Dose Conversion Ratio Research Articles

Opioid analgesic dose and route conversion ratio studies: a scoping review to inform an eDelphi guideline.

Clinicians regularly prescribe opioids to manage acute and chronic cancer pain, frequently to address acute postoperative pain, and occasionally to manage chronic non-cancer pain. Clinical efficacy may be suboptimal in some patients due to side effects and/or poor response, and opioid rotation/switching (conversions) is frequently necessary. Despite the widespread practice, opioid conversion ratios are inconsistent between clinicians, practices, and countries. Therefore, we performed a scoping systematic review of opioid conversion studies to inform an international eDelphi guideline. To ensure a comprehensive review, we conducted a systematic search across multiple databases (OVID Medline, PsycINFO, Embase, EBM-Cochrane Database of Systematic Reviews and Registered Trials, LILACS, IMEMR, AIM, WPRIM) using studies published up to June 2022. Additionally, we performed hand and Google Scholar searches to verify the completeness of our findings. Our inclusion criteria encompassed randomized and non-randomized studies with no age limit, with only a few pediatric studies identified. We included studies on cancer, non-cancer, acute, and chronic pain. The level and grade of evidence were determined based on the Multinational Supportive Care in Cancer (MASCC) criteria. Our search yielded 21,118 abstracts, including 140 randomized (RCT) and 68 non-randomized (NRCT) clinical trials. We compared these results with recently published conversion ratios. Modest correlations were noted between published reviews and the present scoping systematic review. The present scoping systematic review found low-quality evidence to support an opioid conversion guideline. We will use these data, including conversion ratios and type and route of administration, to inform an eDelphi guideline.

Real-world differences in dosing and clinical utilization of OnabotulinumtoxinA and AbobotulinumtoxinA in the treatment of upper limb spasticity

According to prescribing information, potency units are not interchangeable between botulinum toxin A products. This exploratory study compared real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA in adults with upper limb spasticity. In this retrospective study, 101 clinicians provided chart data via online surveys for 215 US post-stroke patients treated for upper limb spasticity with ≥3 onabotulinumtoxinA or abobotulinumtoxinA doses (phase 1: 9/18/2020–12/10/2020; phase 2: 9/30/2021–12/7/2021). Most participating clinicians were physicians (70.3%) specializing in neurology (71.3%) or physiatry (20.8%). In the onabotulinumtoxinA (n = 107) and abobotulinumtoxinA (n = 108) groups, ∼75% of patients had moderate-to-severe spasticity. A range of onabotulinumtoxinA:abobotulinumtoxinA dose ratios (1:2.2 [95% CI: 1.8, 2.6] to 1:4.1 [95% CI: 3.0, 6.0]) was observed across muscles. For the most recent dose, mean number of muscles injected was greater for onabotulinumtoxinA (4.3) versus abobotulinumtoxinA (3.1; P = 0.0003). For onabotulinumtoxinA versus abobotulinumtoxinA, the proportion of injections was 81.3% versus 63.9% (P = 0.0067) in forearm muscles and 23.4% versus 3.7% (P = 0.0001) in hand muscles. Mean injection intervals were similar (onabotulinumtoxinA: 102.0 days; abobotulinumtoxinA: 99.1 days). Differences in real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA for upper limb spasticity were observed. There was no standard dose-conversion ratio, consistent with each product's prescribing information.

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study.

Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs. The dose of LCPT was determined using a dose conversion ratio targeting 0.7 relative to the total daily immediate-release tacrolimus (IR-Tac) dose. On day 7 after converting to LCPT, patients had an abbreviated PK assessment with sampling at: 0 h (pre-dose), 8-, and 12-h post-dose. The PK data analysis was performed using Bayesian estimators. Our results were compared to those of published adult PK data for LCPT and pediatric PK data for IR-Tac and extended release tacrolimus (ER-Tac) formulation (Advagraf). PK data from three adolescent patients on LCPT were evaluated. The mean (±SD) area under the time-concentration curve (AUC) was 240 (±20.22) h*ng/mL. The mean Tmax was 9.01 ± 2.12h, and the % fluctuation was 77.71 ± 3.96%. The AUC, Tmax , and % fluctuation were similar to reported results in adult patients taking LCPT. The AUC was higher and the Tmax was longer than what has been reported in pediatric patients taking IR-Tac and ER-Tac. In addition, the LCPT group showed a lower % fluctuation than patients receiving ER-Tac. The PK evaluation of LCPT in adolescent RTRs showed similar results to adults. Adolescents taking LCPT had a higher AUC, a more attenuated Tmax , and a lower fluctuation than that seen with ER-Tac in pediatrics.

Dose conversion ratio, comparative efficacy, and adverse events after switching from onabotulinum toxin A to abobotulinum toxin A for neurological conditions

ObjectivesOnabotulinum toxin A (ONA, Botox®) and abobotulinum toxin A (ABO, Dysport®) are most frequently used in the treatment of movement disorders. The aim of this study was to identify the dose conversion ratio (ABO dose:ONA dose), comparative efficacy, and adverse events in patients who switched from ONA to ABO. MethodsThere were 64 patients with cervical dystonia (39), hemifacial spasm (16), oromandibular dystonia (5), blepharospasm (3), and extremity dystonia (1) who switched from ONA to ABO. The efficacy, adverse events, duration of action, and severity of the adverse events after the final dose of ONA, initial dose of ABO, and second dose of ABO were investigated in these patients. ResultsThe mean dose conversion ratio was 4.70 (2.27–9.62). The mean efficacy of the final ONA injection was 70.62%; initial ABO injection, 72.27%; and second ABO injection, 73.52%, which showed improvement on a visual analog scale (p = 0.71, p = 0.5). Incidence of adverse events after the final ONA injection was 18.8%; this increased to 39.1% after the initial ABO injection (p < 0.001) and decreased to 14.1% after the second ABO injection (p = 0.77). After the initial ABO injection, 20% of the adverse events were trivial, 36% were mild, and 32% were severe. After the second ABO injection, 7.8% of the adverse events were mild and 6.3% were severe. ConclusionAlthough the mean dose conversion ratio was 4.70, the range was very wide (approximately 2–9). Therefore, we conclude that after the switch from Botox to Dysport, the doses should be tailored to the patients’ clinical situation at treatment initiation, without using a dose conversion ratio.

Clinical Factors Affecting the Dose Conversion Ratio from Intravenous to Oral Tacrolimus Formulation among Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation. Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div). The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively. After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.

Efficacy and Safety of LCP-Tacrolimus (Envarsus XR®) Conversion Therapy in Heart Transplantation

Little is known about the usefulness of LCP-tacrolimus (LCPT, Envarsus XR®) in heart transplantation. Tacrolimus-based immunosuppression use is limited by neurologic adverse reactions and consequent difficulty in titration of drug doses to therapeutic targets. LCPT offers improved bioavailability and lower peak blood concentrations which may lead to fewer neurological adverse effects while allowing for adequate therapeutic trough level titration. We aimed to evaluate outcomes in patients who were transitioned from immediate-release (IR) tacrolimus to LCPT. In this retrospective, single center analysis (1/2015-7/2019), 84 patients were transplanted, and 17 were converted to LCPT, predominantly for neurological adverse events (n=9) or failure to achieve a therapeutic drug level with IR tacrolimus (n=4) or both (n=4). Patients were followed for improvement in symptoms, rates of rejection and renal function. IR tacrolimus was converted to LCPT early post-transplant (median 1 month; 0.5-11 months). Median equivalent dose conversion ratio was 0.77 (LCPT/IR Tacrolimus). Dose stability trend was better with LCPT, which required 1.5 dose changes per month on average as compared to 3.0 changes for IR tacrolimus (range: 0-6.7 vs 0-8.0, respectively, p=0.07). Among 13/17 patients transitioned for neurotoxicity, 8 reported improvement in symptoms, 4 no improvement, and 1 worsening symptoms. In 7 patients, peak levels were checked (2-3 hours post dose) prior to conversion and were not excessively elevated (median 18.1; 15.5-33.4 ng/mL); six of these reported improvement in tremors or headaches after conversion despite moderate peak levels. ISHLT grade ≥ 2R rejections were infrequent and occurred in 1 patient on LCPT after intentional lowering of immunosuppression in the setting of invasive fungal infection. LCPT was associated with worsening renal function with median serum creatinine 0.99 mg/dL prior to conversion and 1.56 mg/dL after conversion (p=0.002). LCPT conversion therapy in heart transplantation allows maintenance of therapeutic drug levels in those difficult to achieve with IR tacrolimus and is associated with improved neurological symptoms and low rates of allograft rejection. However, significant concerns remain with regard to worsening renal function.

Use of Sublingual Tacrolimus in Adults Undergoing Hematopoietic Cell Transplant: A Pilot Study

The national shortage of oral (PO) and intravenous (IV) tacrolimus, as well as the undesirable sequelae of IV administration, call for innovative solutions to conserve existing supply and optimize safety and efficacy of medication delivery. Sublingual (SL) administration of tacrolimus is widely used as an alternative to the IV route in the solid organ transplant population and similar benefits may be appreciated by patients undergoing hematopoietic cell transplant (HCT). The most widely accepted SL:PO dose conversion ratio has been 0.5 based on available evidence. We sought to demonstrate feasibility of SL tacrolimus use and estimate a SL:PO conversion ratio in the HCT setting. Ten adults (median age 60.5 years) undergoing allogeneic HCT received tacrolimus 0.04 mg/kg/dose, based on ideal body weight, twice daily beginning 3 days prior to transplant. Initial doses were given via SL route and a steady state trough level was collected after 4 consecutive doses. Participants were then switched to tacrolimus PO, the dose was adjusted for a goal trough 8-12 ng/mL, and another steady state trough was drawn (Figure 1). Trough concentration was divided by total daily dose for each route to determine the dosing ratio of SL:PO (Table 1). Median trough level following SL administration was 11.3 ng/mL. Three of these were within goal, 3 were low (4.7-6.4 ng/mL) and 4 were elevated (15.9-18.6 ng/mL). Median SL:PO ratio was 0.99. In 5 patients the SL:PO ratio was Results demonstrate reliable absorption with SL tacrolimus use in patients undergoing HCT. This represents an alternative drug delivery method in patients with barriers to PO administration or in the setting of limited availability of the IV product. This preliminary experience identified an SL:PO ratio of 0.99 with some degree of variability. Fluctuating clinical status and changes in interacting medications are important to consider when adjusting doses or converting between routes and may influence this ratio. Further study is needed to better elucidate the a more precise SL:PO dose conversion ratio and understand the impact of various drug-drug interactions.

A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis

BackgroundDaprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule.Methods103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days.ResultsMean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population.ConclusionsThese data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen.Trial registrationClinicalTrials.gov Identifier: NCT02689206; date registered: 02/11/2016.

A Multicenter, Prospective, Observational Study of Conversion from Twice-Daily Immediate-Release to Once-Daily Prolonged-Release Tacrolimus in Liver Transplant Recipients in France: The COBALT Study.

BackgroundIn adult liver transplant patients, the use of prolonged-release tacrolimus may have treatment adherence benefits over the immediate-release formulation. The aim of this study was to characterise real-world practice data on conversion of liver transplant recipients from immediate- to prolonged-release tacrolimus in France.Material/MethodsA prospective, observational study (NCT02143479) was conducted in 18 transplant centers in France between June 2014 and March 2016. Liver transplant recipients (n=398) included patients who changed from immediate-release to prolonged-release tacrolimus within the first three months (early conversion group) (n=205) or between three and 12 months after transplantation (late conversion group) (n=184). Clinical data were collected at an initial baseline outpatient visit and six-month and 12-month follow-up visits. Endpoints included the dose conversion ratio from immediate-release to prolonged-release tacrolimus, number of and reasons for additional visits due to conversion, safety, and tolerability.ResultsBaseline clinical and demographic characteristics were similar between the two cohorts. The mean ±SD ratio of conversion of tacrolimus dose was 1.04±0.28; 1.01±0.28 (early) and 1.08±0.28 (late) (p=0.0247). The mean ±SD time from conversion to the first tacrolimus trough blood concentration was 30.8±42.8 days; 24.8±45.4 days (early) and 37.5±38.7 days (late). Only one patient required an additional visit due to conversion. Reasons for conversion included the physician’s preference (56.3%), center practice (38.6%), and the dosing frequency (36.0%). Conversion was associated with a low rate of graft rejection, and no new safety issues were reported.ConclusionsConversion of liver transplant recipients from immediate-release to prolonged-release tacrolimus within three to 12 months of transplantation was easy to manage and associated with favorable clinical outcomes and safety profiles.

Costs Associated With Intravenous Darbepoetin Versus Epoetin Therapy in Hemodialysis Patients: A Randomized Controlled Trial.

Background:Anemia of chronic kidney disease is associated with adverse outcomes and a reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have improved anemia management, and 2 agents are available in Canada, epoetin alfa (EPO) and darbepoetin alfa (DA). EPO and DA are considered equally effective in achieving target hemoglobin (Hb), but it is not clear whether there is a cost difference. There have been few head-to-head comparisons; most published studies are observational switch studies.Objective:To compare the cost of DA and EPO and to determine the dose conversion ratio over a 12-month period.Design:Randomized controlled trial.Setting:Canadian outpatient hemodialysis center.Patients:Eligible patients were adult hemodialysis patients requiring ESA therapy.Measurements:The primary outcome was ESA cost (Can$) per patient over 12 months. Secondary outcomes included the dose conversion ratio, deviation from target ranges in anemia indices, iron dose and cost, and time and number of dose changes.Methods:An open-label randomized controlled trial of intravenous (IV) DA versus EPO was conducted in 50 hemodialysis patients. Participants underwent a minimum 6-week run-in phase followed by a 12-month active study phase. ESA and iron were dosed using a study algorithm.Results:The median cost was $4179 (interquartile range [IQR]: $2416-$5955) for EPO and $2303 (IQR: $1178-$4219) for DA with a difference of $1876 (P = .02). The dose conversion ratio was 280:1 (95% confidence interval [CI]: 197-362:1) at the end of the run-in phase, 360:1 (95% CI: 262-457:1) at the 3-month point of the active phase, and 382:1 (95% CI: 235-529:1) at the 6-month point of the active phase. There were no significant differences between the 2 groups in weekly iron dose, Hb, serum ferritin, or transferrin saturation. The number of dose changes and the time to Hb stability were similar.Limitations:Results may not be generalizable to hemodialysis units without algorithm-based anemia management, with subcutaneous ESA administration, or to the nondialysis chronic kidney disease population. The effective conversion ratio between EPO and DA is known to increase at higher doses; the Hb targets used in the study were slightly higher than those recommended today so it is possible that the doses used were also higher. Because of this, the cost savings estimated for DA could differ somewhat from the savings realizable in current practice.Conclusions:In this study of hemodialysis patients with comparable anemia management, IV DA cost $1876 less per year per patient than IV EPO. The dose conversion ratio was greater than 350:1 by the 3-month point.Trial registration:ClinicalTrials.gov (NCT02817555).

Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children.

AIMTo describe our institutional experience with conversion from intravenous (IV) fentanyl infusion directly to enteral methadone and occurrence of withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation and analgesia.METHODSWith Institutional Review Board approval, we retrospectively studied consecutively admitted invasively mechanically ventilated children (0-18 years) sedated with IV fentanyl infusion > 5 d and subsequently converted directly to enteral methadone. Data were obtained on subject demographics, illness severity, daily IV fentanyl and enteral methadone dosing, time to complete conversion, withdrawal scores (WAT-1), pain scores, and need for rescue opioids. Patients were classified as rapid conversion group (RCG) if completely converted ≤ 48 h and slow conversion group (SCG) if completely converted in > 48 h. Primary outcome was difference in WAT-1 scores at 7 d. Secondary outcomes included differences in overall pain scores, and differences in daily rescue opioids.RESULTSCompared to SCG (n = 21), RCG (n = 21) had lower median WAT-1 scores at 7 d (2.5 vs 5, P = 0.027). Additionally, RCG had lower overall median pain scores (3 vs 6, P = 0.007), and required less median daily rescue opioids (3 vs 12, P = 0.003) than SCG. The starting daily median methadone dose was 2.3 times the daily median fentanyl dose in the RCG, compared to 1.1 times in the SCG (P = 0.049).CONCLUSIONWe observed wide variation in conversion from IV fentanyl infusion directly to enteral methadone and variability in withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation. In those children who converted successfully from IV fentanyl infusion to enteral methadone within a period of 48 h, a methadone:fentanyl dose conversion ratio of approximately 2.5:1 was associated with less withdrawal and reduced need for rescue opioids.

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PurposeTransdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route.MethodsFifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model.ResultsA one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h−1, respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed.ConclusionsWe describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-2005-x) contains supplementary material, which is available to authorized users.

OnabotulinumtoxinA and AbobotulinumtoxinA Dose Conversion: a Systematic Literature Review.

ObjectiveThis systematic review was performed to elucidate dosing practices, dosing conversions, and related outcomes from randomized, controlled trials that directly compared onabotulinumtoxinA (ONA) and abobotulinumtoxinA (ABO) at various dose conversion ratios for therapeutic use in movement disorders.MethodsA systematic review of three medical literature databases (PubMed, the Cochrane Library, and EMBASE) was performed to identify relevant comparative clinical studies, systematic reviews, and meta‐analyses published in the English language between January 1991 and January 2015. Studies that met predefined inclusion criteria were selected for formal data extraction and quality assessment.ResultsA total of 182 manuscripts were identified, of which four were included for analysis. Targeted clinical applications included neurological disorders. The studies compared ONA to ABO dose conversion ratios of 1:2.5 (n = 1), 1:3 (n = 2), and 1:4 (n = 2). One study compared both 1:3 and 1:4 ratios. An ONA:ABO conversion factor of 1:2.5 was associated with similar efficacy and side effects. An ONA:ABO ratio of 1:3 provided similar or higher efficacy, but an increased rate of adverse effects, and an ONA:ABO ratio of 1:4 was associated with higher efficacy, but with an excessive rate of intolerable side effects.ConclusionA dose conversion ratio of ONA to ABO between 1:2.5 and 1:3.0 provides comparable safety and efficacy for therapeutic movement disorders chemodenervation procedures.

Patient-centric dose equivalency pilot study of incobotulinumtoxin a (xeomin) vs. abobotulinumtoxin a (dysport) in the treatment of glabellar frown lines

Aim: Incobotulinumtoxin A (xeomin) has been proposed as an alternative to abobotulinumtoxin A (dysport) and onabotulinumtoxin A (Botox) in the treatment of glabellar frown lines. A recent study is comparing abobotulinumtoxin A and onabotulinumtoxin A revealed equivalent efficacy with a dose conversion ratio of 2.5:1. We sought to establish effectiveness and dosing equivalency of incobotulinumtoxin A vs. abobotulinumtoxin A. Methods: Inclusion criteria for this pilot study included patients of a single surgeon (LAC) who had previously received a constant dose of abobotulinumtoxin A over at least four consecutive treatment sessions for the previous 12 months to achieve an 85-90% elimination of dynamic glabellar frown lines. The primary outcome sought dose comparison between established maintenance abobotulinumtoxin A dosing and incobotulinumtoxin A first-time dosing. A 2:1 conversion (abobotulinumtoxin A: incobotulinumtoxin A) was chosen in most patients. Secondary outcomes were patient-reported onset of effect, physician-assessed effect at 10-12 weeks, pain associated with administration, and patient perceived need for re-treatment at 2 weeks. Results: A total of 32 subjects were included. The mean dose of incobotulinumtoxin A was 17.1 units (± 6.1, the median dose 20 units). The mean dose of abobotulinumtoxin A was 27.6 (± 11.7, the median dose 27.5 units). The mean difference in treatment units was -10.5 (95% confidence interval, P vs. 90.3% (± 1.8) with abobotulinumtoxin A ( P Conclusion: We found incobotulinumtoxin A at 17.1 (± 6.1) units to be less effective than abobotulinumtoxin A at 27.6 (± 11.7) units in the treatment of glabellar frown lines at 10-12 weeks postadministration. Dosing was less predictable than dosing associated with abobotulinumtoxin A treatment. Larger, randomized controlled trials are indicated to further delineate these differences and to clarify whether this difference from previously published incobotulinumtoxin A dosing may have been due to the small sample size.

Responsiveness to erythropoiesis-stimulating agents and renal survival in patients with chronic kidney disease.

Renal anemia of chronic kidney disease (CKD) is generally treated by erythropoiesis-stimulating agents (ESAs). However, there are individual differences in patients' responsiveness to ESA, which may affect the prognosis of CKD. The effect of ESAs on hemoglobin was followed in 297 CKD patients with renal anemia. Three types of ESA, epoetin alfa or beta, darbepoetin alfa, and epoetin beta pegol, were used in this study and dose of ESA was converted to that of epoetin using a dose conversion ratio (epoetin:darbepoetin alfa:epoetin beta pegol = 200:1:0.93). After initial 12-week administration of ESAs, the patients were divided into three groups: poor, intermediate, and good responders based on ΔHb/week/epoetin dose as an index. Hemoglobin values were followed for 144 weeks. Initial patient characteristics--including age, body mass index, hemoglobin, estimated glomerular filtration rate, transferrin saturation, ferritin, albumin, calcium, parathyroid hormone, C-reactive protein, and urine protein--were similar in the three responder groups, except phosphate in the poor responder group was significantly higher than in the other two groups. The period from ESA use to renal death (RD) was significantly shortest in the poor responder group, and the number of RD patients was fewer in the good responder group. Multivariate Cox regression revealed that low final ΔHb(ΔHb from ESA use to just before dialysis)/week/epoetin dose, and low Hb after 12-week ESA use were significant factors related to responsiveness to ESA, suggesting that hyporesponsiveness to ESA was a risk factor for RD. Cox regression also found that hyperphosphatemia and diabetic nephropathy were risks for RD as well. The study results suggest that hyporesponsiveness to ESA after the first 12-week administration as well as after 12 weeks is a risk for RD in pre-dialysis CKD patients. Furthermore, hyperphosphatemia and diabetic nephropathy are risk factors for RD.

Pharmacokinetics of Cyclosporine a Conversion From Twice-Daily Infusion to Oral Administration in Allogeneic Hematopoietic Stem Cell Transplantation

Twice-daily administration of cyclosporine A (CyA) has often been used for prophylaxis of acute graft versus host disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT). But there have not been any reports that calculated the conversion ratio of the switch from twice-daily intravenous infusion to oral administration of CyA in adult patients. To establish the conversion ratio and the best strategy of twice-daily administration of CyA, the authors investigated the serial changes in the blood CyA concentration during the switch from twice-daily intravenous infusion to oral administration while maintaining high-peak concentration (over 1000 ng/mL) and calculated the bioavailability of Neoral, a micro emulsion cyclosporine, in 11 patients. All the patients underwent allo-HSCT with graft versus host disease prophylaxis consisting of CyA at a high-peak concentration of twice-daily infusion with short-term methotrexate and oral administration. Neoral was started at an oral dose, 2 times daily, at twice the latest dose of intravenous dose according to the bioavailability of healthy volunteers. Micafungin, a mild inhibitor of CYP3A4, was administered for prophylaxis against fungal infection. The total area under the concentration-time curve during oral administration (AUCpo) was nearly the same as AUC during intravenous infusion (AUCiv) (mean ± SD, 7206 ± 1557 ng·h·mL and 7783 ± 897.7 ng·h·mL, respectively). The bioavailability of Neoral, defined as F = AUCpo × DOSEiv/AUCiv × DOSEpo was 0.58 ± 0.15 (mean ± SD, range: 0.41-0.94). When patients were switched from twice-daily infusion to oral administration, the dose conversion ratio of 1:2 seemed to be appropriate. At that time, the target trough level of Neoral was nearly the same as that of the infusion.

Effects of three kinds of erythropoiesis-stimulating agents on renal anemia in Japanese non-dialysis chronic kidney disease patients

Erythropoiesis-stimulating agents (ESAs) are standard therapy for chronic kidney disease (CKD) patients with renal anemia. However, few studies have compared the effects of different ESAs on anemia in identical pre-dialysis CKD patients. Seventy-nine patients who switched from epoetin beta to darbepoetin alfa (Group 1), and 82 patients who switched from darbepoetin alfa to epoetin beta pegol (Group 2) were enrolled in this study. Clinical and laboratory parameters were assessed for 6 months before and after switching ESAs. The prevalence of adverse events, the dose conversion ratio of ESAs, and the frequency of ESA administration were also analyzed. Analysis of variance showed that switching ESAs did not significantly change hemoglobin levels for the study duration in both groups (mean hemoglobin 10.3-10.5 g/dL in Group 1 and 10.4-10.7 g/dL in Group 2). Estimated glomerular filtration rate, blood pressure, transferrin saturation, ferritin, and albumin remained constant in both groups. The prevalence of adverse effects was quite low (0-3.8 %) during both 6-month study periods. The mean dose conversion ratio for epoetin beta:darbepoetin alfa was 163.7 units:1 μg and for darbepoetin alfa:epoetin beta pegol was 1.08 μg:1 μg. The intervals of ESA administration significantly differed (epoetin beta pegol > darbepoetin alfa > epoetin beta). Epoetin beta, darbepoetin alfa, and epoetin beta pegol are effective and well-tolerated agents for managing anemia in Japanese pre-dialysis CKD patients. The intervals of ESA administration to maintain a patient's target hemoglobin were longer in the order of epoetin beta pegol > darbepoetin alfa > epoetin beta.

Dose Conversion Ratio in Hemodialysis Patients Switched from Darbepoetin Alfa to PEG-Epoetin Beta: AFFIRM Study

IntroductionThere is limited information published on switching erythropoiesis-stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo.MethodsEligible patients had received hemodialysis for ≥12 months and DA for ≥7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified.ResultsOf 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 μg DA in the pre-switch EP and 28.6 μg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35).ConclusionIn these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately threefold from the pre-switch to the post-switch period.

Comparative Study of Biological Activity of Four Botulinum Toxin Type A Preparations in Mice

Units of available botulinum toxin preparations are not interchangeable, and the dose-conversion ratios between such preparations remain controversial. To compare the efficacy and safety of four botulinum toxin type A preparations. Murine gastrocnemius compound muscle action potentials (CMAPs) were recorded before and after injecting the four botulinum toxin preparations (onabotulinumtoxinA, abobotulinumtoxinA, new botulinum toxin, and incobotulinumtoxinA). In all preparations, CMAP amplitudes decreased until 4days after receiving the injection and then gradually recovered. On postinjection day 84, the amplitudes returned to baseline in all groups except the high-dose groups. CMAP amplitude in the contralateral limb also decreased up to postinjection days 4 to 7 and then gradually returned to baseline by postinjection day 28. The dose-conversion ratio between onabotulinumtoxinA and abobotulinumtoxinA was determined to be 1:2.6; previous reports of 1:3 were considered too high. A dose-conversion ratio between onabotulinumtoxinA and new botulinum toxin of 1:1 was deemed appropriate. OnabotulinumtoxinA and incobotulinumtoxinA demonstrated a dose-conversion ratio of 1:1.07. The efficacy of incobotulinumtoxinA was slightly lower than that of onabotulinumtoxinA. These dose-conversion ratios are applicable solely from an efficacy standpoint and not for safety. This study was conducted in mice, so it may not translate perfectly to human applications.

Conversion from Epoetin Alfa to Darbepoetin Alfa: Effects on Patients’ Hemoglobin and Costs to Canadian Dialysis Centres

The erythropoiesis-stimulating agents epoetin alfa (EPO) and darbepoetin alfa (DPO) effectively treat the anemia that occurs in most patients undergoing hemodialysis. Published studies indicate that these 2 agents have similar efficacy and safety outcomes, but their relative costs in actual practice in Canada have not been extensively studied. To determine the relative utilization and cost of erythropoiesis-stimulating agents in Canadian practice. Secondary objectives were to examine various clinical parameters in patients receiving these drugs. In this retrospective, open-label, observational study, 3 hospital-based hemodialysis centres in Ontario, Canada, converted patients from EPO to DPO over the period July 2004 to April 2006. The starting dose-conversion ratio was 200:1. The dose of DPO was changed, as needed, to achieve the same target hemoglobin (Hb) as before the conversion (110-120 g/L). For 3 to 6 months before conversion, and for 6 to 12 months after, weekly dose of erythropoiesis-stimulating agent, dose-conversion ratio, serum Hb, ferritin, and transferrin saturation were recorded for each patient at all 3 sites. One site also documented medication administration errors before and after the conversion. Data were collected for a total of 442 patients. Baseline patient characteristics were similar across the 3 sites. The median dose-conversion ratio for each hemodialysis centre ranged from 288:1 to 400:1, and the average annual per-patient savings varied between $2140 and $4711. No clinically meaningful differences between EPO and DPO were reported in terms of patients' serum hemoglobin levels, iron dose, or number of transfusions. With DPO, the relative risk of medication administration errors was reduced by 72% (p < 0.001) (based on data from one site). In this real-world evaluation of the clinical effectiveness and cost-efficiency of switching patients from EPO to DPO, patients' clinical outcomes were maintained while considerable reductions in cost were achieved.