Median Total Daily Dose Research Articles

Automated insulin delivery systems in elderly patients with brittle type 2 diabetes

PurposeGeriatric diabetes is complicated by the frailty of this population, and hypoglycemia with insulin is not uncommon in these patients. Automated Insulin Delivery (AID) systems may provide better glycemic control in elderly patients with brittle type 2 diabetes. MethodsThirty-four patients (≥ 60 years) including cancer patients with brittle diabetes were switched to an AID system from multiple-dose insulin (MDI) treatment. HbA1c level, weight, total daily insulin requirement, and C-peptide, creatinine, and lipids were followed for at least six months. ResultsThere were 34 patients (14 male, 41.2 %) with a median age of 67 (IQR 63.0–75.5). Six patients (17.6 %) were on chemotherapy and/or steroids (Ch/S). The patients’ initial median HbA1c % was 9.3 (IQR 7.6–11.0), c-peptide level was 0.9 (IQR 0.5–2.2) ng/mL, and median total daily insulin dose was 41 IU (IQR 32–53).Six months after the patients were switched to an AID system their HbA1c % decreased to 7.1 (IQR 6.5–8.1), p < 0.001 and c-peptide increased to 1.21 (IQR 0.2–1.7) ng/mL, p = 0.878. Total insulin dose decreased with AID systems [32 IU (IQR 23.9–37.8)), p < 0.001].There was a decrease in median HbA1c % in patients on Ch/S [8.7 (IQR 7.0–11.5) to 6.9 (IQR 6.3–9.2)] however it didn’t reach statistical significance p = 0.225. Total insulin dose also decreased without statistical significance [33 IU (IQR 41–28) to 28 (IQR 23–35), p = 0.173].The mean time in range (TIR) percent of the patients with AID systems were as follows; <54 mg/dL was 0.5 %, 56–70 mg/dL was 1.3 %, 70–180 mg/dL was 64.8 %, >180 mg/dL was 26.7 % and > 250 mg/dL was 6.7 %. ConclusionAlthough AID systems are tested mostly in young type 1 patients our results show that elderly patients with brittle type 2 diabetes also benefit from an AID system. Even in very frail patients such as cancer patients, improvement can be seen.

Effect of letermovir initiation on tacrolimus concentrations among lung transplant recipients receiving concomitant azole antifungal prophylaxis.

The antiviral letermovir has been increasingly used as off-label cytomegalovirus prophylaxis in solid organ transplant recipients. Observational studies have reported notable increases in tacrolimus (FK) exposure following letermovir; however, whether a significant interaction occurs in the setting of existing moderate-to-strong CYP3A4 inhibition is unknown. Therefore, the purpose of this study was to evaluate FK trough changes before and after letermovir among lung transplant recipients receiving azole antifungal prophylaxis. This retrospective cohort study included lung transplant recipients newly initiated on letermovir between 2019-2022 following valganciclovir intolerance. Tacrolimus doses and concentrations were collected up to 30 days before and after the letermovir start date. No pre-emptive FK dose adjustments occurred prior to letermovir initiation. Patients admitted to the hospital or lacking an appropriately timed trough in the pre- or post-period were excluded. A total of 78 lung transplant recipients receiving FK (1.5mg median total daily dose) and itraconazole (56.4%), isavuconazole (25.6%) or posaconazole (17.9%) prophylaxis were included. Letermovir was started at a median of 8.4 months post-transplant. The pre-/post-letermovir median FK trough was 9.6/9.0ng/mL (p = .151), median dose-corrected trough was 4.2/4.7ng/mL/mg (+11.9%, p = .032), and median weight-based dose-corrected trough was 362/326 [ng/mL]/[mg/kg/day] (-9.9%, p = .036). There was no significant difference in the proportion of patients within their goal trough range before and after letermovir initiation (62%vs. 72%, p = .229). Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate-to-strong CYP3A4 inhibitors.

Evaluation of Continuous Infusion Vancomycin in a Pediatric Hematology/Oncology Population.

Continuous infusion vancomycin (CIV) may benefit children who are unable to achieve therapeutic concentrations with intermittent vancomycin dosing and may facilitate outpatient administration by alleviating the burden of frequent dosing intervals. Previous studies have used variable dosing regimens and steady-state concentration goals. The purpose of this study was to evaluate the total daily dose (TDD) of CIV required to achieve therapeutic steady-state concentrations of 15-25 µg/mL in pediatric hematology/oncology patients. A single-center retrospective study was performed for patients treated with CIV from January 2017 to June 2019. The primary outcome was the TDD required to achieve therapeutic steady-state concentrations on CIV. Secondary outcomes included time to reach therapeutic steady-state concentrations, CIV indications and adverse events associated with CIV. Data were collected for 71 courses of CIV in 60 patients. Median patient age was 4 years (range: 0.4-20 years). The median TDD required to achieve initial therapeutic concentrations was 50.3 mg/kg/d (interquartile range: 38.8-59.2) and was further divided into age-based cohorts. TDD in mg/kg was significantly lower in the older cohort ( P < 0.001), but there was no statistically significant difference between age-based cohorts with TDD in mg/m 2 ( P = 0.97). Median time to achieve first therapeutic concentration was 19.3 hours (range: 8.6-72.3 hours). The most common indication for CIV was ease of outpatient administration (69.0%). Acute kidney injury incidence was minimal (4.2%). CIV is associated with rapid attainment of target concentrations in pediatric hematology/oncology patients and is safe and well tolerated.

Characterising approaches to steroid therapy in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2.

We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and examine the association between steroid therapy and key clinical markers of severity. We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS-TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo-pituitary-adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2 /day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2 /day (interquartile range 232.5-355.5) and treatment length of 26.0 days (interquartile range 19.0-32.0). Dosing regimens predominantly involved a short course of high-dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). Prolonged, high-dose steroid therapy is often used in the management of severe PIMS-TS with the potential for HPA axis suppression and should be withdrawn carefully.

A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years.

Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented. A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics. Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed. 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]) and polypharmacy (mean 6.26 medications [SD 4.61]) were included in this analysis. Clinical indications were for: chronic pain (71.9%), psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. 37.3% experienced treatment related adverse events. These were graded mild (67%), moderate (31%), severe (<2%, n = 23) and two (0.1%) serious adverse events. Statistically significant improvements at a p value of <0.001 across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: physical function, 34.4%: emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years (p = 0.481). Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was significant improvement (p<0.001) across all measured clinical outcomes over two years. Results are subject to limitations of Real World Data (RWD) for causation and generalisability. Future high quality randomised controlled trials are awaited.

MPN-141 Retrospective Comparison of Patient Outcomes on Pacritinib Versus Ruxolitinib in Patients With Myelofibrosis and Thrombocytopenia.

Pacritinib (PAC) is a JAK2/IRAK1 inhibitor for patients with myelofibrosis (MF) and thrombocytopenia. Unlike the JAK1/2 inhibitor ruxolitinib (RUX), which is used at lower doses in patients with thrombocytopenia, PAC has been studied at full dose regardless of platelet count. This analysis focused on PERSIST-2 patients with platelet counts ≤100 × 109/L who were randomized to PAC 200mg BID and patients who received RUX on best available therapy (BAT) prior to week 24. Endpoints included percent of patients with 35% spleen volume reduction (SVR), 50% modified total symptom score (mTSS) reduction (based on early satiety, abdominal discomfort, night sweats, itching, bone pain, and rib pain), and improvement in disease symptoms measured by Patient Global Impression of Change (PGIC). Safety analyses were based on all treated patients; efficacy analyses were based on the intention-to-treat population randomized at least 22 weeks prior to study end. The Fisher Exact test was used to describe differences in response. Logistic and Cox regression was used to adjust for differences in baseline characteristics. Safety analysis included 106 patients on PAC and 44 on RUX; efficacy analysis included 74 on PAC and 32 on RUX (median total daily dose 10 mg). Baseline characteristics were similar between groups, including median platelet count (55 vs 61 × 109/L) and percent receiving RBC transfusion (46% vs 43%). Patients treated with PAC vs RUX achieved higher rates of SVR (22% vs 3%, p=0.02) and numerically higher rates of mTSS response (35% vs 19%; p=0.11) and "much" or "very much" improved symptoms (35% vs 16%, p=0.06) at week 24. Among RUX patients with an available PGIC measure at week 24, 50% reported either no improvement or worsening symptoms, while 76% of PAC patients reported improvement. The adjusted hazard ratio on PAC vs RUX was 0.46 [95% CI: 0.15-1.43]. Bleeding occurred at similar rates (43% vs 41%) on PAC vs RUX. Fatal AEs occurred in 8% on PAC compared to 11% on RUX. PAC yielded higher response rates and a similar safety profile to lower-dose RUX in patients with MF who have moderate or severe thrombocytopenia. This study was supported by CTI BioPharma.

Pre- and peri-operative characteristics, complications and outcomes of patients with biochemically silent pheochromocytomas; a case series.

Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers. Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded. Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression. The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable.

Do buprenorphine doses and ratios matter in medication assisted treatment adherence.

IntroductionBuprenorphine (BUP), generally prescribed as buprenorphine/naloxone, is a key component of medication-assisted treatment (MAT) to manage opioid use disorder. Studies suggest higher doses of BUP increase treatment adherence. Routine urine drug screens (UDS) assist in monitoring MAT adherence via measurement of excreted BUP and its metabolite, norbuprenorphine (NBP). The clinical significance between BUP/NBP concentrations and their ratios for assessing adherence and substance use is not well-described.MethodsWe conducted a single-center, retrospective chart review of 195 clients age ≥18 years enrolled in a local MAT program from August 2017 to February 2021. Demographics, BUP doses, prescription history, and UDS results were collected. Participants were divided based on MAT adherence (<80% vs ≥80%) and median total daily dose (TDD) of BUP (≥16 mg vs <16 mg) in addition to pre- and post-COVID-19 cohorts.ResultsMedian BUP/NBP urinary concentrations were significantly correlated with MAT adherence (P < .0001 for each) and a reduced percentage of positive UDS for opioids (P = .0004 and P < .0001, respectively) but not their ratios. Median TDD of BUP ≥16 mg (n = 126) vs <16 mg (n = 68) was not correlated with MAT adherence (P = .107) or incidence of nonprescription use (P = .117). A significantly higher incidence of UDS positive for opiates (P = .049) and alcohol (P = .035) was observed post-COVID-19.DiscussionClients appearing adherent to MAT who had higher concentrations of urinary BUP/NBP demonstrated a reduced incidence of opioid-positive UDS independent of the BUP dose prescribed. An increase in opioid- and alcohol-positive UDSs were observed during the COVID-19 pandemic.

Tacrolimus dose adjustment is not necessary in dose to dose conversion from a twice daily to a prolonged release once daily dose form

Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration–time curve (AUC) 0–24 and Ctrough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9–1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m2. The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91–1.04). The geometric means (%CV) of Ctrough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of Ctrough was 0.89 (90%CI 0.82–0.98), which was below 0.9. The newly calculated target Ctrough level of OD TAC was 4.8–6.2 ng/mL. The best abbreviated AUC0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) − 4.26. The GMR AUC0-24 was within the range of 0.9–1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of Ctrough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC0-24 regardless of CYP3A5 genotypic polymorphism. However, the Ctrough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).

When There Is No Trough: Use and Outcomes of Continuous-Infusion Vancomycin at a Free-Standing Children's Hospital.

There is minimal published literature regarding the use of continuous-infusion vancomycin (CIV) in children. The objective of this study was to describe the use, dosing requirements, and outcomes of CIV at a free-standing children's hospital. This is a retrospective review of patients who received CIV while admitted to Nationwide Children's Hospital between July 1, 2010, and June 30, 2020. The total daily dose (TDD) of vancomycin required to attain a target serum vancomycin concentration (SVC) was compared between CIV and intermittent-infusion vancomycin (IIV) administration regimens. Safety outcomes and treatment failure were also explored. Fourteen patients (77% male) with a median age of 7 years (IQR = 1, 10 years) were included. Most patients (71%) were started on CIV in anticipation of outpatient parenteral antimicrobial therapy. The median TDD required to achieve a target SVC was higher with IIV compared with CIV (82.4 mg/kg/day vs 50.5 mg/kg/day; p = 0.02). Despite higher TDD with IIV, median SVC with IIV was similar to SVC with CIV (16.6 mg/L vs 17.6 mg/L; p = 2.00). There were no safety concerns or therapeutic failures identified with CIV. Continuous-infusion vancomycin was a well-tolerated and effective alternative to IIV for the patients included in this study. The TDD of vancomycin required to achieve a target SVC was lower in patients receiving CIV compared with those receiving IIV.

A Retrospective Cohort Evaluation of a Pharmacist-Led Approach for Transitioning Patients to an Angiotensin Receptor—Neprilysin Inhibitor

Background: Heart failure guidelines recommend replacing an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) with an angiotensin receptor neprilysin inhibitor (ARNI) to reduce morbidity and mortality in NYHA Class II–III patients with reduced ejection fraction (HFrEF). Objective: This study aims to determine if a pharmacist-led outpatient ARNI replacement and titration program led to more patients achieving target doses of ARNI compared to usual care. Methods: A single health system, retrospective electronic medical record review identified 791 patients with active ARNI prescriptions and at least two outpatient cardiology visits with a pharmacist or usual care provider between January 2015 through September 2018. The primary outcome was the percentage of patients who achieved a target ARNI dose of 97/103 mg twice daily. The secondary outcomes were the median dose achieved, number of visits required to achieve target dose, hospitalizations, and all-cause death. Results: ARNI was initiated and continued by a pharmacist in 64 patients and 727 by usual care. More patients in the pharmacist group, 60.9% (n = 39), achieved target dose vs. 18.0% (n = 131) of patients managed by usual care (95% CI, 0.31–0.55, p < 0.0001). The pharmacist group also had higher median total daily dose of ARNI (200 mg (IQR = 300) vs 100 mg (IQR = 100), p < 0.0001) and more likely to achieve a higher total daily dose in fewer visits. Conclusions: An advanced practice provider pharmacist-led outpatient ARNI replacement and titration program was more effective in achieving target doses of ARNI in HFrEF patients as compared to usual care.

Transdermal buprenorphine for in-hospital transition from full agonist opioids to sublingual buprenorphine: a retrospective observational cohort study

Introduction Patients with opioid use disorder may have difficulty transitioning from full-agonist opioids to sublingual buprenorphine due to the risk of precipitated opioid withdrawal. Novel strategies have been developed to facilitate this transition, including the use of micro-dosing with transdermal buprenorphine. We began using a transdermal buprenorphine transition strategy at our hospital in 2019. Methods We performed a retrospective observational cohort study of patients treated with transdermal buprenorphine to facilitate transition from full-agonist opioids (prescribed or recreational) while hospitalized between January 2019 and December 2020. Patients were excluded if transdermal buprenorphine was given for pain, if they did not receive at least one dose of sublingual buprenorphine while hospitalized, or if their clinical course precluded analysis of their tolerance of the transition protocol. Data on the doses and timing of medications, symptoms during transition, and hospital outcomes were abstracted from the electronic medical record. Results We identified 41 cases that satisfied inclusion and exclusion criteria. Thirty-five cases involved a transition from medically indicated opioids; of these, 8 cases involved a transition from methadone. Six cases involved a transition from illicit opioids used prior to hospital presentation. For patient transitioning from medically indicated opioids, the median milligram morphine equivalent (MME) on the day prior to transdermal buprenorphine application was 63.8 (range 0-900, IQR 153.8) and the median MME on the day of transdermal buprenorphine application was 34.5 (range 0-600, IQR 65.3). The median initial dose of sublingual buprenorphine administered was 8 mg (range 2-8mg, IQR 6mg), the median total first-day dose was 16mg (range 2-24mg, IQR 16mg), and the median total daily dose on the last day of follow-up was 16mg (range 2-24mg, IQR 16mg). In 38 cases, patients completed the transition to sublingual buprenorphine and were still taking buprenorphine at the time they left the hospital. The transition protocol was fairly well-tolerated, with 59% of cases tolerating it well and 32% tolerating it fairly. Discussion Our findings suggest that the use of transdermal buprenorphine to facilitate transition to sublingual buprenorphine is generally well-tolerated, and may be helpful in hospitalized patients. We identified several areas for improvement in future practice by reviewing the clinical courses of patients who tolerated transition poorly. Limitations of the study include its retrospective chart review design, the lack of a standardized transition protocol during the study period, and the lack of standardized data in the medical record regarding patients' tolerance of the transition protocol. Future research should include prospective studies using a standardized protocol and structured, pre-planned assessments of opioid withdrawal during the transition period. Conclusion The use of transdermal buprenorphine to facilitate induction of sublingual buprenorphine therapy in hospitalized patients with OUD was generally well-tolerated in this single-center retrospective observational study. Further prospective research is needed to demonstrate efficacy and optimize treatment protocols.

Assessment-of-vancomycin-pharmacokinetic-parameters-among-malaysian-adult-patients-in-penang-with-different-kidney-functions

Introduction: Vancomycin is indicated for highly resistant gram-positive systemic infections. The targeted trough and 24-hour area under the concentration-time curve (AUC24) level of vancomycin must be achieved for efficacy and safety. Local population-based pharmacokinetic parameters including the elimination rate constant (Ke), half-life (t1/2), volume of distribution (Vd) and vancomycin clearance (Clvanco) can allow better vancomycin dosing determination. Objective: This study aims to determine the pharmacokinetic parameters in the Malaysian adult patients in Penang based on different kidney functions. Method: This was a retrospective, single-centered study conducted in the Clinical Pharmacokinetics Department, Penang General Hospital from 1 January 2016 to 31 December 2017. This study included adult patients who had been treated with intravenous vancomycin under therapeutic drug monitoring. The patients’ personalised vancomycin pharmacokinetic parameters were determined using a series of pharmacokinetic equations. Result: From the recruited 26 patients, 73.1% were male and 46.2% were above 50 years old. A total of 34.6% patients had the actual body weight / ideal body weight ratio of more than 1.0. The median total daily dose was 34.72 mg / kg. The median for Cmax (peak serum concentration) was 26.0 mg /L while Cmin (trough serum concentration) was 14.20 mg / L. The median for AUC24 is 412.08 mg*hr / L. The overall median for Ke and t1/2 were 0.091 hr-1 and 7.62 hours, respectively. The median Vd was 0.90 L / kg. It was found that with increasing creatinine clearance, the Ke and Vd increased while the t1/2 decreased. Conclusion: The vancomycin pharmacokinetic data from this study varied according to different degree of creatinine clearances.

1108. Evaluation of Vancomycin Dosing in Adolescents

BackgroundPediatric vancomycin dosing varies based on age and renal function. Recent literature suggests previously recommended doses of 45-60 mg/kg/day may be insufficient to achieve an AUC:MIC ratio of 400-600 mg-hr/L and higher doses of at least 60 mg/kg/day may be required. However, data to guide dosing in adolescents is limited. MethodsA single-center, retrospective chart review of patients aged 12 to 18 years who received vancomycin and had therapeutic drug monitoring (TDM) performed between July 2017 to June 2020 were included. The primary endpoint was the median total daily dose (TDD) of vancomycin required to achieve therapeutic serum concentrations. Secondary endpoints were to characterize how factors such as age, weight, trough versus AUC monitoring, malignancy, and trauma may influence dosing. The safety endpoint was the development of acute kidney injury (AKI).Results130 vancomycin courses in 86 patients were included. Baseline characteristics are presented in Table 1. Of the 130 vancomycin courses, 50 courses (38%) achieved therapeutic serum concentrations at a median TDD of 49.8 mg/kg/day (IQR 42 – 59.4). This was not statistically different from the sub- or supra-therapeutic groups (p=0.22). Based on age, the median TDD for 12-14 year olds was higher at 60 mg/kg/day (IQR 45-78.8; n=14) than for 15-16 and 17-18 year olds [45.3 mg/kg/day (IQR 41.1-51; n=15), 48 mg/kg/day (IQR 42-52; n=21), respectively]. Obese patients needed a median TDD of 43.5 mg/kg/day vs at least 51 mg/kg/day in healthy and overweight patients. Finally, AUC guided dosing resulted in a slightly lower overall median TDD vs trough guided dosing (45.8 mg/kg/day vs 50.5 mg/kg/day). Additional dose requirements based on age, weight, TDM and other characteristics are presented in Table 2. Of the 15 patients who developed AKI per pRIFILE criteria, 2 were classified as injury and 3 as failure.Table 2. Total Daily Dose Course Analysis ConclusionTo achieve therapeutic levels, adolescents 12 to14 years old need higher empiric doses of 60 mg/kg/day compared to 45 mg/kg/day in 15 to 18 year olds. Obese patients, however, may require lower TDD than underweight, healthy, and overweight patients. Patients that receive AUC versus trough monitoring may also require lower TDD to achieve therapeutic concentrations. More data is needed to further evaluate our findings.Disclosures All Authors: No reported disclosures

1102. Evaluation of Vancomycin Accumulation in Patients with Obesity

BackgroundCurrent vancomycin guidelines recommend using actual body weight for dosing. However, in patients with obesity, this may result in lower initial vancomycin concentrations that can accumulate with continued doses due to differences in volume of distribution. The objective of this study is to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation.MethodsThis is a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a BMI ≥ 30 kg/m2 and with ≥ 2 vancomycin serum trough concentrations within the same encounter in 2019 were screened. Patients were excluded if they were pregnant, had unstable renal function or severe renal impairment, received < 3 doses before a concentration was drawn, or had inconsistent dosing prior to a concentration draw. Linear kinetics were used to correct for differences in timing of concentration or dose changes. The major endpoint was the incidence of vancomycin accumulation, defined as a 20% increase in trough concentration between the first and any subsequent trough concentrations within the first 10 days of therapy. Minor endpoints included the percentage of supratherapeutic concentrations and the incidence of acute kidney injury (AKI). Descriptive statistics were used to evaluate endpoints and multivariable logistic regression was used to evaluate factors associated with accumulation.ResultsWe screened 543 patients, and 162 were included in our analysis. The median age was 56.5 years (interquartile range [IQR] 43 - 65.3), and 62.3% were male. The median weight was 112.7 kg (IQR 99.8 - 122.6) and the median BMI was 36.8 kg/m2 (IQR 33.1 - 41). The median total daily vancomycin dose at initiation was 28.7 mg/kg/day (IQR 25.4 - 31.2). Vancomycin accumulation occurred in 99 patients (61.1%) within the first 10 days of therapy and AKI occurred in 21 patients (14.9%). No factors studied, including age, gender, obesity class, initial dose, SCr, or frequency were associated with accumulation.ConclusionMost patients with obesity experienced vancomycin accumulation within the first 10 days of therapy. Providers should be cautious when assessing a vancomycin concentration early in the treatment course.Disclosures All Authors: No reported disclosures

The Impact of Adding Prandial Insulin to a Basal Based Regimen with Insulin Glargine in Type 2 Diabetic Patients.

Background: Type 2 diabetes (T2D) is a progressive disease that should be managed with insulin in case of oral glucose lowering drugs (OGLDs) failure. If basal insulin is not sufficient, rapid acting insulin will be added before the largest meal. We assessed the impact of adding one prandial insulin to a basal based regimen and insulin glargine in patients with type 2 diabetes to measure the percentage of subjects achieving the HbA1c target by the end of 24 weeks of treatment in routine clinical practice. Methods: This study was a 24-week observational study of patients with T2D not adequately controlled with OGLDs and basal insulin, for whom the physician had decided to initiate prandial insulin. The study endpoint was assessed at visit 1 (baseline), visit 2 at week 12 (±1 week) and visit 3 at week 24 (±1 week). The percentage of patients who achieved HbA1c targets was assessed at week 24. Statistical analyses were performed using IBM SPSS for Windows v 19 (IBM, Armonk, New York, USA). Logistic regression analysis was used to detect predicting factors of achieving the HbA1c target by week 24. P<0.05 was considered as significant level. Results : Four hundred and eighteen patients with a mean±SD age of 56.24±9.85 years and a mean±SD duration of diabetes of 12.50±7.16 years were included. The median total daily dose of basal insulin was 24 units, while prandial insulin was started with 6 (4, 10) U/day, titrating up to 10 (8, 18) U/day at week 24. The daily dose of prandial insulin was the only factor that could significantly predict achieving targeted HbA1c by week 24 [OR: 1.04; 95% CI: 1.007,1.079; p-value: 0.019]. At week 24, 96 (22.9%) subjects achieved the HbA1c target with one prandial insulin. Conclusion : The results of our study suggest that “basal plus therapy” can lead to good glycemic control with a low risk of hypoglycemia and weight gain in patients with type 2 diabetes.

Comparison between conventional dosing versus personalized pharmacokinetic dosing of vancomycin: a pilot study from a Malaysian private hospital

Pharmacist led vancomycin dosing is not a common practice in private hospital settings of the Malaysian healthcare system. The lack of this pharmacist led system has led to conventional vancomycin dosing without considering the differences in patients pharmacokinetic parameters. This study aims to compare the differences in vancomycin doses between conventional dosing and pharmacist-led personalized pharmacokinetic dosing. A retrospective pilot study was conducted on inpatient adults who were prescribed with intravenous vancomycin in a private hospital. Personalized vancomycin doses were retrospectively calculated by using the pharmacokinetic parameters and was then compared with the actual conventional doses used in the patients. The area under concentration curve over 24 hours/minimum inhibitory concentration (AUC24/MIC) ratio achieved by the doses was also compared. The targeted AUC24/MIC ratio was 400-600 to ensure efficacy and safety of the therapy. A total of 24 patients with a median age of 55.50 years were conveniently sampled. The patients were mostly male (58.3%) and were admitted to the neurosurgical ward (33.3%). Vancomycin was mainly prescribed as empirical treatment (58.3%) for a median treatment period of 5.00 days (IQR 4.00 – 7.00 days). The conventional doses had significant (p &lt; 0.001) lower median total daily dose (2000 mg versus 2500 mg) and lower AUC24/MIC ratio (385 versus 495) as compared to personalized doses. In conclusion, the personalized pharmacokinetic dosing method was significantly more able to achieve the targeted AUC24/MIC ratio. Vancomycin personalized dosing should be considered in the Malaysian private hospital setting.

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

Background and aims:Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.Methods:Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher’s exact test was used for categorical data and Kruskal–Wallis test or Wilcoxon rank sum were used for continuous data.Results:A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.Conclusion:Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor. The reviews of this paper are available via the supplemental material section.

Canadian Real-World Outcomes of Omnipod Initiation in People with Type 1 Diabetes (COPPER study): Evidence from the LMC Diabetes Registry.

AimsTo investigate real‐world clinical outcomes in adults with type 1 diabetes who initiated the Omnipod Insulin Management System (Insulet Corp., Acton, MA, USA) compared to a matched cohort who maintained multiple daily injection therapy.MethodsThis retrospective observational study used data from the Canadian LMC Diabetes Registry. Adults with type 1 diabetes who switched from multiple daily injections to the Omnipod system as usual standard of care between January 2011 and April 2019 were matched to a cohort of adults with type 1 diabetes who maintained multiple daily injection therapy, using propensity‐score matching. The primary outcome was change in HbA1c at 3‐ to 6‐month follow‐up.ResultsPropensity‐score matching resulted in a final analytical cohort of 286 individuals (143/cohort). HbA1c in the Omnipod cohort was reduced by a mean ± sd of –3 ± 10 mmol/mol (–0.2 ± 1.0%; P = 0.005) with no change in the MDI cohort [0 ± 10 mmol/mol (0.0 ± 1.0%); P = 0.74]. HbA1c change was seen only in persons with baseline HbA1c ≥75 mmol/mol (≥9.0%) [Omnipod cohort: –15 ± 12 mmol/mol (–1.4 ± 1.1%); P < 0.001] with a between‐treatment difference [mean (95% CI)] of –12 (–18, –6) mmol/mol [–1.1 (–1.6, –0.5) %, P < 0.001]. The median total daily dose of insulin was lower following Omnipod initiation (baseline 0.63 U/kg vs follow‐up 0.53 U/kg; P < 0.001), with no change in the MDI cohort (baseline 0.68 U/kg vs follow‐up 0.67 U/kg; P = 0.23).ConclusionsAdults with type 1 diabetes who initiated use of the Omnipod system in a real‐world clinical setting had lower HbA1c and total daily dose of insulin at 3‐ to 6‐month follow‐up compared to a matched cohort of adults who maintained multiple daily injection therapy. A treatment difference in HbA1c change was seen only in people with baseline HbA1c ≥ 75 mmol/mol (9.0%). (Clinical trials registration: NCT04226378).

EXPRESS: Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics.

Oral treprostinil may be an option for low- and intermediate-risk patients with pulmonary arterial hypertension, a rare lung vascular disease. This open-label extension study collected data on participants who completed previously reported, placebo-controlled oral treprostinil studies. Eligible participants had completed the prospective parent studies and took increasing doses of oral treprostinil twice daily; some later transitioned to three times daily dosing. Investigators measured 6-minute walk distance at Month 12 as the sole efficacy measure but collected adverse events throughout the study. A single center measured pharmacokinetics in 13 subjects who changed dosing from twice daily to three times daily. Eight hundred and ninety-four participants enrolled and 71% completed one year of therapy, with a median total daily dose of 7 mg and a median 6-minute walk distance increase of 22 m (interquartile range, −14 to 67 m). Subjects achieving higher doses had larger increases in 6-minute walk distance; 42% of participants completed three years of therapy. Adverse events were typical for prostacyclin class therapy, but prostacyclin-type adverse events may have been better tolerated with three times daily dosing in 105 participants. In 13 participants transitioned to three times daily dosing with pharmacokinetic measurements before and after, trough drug levels were higher with three times daily dosing. Oral treprostinil is associated with modest but durable, dose-responsive effects on exercise tolerance for those who remained on therapy at one year in this prospective, uncontrolled study. Three times daily dosing was associated with higher trough levels and better tolerability. The recently completed Freedom-EV study will provide further insights into the utility of oral treprostinil (https://clinicaltrials.gov/show/NCT01560624).