Preemptive Dose Reduction Research Articles

P8.122: Tacrolimus Dose Reduction as an Effective Therapeutic Approach to the Patients With Active BK Virus Replication And Nephrotoxicity

Background: BK viral nephropathy (BKVN) affects a significant proportion of kidney grafts in the early post-transplant period and often leads to functional failure of these grafts. The intensity of immunosuppressive therapy plays a significant role in the activation of BK viral (BKV) replication. Methods: 457 per-protocol biopsies of kidney grafts were performed in a group of 161 newly transplanted patients. The incidence of histological signs of tacrolimus nephrotoxicity as a manifestation of excessive immunosuppression was calculated using the Calcineurin Inhibitor Nephrotoxicity Score (CINS). In case of detection of simultaneous toxicity and substantial BKV replication, the dose of tacrolimus and/or mycophenolate was reduced and the effect on the inhibition of BKV activation and regression of toxic changes were compared. In parallel, we studied the effect of pre-emptive reduction of tacrolimus dose on the development of BKV replication in isolated detections of toxicity during the subsequent period. Results: The reduction of tacrolimus and mycophenolate dose in patients with histological evidence of toxicity and significant BKV replication was associated with an early and significant decrease in the BKV plasma load compared to isolated mycophenolate reduction (P = 0.023), significant decrease in CINS (P = 0.001) and better functional parameters at the end of this one-year follow-up (P = 0.024). A pre-emptive dose reduction of tacrolimus in case of toxicity evidence led to a marked reduction in the incidence of substantial BKV viremia during the subsequent period. Conclusions: The reduction of tacrolimus and mycophenolate dose in patients with histologically verified tacrolimus nephrotoxicity represents a more effective approach to attenuate significant BKV replication than a single-dose reduction of mycophenolate, including the regression of toxic changes. Pre-emptive tacrolimus dose reduction in case of toxicity signs is associated with a lower incidence of significant BKV replication during the first year after transplantation, without increasing the risk of acute rejection. Supported by MH CZ – DRO (FNOl, 00098892) and by grant IGA_LF_2022_03.

A warfarin-antibiotic drug-drug interaction: a podiatric surgical case report

Several groups of antibiotics are known to interact with warfarin, presenting a challenge to the prescriber trying to manage underlying clinical infection, whilst mitigating the risk of coagulopathy. The authors present a case report of a 64-year old warfarinised patient who underwent forefoot surgery and developed a subsequent post-operative infection with combinations of antibiotics, leading to excessive anticoagulation and an adverse drug event. From reviewing both local and national guidance, careful monitoring is mandatory, dosing adjustments and pre-emptive dose reduction might also be needed. Consultation within the wider multi-disciplinary network will be central to decision making and implementing safety netting measures.

Liposomal irinotecan pre-emptive dose reduction in patients with pancreatic ductal adenocarcinoma: 667 patients' experience within a population-based study.

Background:Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is currently the standard second-line treatment for patients with pancreatic ductal adenocarcinoma (PDAC) after previous failed gemcitabine-based therapy. This population-based study aimed to evaluate the efficacy and safety of nal-IRI + 5-FU/LV and the association of pre-emptive nal-IRI dosing with treatment outcomes in patients with PDAC.Methods:We retrospectively enrolled a total of 667 consecutive patients with PDAC who received nal-IRI plus 5-FU/LV treatment between August 2018 and November 2020 at 9 medical centers in Taiwan. Patients were allocated into groups according to pre-emptive nal-IRI dosing (⩾75%, 50–74%, <50%) for comparison of treatment efficacy and safety.Results:The median overall survival (OS) and time to treatment failure (TTF) were 5.9 months [95% confidence interval (CI), 5.3–6.5] and 2.8 months (95% CI, 2.6–3.0), respectively. The median OS was 6.5 months (95% CI, 5.7–6.7), 5.0 months (95% CI, 3.4–6.5), and 4.1 months (95% CI, 2.7–5.6), respectively, among the ⩾75%, 50–74%, and <50% pre-emptive nal-IRI dosing groups, whereas the median TTF of the three groups was 3.0 months (95% CI, 2.6–3.4), 2.6 months (95% CI, 2.3–2.9), and 1.9 months (95% CI, 1.6–2.2), respectively. Pre-emptive nal-IRI dosing <50% was an independent negative prognostic factor for OS and TTF in multivariate analyses. The most common severe adverse events were neutropenia (22.9%), anemia (21.1%), and hypokalemia (15.4%). Patients in the <50% pre-emptive nal-IRI dosing group had a significantly lower incidence of neutropenia and non-neutropenic infection than those in the other groups.Conclusion:Our results support the use of nal-IRI + 5-FU/LV as standard clinical practice for treating patients with PDAC based on this large population-based study. Our findings encourage physicians to provide adequate doses of nal-IRI in order to achieve better outcomes without compromising safety profiles.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

Dose Reduction of First and Second Generation TKIs Is Effective in the Maintenance of Major Molecular Response and May Predict Successful Tfr in CML Patients

Introduction: As patients (pts) diagnosed with chronic myeloid leukaemia (CML) in CP are predicted to have a life expectancy comparable to that of the normal population, clinical concern has focused on the burden of long-term side effects and quality of life. Stopping tyrosine kinase inhibitor (TKI) is possible in a selected group of pts, resulting in a 50% chance of treatment free remission (TFR). Limited data, however, are available on the outcome of TKI dose reduction (DR) in maintaining molecular responses.Methods: We retrospectively analysed the outcome of TKI DR in pts in ≥MR3 treated at our centre from Jan 2000 until May 2015. We defined different low dose groups (LDG), according to the actual TKI dose: for imatinib (IM), 300mg and 200mg; for dasatinib (DAS), 70-80mg, 50mg, 40mg and 20mg; for nilotinib (NIL), 400-450mg, 300mg or ≤200mg; and for bosutinib (BOS), 300mg, 200mg and <200mg.Given the ‘real life’ setting, pts may have received either 1) multiple DRs of the same TKI or 2) different TKIs at different low doses. For scenario 1): we analysed the dose that maintained ≥MR3 and was used for the longest period of time. In case of loss of molecular response on a lower dose level, the next dose was considered a further ‘case’ and the patient was analysed more than once. In scenario 2) the patient was analysed once for each TKI received at low dose. MR3 and MR4 were defined conventionally. The molecular recurrence free survival (MRFS) was estimated by Kaplan-Meier.Results: We included 232 pts (IM=83 pts, cases=85; DAS=75, cases=79; NIL=72, cases=73; BOS=32, cases=33), of whom 8 pts were included in two different LDG on the same TKI (because of loss of response on the lower dose: imatinib n=2, dasatinib n=4, nilotinib n=1, bosutinib n=1). 22 and 4 pts received 2 low dose (LD) TKIs and 3 LD TKIs respectively. The total number of cases was 270. Reasons for DR included any degree of adverse event deemed significant by the clinician or pre-emptive DR at the time of introduction of a subsequent TKI due to intolerance to the previous TKI. All IM pts were treated first line, whereas the majority of pts (n=159, 88.8%) received their current 2GTKI as ≥ 2 line. Median follow-up on LD TKI was 25.3 months (1.9-175). Patient characteristics by TKI are shown in Tables 1-4.The 2-year MRFS were: IM, 88.4% (95% CI, 87.7-89.1%), and 92.7% and 77.2% for LDG1 and LDG2 respectively; DAS 92.8% (95% CI, 92.2-93.4%); and 100%, 96.2%, 92.3% and 85.6% for LDG1, LDG2, LDG3 and LDG4 respectively; NIL 93.4% (95% CI, 92.6-94.1%); and 93.3%, 88.9% and 100% for LDG1, LDG2 and LDG3, respectively; BOS 91.7% (95% CI, 90-93%); and 100% for LDG1 and LDG2 and 75% for LDG3 (Figure 1 a,b,c and d).One patient on NIL required DR for grade 3 liver toxicity, progressed to blast crisis after losing MR3 on 300mg daily and died post allo-SCT. One patient, who had achieved only CHR on IM, developed a T315I mutation on 50mg DAS second line while in MR3, having lost MR4, and was changed to ponatinib. One patient on DAS died of an unrelated brain tumour.In each TKI cohort, 59/83 pts (71%) remained on LD IM, 51/75 (68%) pts on LD DAS, 35/72 (48.6%) pts on LD NIL and 30/32 (93.7%) pts on LD BOS. 55 pts stopped LD TKI while in sustained MR4 or greater (IM n=21/83 [25.3%], DAS n=12/75 [16%], NIL n=20/72 [27.8%], BOS n=2/30 [6.6%]) with a 2-year probability of TFR of 79.4% (95% CI, 78.3-80.5%) (compared to 50% at 2 years in EURO-SKI), with a median observation time of 28 months (5-83.7) in non-relapsing pts. TFR in the different cohorts were 85.7%, 62.3%, 80% and 100% for IM, DAS, NIL and BOS respectively.Conclusion: For selected pts in ≥MR3 lowering the TKI dose can improve the tolerability of TKI therapy without impacting responses. The higher rate of TFR observed in our pts than in published stopping studies probably reflects cohorts of pts already shown to maintain deep responses on lower than standard doses of TKI, and mirrors the results of the UK NIHR Destiny study. [Display omitted] DisclosuresApperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

Preemptive dose reduction of warfarin in patients initiating metronidazole

The goal of this study was to determine if preemptive dose reduction (PDR) of warfarin is effective in maintaining therapeutic anticoagulation in patients initiating metronidazole. This is a retrospective, single-center, cohort study in a pharmacist-managed anticoagulation clinic of a university affiliated Veteran's Affairs (VA) Medical Center. Subjects were anticoagulation patients initiating metronidazole between 1 January 2002 and 30 March 2009. At the time of metronidazole initiation, patients were managed with PDR of warfarin or no dose reduction. The primary outcome was the average change in International Normalized Ratio (INR) between patients that received PDR vs. those that did not. In total, 20 patients met inclusion criteria with seven patients receiving PDR at the time of initiation of metronidazole, whereas 13 did not. Patients managed with PDR and those that were not were similar in age (mean±SD 69.4±12.9 years vs. 72.1±9.9 years, p=0.61), mean baseline INR before metronidazole (2.58±0.49 vs. 2.57±0.66, p=0.98), and mean time to follow-up after initiation of metronidazole (5.6±2.9 days vs. 7.0±3.7 days, p=0.40), respectively. The primary outcome was statistically significant with a mean difference in INR of 1.28 (p=0.01) between patients manag-ed with PDR vs. those that were not. The mean preemptive warfarin dose reduction was 34.6%±13.4% which resulted in no significant increase in INR (p=0.61). Secondary outcomes including INR values >4.0 (0% vs. 46%, p=0.05), the average number of warfarin doses omitted (0.43±0.79 vs. 1.15±1.27, p=0.17), use of phytonadione or fresh frozen plasma, and rates of bleeding events were not significantly different be-tween groups. No thromboembolic events occurred during the 30 days following metronidazole therapy. In patients determined to be appropriate candidates for PDR, a 30%-35% reduction in mean daily warfarin dose was effective in maintaining therapeutic anticoagulation in patients started on concomitant metronidazole.

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day -1 (30% lesser than the usual starting dose). The dose was reduced by 30-40% if the 48-h steady-state concentration was 7-10 ng/ml, and by 40-50% if it was 10-15 ng/ml. No change was made if the concentration was <7 ng/ml. Subsequently, concentrations were generally monitored 2-3 times a week with dose adjustments as necessary. None of the 170 levels (3-12 per patient; median 5) obtained between days +1 and +16 were subtherapeutic (<5 ng/ml) and only 34 levels (20%) were >15 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent.

Tacrolimus Dosing in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients Receiving Concomitant Voriconazole.

Tacrolimus is an effective immunosuppressive agent for allogeneic HSCT. It is primarily metabolized by the CYP450 3A4 isoenzyme. Voriconazole is often used to prevent fungal infections after allogeneic HSCT. It is metabolized by the CYP450 3A4, 2C9 and 2C19 isosenzymes. Studies in healthy volunteers and case reports in HSCT recipients have shown significant drug interaction between the two requiring reduction of tacrolimus dose. Ordinarily, tacrolimus prophylaxis is initiated at the dose of 0.03 mg/kg IV daily on day -1. After starting tacrolimus at this dose and having to reduce the dose substantially within 2–3 days in all patients receiving concomitant voriconazole 200 mg twice daily orally from day 0, we implemented a simple, pre-emptive tacrolimus dose reduction strategy to maintain steady-state levels between 5 and 15 ng/mL in patients on IV tacrolimus. As a first step, IV tacrolimus was initiated at the reduced dose of 0.022 mg/kg adjusted body weight per day. As a second step, tacrolimus dose was reduced by 30–40% if the steady-state level 48 h after initiation of tacrolimus (day +1) was between 7 and 10 ng/mL, and by 40–50% if the level was between 10 and 15 ng/mL. No change was made if the level was <7 ng/mL. Subsequently, tacrolimus levels were monitored 2–3 times a week and the dose adjusted as needed. In this report, we evaluate the pharmacokinetic effects of concomitant voriconazole administration on blood tacrolimus levels in 27 consecutive allogeneic HSCT recipients (28–64 years; median 55) in whom the pre-emptive dose-modification strategy was used during the first 2 weeks after HSCT while they were receiving IV tacrolimus. A total of 170 levels (3–12 per patient; median 5) were checked between day +1 and day +16. None of the levels was subtherapeutic (<5 ng/mL), and 34 (20%) were >15 ng/mL. 24 of 27 patients required dose-reduction from day 0 to day +1 based on levels. Every single patient required dose-reduction at least twice. An increase in the dose was needed in only 2 patients after initial dose-reduction. The figure below shows the minimum, maximum, and median tacrolimus doses; depicting a steady decline in the median dose. [Display omitted] The figure below illustrates that the median tacrolimus levels remained fairly steady as the median absolute tacrolimus dose, the median tacrolimus dose on a mg/kg basis, and the median per cent tacrolimus dose (100% being the baseline mg/kg dose) declined substantially. [Display omitted] It is clear from the above figure that lack of pre-emptive dose-reduction would have resulted in tacrolimus levels climbing steadily. Based on these findings, we recommend starting tacrolimus at 0.02–0.022 mg/kg rather than at 0.03 mg/kg if patients are getting concomitant voriconazole, checking levels regularly, and reducing the drug dose by 30–40% if the level is between 7 amd 10, and by 40–50% if the level is between 10 and 15.

BENEFITS OF PREEMPTIVE DOSE REDUCTION FOR SANDIMMUNE TO NEORAL CONVERSION IN STABLE RENAL TRANSPLANT RECIPIENTS

241 We previously reported a high incidence of nephrotoxicity in stable renal transplant patients converted from Sandimmune to Neoral using a 1:1 dosing ratio. Serum creatinine concentration (sCr) transiently increased to more than 30% above baseline in 68 of 141 (48%) consecutive patients. Moreover, 74% of patients required a reduction in dose after conversion. This experience prompted the current study in which 23 stable patients were converted from Sandimmune to Neoral using a preemptive 20% dose reduction (group 1). Outcomes of patients in group 1 were compared to those of 23 patients converted using a 1:1 dosing ratio and matched for age, baseline sCr, and baseline trough CsA levels (group 2). Baseline Sandimmune dose was 4.3±1.6 mg/kg/d in group 1 and 4.6±1.4 mg/kg/d in group 2 (p=NS). Neoral dose was reduced on the basis of an elevated sCr (>15% above baseline) or a lesser elevation associated with a CsA level >200 ug/L. In each group, baseline sCr and trough CsA levels were compared to those obtained 4 days, 11 days, and at last follow-up after conversion: TableThe percent change in peak sCr after conversion was 12±20% in group 1 and 37±41% in group 2 (p<0.04). In group 1, 3 of 23 patients required additional Neoral dose reductions while 15 of 23 patients in group 2 required dose reductions (p=0.001). However, at last follow-up, the dose reductions in each group were not different (-21±11%, group 1 vs-19±18%, group 2; p=NS). Conclusion: Compared to conversion using a 1:1 dosing ratio, conversion from Sandimmune to Neoral using a preemptive 20% dose reduction results in less short-term nephrotoxicity and comparable dose reductions. Preemptive dose reduction may allow Sandimmune to Neoral conversion with less frequent laboratory monitoring.