protocol guidance, consecutive loading and maintenance doses, plus trough sampling orders should be trialled. Protocol integrated instructions on dosing adjustment as done for other TDM drugs should be explored. Occasional nursing omissions of both 12-hourly loading doses on Day 1 of treatment should be addressed with practice educators. Reliance on an external laboratory and third party to communicate trough sample results was associated with delays. This should be investigated further as a cause of dose adjustment issues. ePMA availability of samples, direct laboratory communication with prescribers/pharmacists and investigations into cost-effectiveness of internal laboratory assays should be considered. Interventions should be agreed with stakeholders and reaudit occur. Earlier sampling and dosing practices better representing local the patient population could be investigated further as part of an antimicrobial stewardship improvement project.

B-329 Comparison Between Trough and AUC Monitoring of MPA in Patients With and Without Organ Transplantation. Influence of the Co-administered Immunosuppressant

Abstract Background Monitoring of mycophenolic acid (MPA) could be performed by measurement of trough concentrations with target therapeutic range of 1.3 to 3.5 mg/L, or by calculation of area under the drug concentration vs time curve (AUC) utilizing 3 or 4 samples within a dosing interval, with a target range of 30 to 60 mg*h/L. AUC is considered more reliable compared to trough levels, and MPA kinetics are dependent on the type of the co-administered calcineurine inhibitor. This study compares trough vs AUC MPA monitoring received alone or in co-administration with Cyclosporine (CsA) or with Tacrolimus (TAC). Methods 77 transplanted patients receiving MPA, 25 of them on CsA, 49 on TAC, and 20 non-transplanted patients on MPA alone, were evaluated more than once, yielding 260 monitoring consults included for assessment: 45 for MPA alone, 108 for MPA combined with CsA, and 117 consults for the MPA combined with TAC. MPA, CsA, and TAC levels were measured by validated LC/MS/MS methods. Validated pharmacokinetic programs for the calculation of MPA AUC were used, adapted to the type of calcineurine inhibitor. Assessment was made by comparison of the distribution and coincidence between trough levels and AUC with respect to the above therapeutic ranges. Results Transplanted patents: when combined with CsA, MPA AUC was in the target range in 61% of cases, under it—in 31%, and in 8%—over it, while trough levels were 52% under, 42.5% within, and 5.5% over the therapeutic range; agreement between trough MPA and MPA AUC was poor—there was coincidence in 37.5% of sub-therapeutic, 63% of therapeutic and 0% of supra-therapeutic ranges, 3 cases were identified with sub-therapeutic trough and supra-therapeutic AUC; when combined with TAC, MPA AUC was in the target range in 63% of cases, under it—in 13%, and in 24%—over it; trough levels being 23% under, 60% within and 17% over the therapeutic range; agreement between trough MPA and MPA AUC was much better, compared to the combination with CsA: there was coincidence in 56% of sub-therapeutic, 84% of therapeutic and 80% of supra-therapeutic ranges. Nevertheless, 1 case was found with sub-therapeutic trough and supra-therapeutic AUC. In non-transplanted patients MPA AUC was in the target range in 47% of cases, under it—in 13%, and in 40%—over it; trough levels being 18% under, 53% within and 29% over the therapeutic range; agreement between trough MPA and MPA AUC showed coincidence in 75% of sub-therapeutic, 75% of therapeutic and 92% of supra-therapeutic ranges. Conclusion This study confirms that MPA AUC is more relevant than trough monitoring for dose individualization. It also shows that MPA trough levels are much more concordant with MPA AUC in non-transplanted patients and in transplanted patients on TAC, while in combination with CsA, discordance remains significant.

Impact of CYP3A5 Genotype on De-novo LCP Tacrolimus Dosing in Kidney Transplantation

The CYP3A5 gene encodes an enzyme called cytochrome P450 3A5, which is involved in the metabolism of many drugs, including tacrolimus. Tacrolimus is an immunosuppressive medication commonly used in kidney transplantation to prevent organ rejection. The CYP3A5 genotype can influence the metabolism and clearance of tacrolimus, leading to variations in the drug levels and response. LCP tac (an extended-release form of tacrolimus) has a recommended starting dose of 0.14 mg/kg/day in kidney transplants. Rao et al assessed the influence of CYP3A5 genotypes on perioperative LCP tac dosing and monitoring in adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured, and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). They concluded that CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers. Pharmacogenet Genomics. 2023 Apr 1;33(3):59-65. doi: 10.1097/FPC.0000000000000494.

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease

PurposeLoss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD.MethodsIn this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR.ResultsFollowing immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68–1.00) for regaining clinical remission, 0.87 (0.71–1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10−4).ConclusionImmunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation.

LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring. This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race. CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

Anticoagulation for mechanical heart valves during pregnancy: A case report and a literature review

Most previous treatment guidelines for pregnant women with mechanical heart valves recommend that low molecular weight heparin (LMWH) should be applied once every 12 hours and only as required to reach peak anti-Xa levels of approximately 1.0 to 1.2 IU/mL, but it is commonly associated with subtherapeutic trough levels, consequently with an inadequate level of anticoagulation. Our case report here together with a literature review suggests that dose-adjusted (Target trough anti-Xa levels of 0.6 to 0.7 IU/mL and with peak anti-Xa levels of around 1.0 to 1.2 IU/mL or < 1.5 IU/mL) LMWH should be given thrice daily throughout pregnancy. In addition, the findings of this rare case indicate that a combination of LMWH and warfarin is effective in the treatment of small thromboses in pregnancy. In the 1st trimester of pregnancy, a 28-year old pregnant female with a mechanical valve had a significant increase in the aortic valve flow rate and suspected mechanical valve thrombosis. The peak velocity of the pregnant female aortic mechanical valve increased, and mechanical valve thrombosis was suspected. We adjusted the enoxaparin sodium dose every 12 hours to 1 injection every 8 hours, with a total daily dose of 160 mL. Based on the original application of LMWH, warfarin (3 mg/day) was recommended. The pregnant woman delivered a live baby by cesarean section, and the peak flow velocity of the mechanical valve in the aortic position was reduced to nearly equivalent to the patient's pre-pregnancy status. The mother and the baby were in good health at the time of discharge. LMWH is administered twice daily, and anti-Xa trough levels are mostly in a subtherapeutic state, which may lead to insufficient anticoagulation and thrombosis. Dose-adjusted LMWH thrice daily throughout pregnancy is the recommended treatment for pregnant women with mechanical heart valves. The combination of LMWH and warfarin exhibited good efficacy for the treatment of small thromboses.

888. A Predictive Model for Subtherapeutic Vancomycin Troughs in Adults

Abstract Background Vancomycin is a first line agent in the treatment of methicillin-resistant Staphylococcus aureus infections. The ability to predict sub-therapeutic troughs would limit potential for development of resistance. The purpose of this study was to develop a predictive model for sub-therapeutic vancomycin troughs in adults. Methods This retrospective cohort study included adults 18 years and older ordered a pharmacy to dose vancomycin consult. Exclusion criteria included patients with cystic fibrosis, pregnancy, no steady-state trough, or required dialysis during therapy. Patients with sub-therapeutic vancomycin troughs (&amp;lt; 10 mg/L) were compared to patients with therapeutic troughs (10-20 mg/L). A K-nearest neighbors (KNN) regression model to predict an initial sub-therapeutic vancomycin level based on age, gender, race, BMI, loading dose, frequency, creatinine clearance, and institutional vancomycin dosing guideline adherence was developed and validated using 10-fold cross validation. The association of vancomycin dosing guideline adherence with initial sub-therapeutic vancomycin trough was evaluated in a multivariable logistic regression model adjusted for age and creatinine clearance. Results A total of 1,615 subjects were included; 494 (30.5%) subjects experienced a sub-therapeutic trough. A KNN regression model to predict an initial sub-therapeutic vancomycin level had an area under the ROC curve of 0.82, and an accuracy of 0.77 (95% CI 0.75-0.79, baseline accuracy 0.69). After adjusting for age and creatinine clearance, guideline dosing adherence was associated with significantly lower odds of an initial sub-therapeutic vancomycin level compared to guideline dosing non-adherence (OR 0.37, 95% CI 0.20-0.66, p-value 0.001). Conclusion A predictive model, based on readily available data points, for an initial sub-therapeutic vancomycin level was reasonably accurate. Adherence to the institutional vancomycin dosing guideline was associated with greater than 60% lower odds of an initial sub-therapeutic vancomycin level. Disclosures All Authors: No reported disclosures.

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India

ObjectivesPosaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. MethodsWe retrospectively analyzed the factors associated with posaconazole levels <1.25 μg/ml in 164 patients receiving the DR tablet for therapeutic purposes. ResultsOf the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. ConclusionThis is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

Vancomycin area under the curve/minimum inhibitory concentration and trough level concordance-evaluation on an urban health unit.

A vancomycin AUC/MIC (area under the curve/minimum inhibitory concentration) of 400-600 mg•h/L is associated with improved clinical outcomes for the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections. Currently, there are still limited studies evaluating the relationship between vancomycin trough and AUC. To evaluate the correlation between vancomycin trough and AUC/MIC and determine if trough-guided monitoring is an adequate predictor of AUC/MIC in the Urban Health population at St Paul's Hospital. This was a retrospective chart review of 29 patients from November 2019 to February 2021. Patient demographics and laboratory data were collected from electronic medical records. The two-level equation-based approach was used to calculate AUC/MIC. The proportion of AUC/MIC values within target (400-600 mg•h/L) despite subtherapeutic troughs, and the proportion of AUC/MIC values supratherapeutic when trough is within target (15-20 mg/L) were the primary endpoints. Fifty-seven sets of levels were collected and 75% of vancomycin troughs and AUC24 were found to be discordant. When trough was 10-14.9 mg/L, AUC24 was > 400 mg•h/L in 94% of cases and when trough was 15-20 mg/L, AUC24 was > 600 mg•h/L in 69% of cases. There was a moderate correlation between vancomycin trough and AUC24h (R 2 = 0.57; p < 0.001). A vancomycin trough between 15 and 20 mg/L may result in an AUC/MIC greater than necessary for clinical efficacy. Considering these findings and the practical concerns of AUC-guided monitoring, a modest reduction in target troughs to prevent vancomycin toxicity warrants clinical consideration and further evaluation.

1096. Evaluation of Vancomycin Pharmacokinetics in Intravenous Drug Users

BackgroundPeople who inject illicit drugs (PWID) are 16 times more likely to develop methicillin-resistant Staphylococcus aureus (MRSA) infections including severe infections like bacteremia and endocarditis. Vancomycin is recommended as the drug of choice for empiric and targeted coverage in both severe and non-severe MRSA infections. Pharmacokinetic literature has suggested up to 31% higher renal clearance in intravenous drug users (IVDU) compared to non-IVDUs. This increased clearance may theoretically lead to more frequent sub-therapeutic troughs in otherwise standard dosing schemes. There is a paucity of data examining vancomycin pharmacokinetics following typical dosing schemes in IVDU population.MethodsThis was a single-center, retrospective chart review that examined therapeutic drug monitoring in patients treated with vancomycin between January 1st, 2015 through July 31st, 2020. Patients were identified as either IVDU or non-IVUD groups based on ICD-9/10 codes. The primary outcome was the difference between mean first vancomycin steady state troughs. Secondary outcomes were differences in time to first therapeutic trough, mean number of days on vancomycin based on infection, rate of acute kidney injury (AKI) after vancomycin, and rate of vancomycin failure.ResultsA total of 158 patients were included in the analysis (77 IVDU vs. 81 non-IVDU). Mean first vancomycin steady state trough were significantly less in IVDU group compared to non-IVDU group (11.85 vs. 13.98 mcg/mL P = 0.007). Mean time to first therapeutic trough and mean number of days treated were significantly higher in IVDU versus non-IVDR samples (65.9 vs. 50.2 hours P = 0.044 and 5.4 vs. 12.3 days P = 0.017, respectively). There was no detectable difference in rates of AKI and vancomycin failure.Primary outcome graph for patients with IV drug use Primary outcome graph for patients without IV drug use ConclusionVancomycin use in patients with IVDU resulted in significantly lower steady state troughs compared to patients who were non-IVDU. These patients also had a longer time to first therapeutic trough. Patient populations who are IVDU may require additional consideration as a special population for future development of vancomycin pharmacokinetic models.Disclosures All Authors: No reported disclosures

P022 Biologic Therapy and Therapeutic Drug Monitoring in Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). Patients with concomitant PSC-IBD are at higher risk for IBD-related complications including dysplasia and malignancy, however the typical clinical IBD course is less severe. The aim of this study was to identify the prevalence of biologic use and therapeutic drug monitoring (TDM) in a cohort of PSC-IBD patients. Retrospective analysis of patients with PSC-IBD on biologic therapy who underwent TDM from Jan. 2018 to Aug. 2020 at the University of Virginia. Demographic data including age, disease duration, and comorbidities were recorded. IBD categorizations were recorded according to the Montreal Classification. Treatment outcomes including therapy changes after TDM were obtained. A total of 157 patients with PSC-IBD were identified. Of these, 29 patients (19%) were treated with biologic therapy during the study period. 13 patients underwent reactive TDM due to primary or secondary loss of response and one patient underwent proactive TDM during the study period. Median duration of IBD in this group was 9 years, and the median duration of concomitant PSC-IBD was 5.8 years. 20 TDM tests were obtained in these 14 total patients. Sub-therapeutic drug levels were found in 12 tests among 8 patients, and 3 showed detectable anti-drug antibodies. 8 showed appropriate trough levels. TDM resulted in a change to IBD therapy (i.e., dose escalation, change in biologic therapy used, or addition of IBD medication) in 17 out of 20 tests. Herein we describe epidemiologic data of biologic use in PSC-IBD patients at an academic center. PSC-IBD classically follows a less severe clinical presentation and course. However, our study demonstrates that a subset of PSC-IBD patients exist which require biologic therapy and follow a more refractory clinical trajectory. In this subset, TDM showed a high incidence of sub-therapeutic trough levels and anti-drug antibodies, leading to a change in therapy in 85% of TDM instances. Larger studies are recommended to better understand this unique subset of PSC-IBD patients.

Levels of Biosimilar Infliximab during and after Induction Treatment in Crohn's Disease and Ulcerative Colitis-A Prospective Polish Population Study.

Background: Primary lack or secondary loss of response to therapy with infliximab is a significant problem. This study aimed to evaluate the response to treatment in patients with Crohn’s disease (CD) and ulcerative colitis (UC) achieving therapeutic and sub-therapeutic trough levels of biosimilar infliximab (CT-P13). Results: A total of 65 patients (32 with CD and 33 with UC) were recruited. The overall response rate in both CD and UC patients exceeded 80%. There were no significant differences in treatment response and CT-P13 levels for patients with CD or UC. We did not find significant differences in the percentage of patients achieving drug levels of 3 μg/mL at week 6, 10, or 12; a significant decrease was observed at week 14. Up to 55.5% of patients with CD and 64.3% of patients with UC with sub-therapeutic CT-P13 levels at week 14 primarily responded to treatment. Conclusions: Intermediate measurements of drug levels at weeks 10 and 12 did not capture any pronounced decrease in infliximab concentrations below therapeutic levels in either group, thus suggesting no clinical usefulness. A significant percentage of patients primarily responded to treatment despite sub-therapeutic drug levels after the induction phase.

The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

BackgroundGanciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker.Case presentationWe report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0–12 h was measured at 51 μg h/mL, which was within the therapeutic range (40–60 μg h/mL). Afterward, viral load decreased and became undetectable.ConclusionsThis case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

P530 Proactive therapeutic drug monitoring of anti-TNF agents is associated with higher mucosal healing rates in Crohn’s disease

Abstract Background Reactive therapeutic drug monitoring (TDM) is routinely used in managing secondary loss of response to anti-TNF agents. Proactive TDM use has been associated with better clinical outcomes but its use in routine practice is still controversial. We aimed to investigate whether using proactive TDM strategy will result in higher mucosal healing and clinical remission rates. Methods After review of electronic case files, all patients that received anti-TNF treatment for active disease from 01.01.2017-01.02.2021. and responded to induction were included. Patients starting treatment for postoperative prophylaxis were excluded from the study. In the proactive group TDM was performed in week 14 and patients with subtherapeutic trough levels were dose optimized and underwent subsequent TDM measurments until the target trough level was reached. In the reactive group TDM was performed in the case of loss of response. Mucosal healing was defined as SES CD 3 for patients with CD and Mayo endoscopic score of £ 1 for UC patients. Clinical remission after 52 weeks was defined by the attending physician. Results A total of 161 IBD patients were included, 109 patients with CD and 52 patients with UC. There were 69 patients in the proactive group and 92 patients in the reactive group. No significant difference regarding age at diagnosis, age at treatment initiation, disease duration , prior immunomodulator use and time do endoscopy was observed between groups. A higher proportion of patients in the proactive group achieved mucosal healing but the difference between groups was not significant in the total cohort (proactive 52.4% vs reactive 42.2%; p=0.250). A significantly higher proportion of CD patients (n=109) in the proactive group achieved mucosal healing compared to the reactive group (56.8% vs 34.8%; p=0.039). No significant difference in mucosal healing rates between the groups was observed in UC cases. No significant difference in clinical remission rates was observed between the proactive and reactive group in the total cohort, CD and UC patients respectively. Conclusion Proactive TDM strategy is a valuable tool in managing CD patients resluting in higher rates of mucosal healing. Further studies are needed to define the optimal timepoints for proactive TDM.

Retroperitoneal fibrosis as a postoperative complication following renal transplantation in cats.

The aim of this report was to describe the clinical signs, diagnostic imaging findings, surgical management, histopathological findings, outcome and possible risk factors for cats that developed retroperitoneal fibrosis (RPF) following renal transplantation. Medical records of cats that underwent renal transplantation and developed clinically significant RPF between 1995 and 2019 were reviewed. Eighty-one cats underwent 83 renal transplantations. Of these 81 cats, six developed clinically significant RPF. For all six cats, renal transplantation was performed using cold organ preservation solution and ureteral papilla implantation. Immunosuppression protocol included ciclosporin and prednisolone. All cats had at least one subtherapeutic trough ciclosporin level (<250 ng/ml) in the postoperative period. Cats presented with moderate-to-severe azotemia 39-210 days following renal transplantation. Abdominal ultrasonography and contrast pyelography revealed various degrees of hydroureter and hydronephrosis of the transplanted kidney. Surgical examination revealed a layer of dense fibrous tissue surrounding the transplanted kidney, ureter and bladder resulting in ureteral obstruction. Ureteral obstruction was managed by reimplantation of the proximal ureter or renal pelvis to the bladder. Histopathologic examination of the fibrous tissue and affected portion of the distal ureter revealed fibrous connective tissue with lymphoplasmacytic infiltration and perivascular inflammation suggestive of an autoimmune type reaction. Of the six cats, two died within 5 days after revision surgery, two developed signs consistent with recurrent partial ureteral obstruction (40 and 41 days after revision), one was euthanized 6 years later for an unrelated disease and one was lost to follow-up. The incidence of RPF in this population of cats was relatively low (7%), but still represents a significant cause of morbidity and mortality. The cause of RPF remains unknown, although investigation into suboptimal immunosuppression as a potential cause for local rejection reaction is warranted.