Bayesian Vancomycin Model Selection for Therapeutic Drug Monitoring in Neonates.

BACKGROUND AND OBJECTIVE: Pharmacokinetic models can inform drug dosing of vancomycin in neonates to optimize therapy. However, the model selected needs to describe the intended population to provide appropriate dose recommendations. Our study aims to identify the population pharmacokinetic (PopPK) model(s) with the best performance to predict vancomycin exposure in neonates in our hospital. METHODS: Relevant published PopPK models for vancomycin in neonates were selected based on demographics and vancomycin dosing strategy. The predictive performance of the models was evaluated in Tucuxi using a local cohort of 69 neonates. Mean absolute error (MAE), relative bias (rBias) and relative root mean square error (rRMSE) were used to quantify the accuracy and precision of the predictive performance of each model for three different approaches: a priori, a posteriori, and Bayesian forecasting for the next course of therapy based on the previous course predictions. A PopPK model was considered clinically acceptable if rBias was between ± 20 and 95% confidence intervals included zero. RESULTS: A total of 25 PopPK models were identified and nine were considered suitable for further evaluation. The model of De Cock et al. 2014 was the only clinically acceptable model based on a priori [MAE 0.35 mg/L, rBias 0.8 % (95% confidence interval (CI) - 7.5, 9.1%), and rRMSE 8.9%], a posteriori [MAE 0.037 mg/L, rBias - 0.23% (95% CI - 1.3, 0.88%), and rRMSE 6.02%] and Bayesian forecasting for the next courses [MAE 0.89 mg/L, rBias 5.45% (95% CI - 8.2, 19.1%), and rRMSE 38.3%) approaches. CONCLUSIONS: The De Cock model was selected based on a comprehensive approach of model selection to individualize vancomycin dosing in our neonates.

Liposomal amphotericin B exposure in critically ill patients: a prospective pharmacokinetic study.

Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal drug. Little is known about its pharmacokinetics (PK) in critically ill patients. The aim of this study was to document the PK of L-AmB in this population. It was also explored if covariates may be identified that influence its exposure. All adult, critically ill patients (at the intensive care unit or hematology ward) treated with L-AmB between October 2016 and January 2020 were eligible for this study. The administered dose was left at the discretion of the treating clinician. Plasma samples were collected at predose and 1, 2, 4, 8, 12, 16, 20 and 24 h postdose at an early (day 2-3) and/or later (≥ day 6) treatment day. Additionally, daily trough concentrations were collected until day 14. Of 33 included patients, 31 were evaluable; their median [IQR] age and body weight was 59 [54-64] years and 68 [59-77] kg, respectively. L-AmB was administered at doses between 2.7 mg/kg and 12.3 mg/kg, with a median [IQR] trough concentration of 3.1 [2.0-4.7] mg/l. The overall median area under the 24 h concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were 169.0 [117.0-253.0] mg h/l and 23.2 [16.9-33.7] mg/l, respectively. A considerable intra- and interpatient PK variability for Cmax and AUC0-24 was observed but no explaining variables, except the administered dose, could be identified. The PK of L-AmB in critically ill patients was documented. A considerable variability in exposure was observed between and within patients; however, it was not associated with a multitude of patient-related characteristics.

L-AmB is marketed for decades to treat invasive fungal infections; however, not much is known about its exposure. We documented L-AmB exposure in 31 critically ill patients. Although median exposure was similar compared to noncritically ill patients, a considerable variability was observed.

Exposure to intravenous posaconazole in critically ill patients with influenza: A pharmacokinetic analysis of the POSA-FLU study.

BACKGROUND: Data on posaconazole in the critically ill are scarce. In the POSA-FLU study, we examined the prevention of influenza-associated pulmonary aspergillosis with posaconazole in this population. METHODS: In this observational sub-study, we performed a pharmacokinetic analysis, including protein binding and target attainment (TA). Blood samples were collected over a 24 h-dosing interval on both an early (Day 2 or 3) and a later (≥Day 4) treatment day. RESULTS: Target attainment was shown for AUC0-24 and Cmin prophylaxis but not for Cmin treatment. Moreover, a saturable protein binding with a significant, positive relationship between albumin concentrations and the maximum binding capacity was observed. CONCLUSIONS: Our analysis indicates that posaconazole may be a suitable drug to further investigate for prophylaxis, as TA for prophylaxis was reached. Exposure targets for treatment were insufficiently attained in this population.

Isavuconazole in the Treatment of Aspergillus fumigatus Fracture-Related Infection: Case Report and Literature Review.

Aspergillus fracture-related infection (FRI) is a rare, but severe complication in trauma surgery. The optimal antifungal treatment for Aspergillus osteomyelitis, including FRI, has not been established yet, as only cases have been documented and data on bone penetration of antifungal drugs are scarce. We describe a patient with Aspergillus fumigatus FRI of the tibia who was treated with isavuconazole after developing liver function disturbances during voriconazole therapy. Isavuconazole, the active moiety formed after hydrolysis of the prodrug isavuconazonium sulfate by plasma esterases, was administered in a maintenance dose of 200 mg q24 h, followed by 150 mg q24 h. The patient completed a six-month antifungal treatment course. Although fracture union was not achieved during six months of follow-up after therapy cessation, no confirmatory signs of FRI were observed. Additionally, two literature searches were conducted to review available data on antifungal treatment of Aspergillus osteomyelitis and bone penetration of antifungals. One hundred and eight cases of Aspergillus osteomyelitis, including six (5.6%) FRI cases, were identified. Voriconazole and (lipid formulations of) amphotericin B were the most commonly used antifungals. In three (2.8%) cases isavuconazole was prescribed as salvage therapy. Data on antifungal bone penetration were reported for itraconazole, voriconazole, amphotericin B, anidulafungin and 5-fluorocytosin. Isavuconazole might be a promising alternative for the treatment of Aspergillus osteomyelitis. However, standardized case documentation is needed to evaluate the efficacy of isavuconazole and other antifungals in the treatment of Aspergillus osteomyelitis, including FRI.

Meropenem Target Attainment and Population Pharmacokinetics in Critically Ill Septic Patients with Preserved or Increased Renal Function.

PURPOSE: Critically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function. PATIENTS AND METHODS: A single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation <70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4. RESULTS: In total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis. CONCLUSION: This study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03560557).

Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients.

Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill patients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10-15 mg/L was selected, corresponding to a free area under the concentration-time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra- and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the predefined target trough concentrations.

Concomitant Treatment with Voriconazole and Flucloxacillin: A Combination to Avoid.

BACKGROUND: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. METHODS: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. RESULTS: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0-1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7-5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (<1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. CONCLUSION: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously.

Interaction between flucloxacillin and azoles: Is isavuconazole next?

BACKGROUND: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. It has been previously reported that an interaction between flucloxacillin and voriconazole may lead to subtherapeutic voriconazole exposure, when used concomitantly. Since isavuconazole is also metabolised via cytochrome P450 enzymes, the same interaction may be expected. OBJECTIVES: We aim to document exposure to isavuconazole in patients concomitantly treated with flucloxacillin. PATIENTS: We report two patients treated with both isavuconazole and flucloxacillin, in whom we determined isavuconazole concentrations. RESULTS: Low isavuconazole trough concentrations (<1 mg/L) were observed in two patients under concomitant treatment with flucloxacillin. CONCLUSIONS: In combination with flucloxacillin, low isavuconazole concentrations were observed but an adequate isavuconazole exposure may be reached with dose augmentation. Therapeutic drug monitoring of isavuconazole is recommended to ensure an adequate exposure.

A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation.

BACKGROUND: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. METHODS: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit's binding sites over time. RESULTS: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2-4.7) mg/L under ECMO and 2.5 (1.4-3.9) mg/L without ECMO (p = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. CONCLUSIONS: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study.

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

Concomitant use of isavuconazole and CYP3A4/5 inducers: Where pharmacogenetics meets pharmacokinetics.

BACKGROUND: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolised by CYP3A4 and CYP3A5, and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450 inducers is contraindicated, although it is known that some CYP450 inducers are less potent in comparison with rifampin. OBJECTIVES: We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction effect has never been studied in combination with the patient's CYP3A genotype. PATIENTS: We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations. RESULTS: These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450 induction interaction. CONCLUSIONS: CYP3A inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low-isavuconazole exposure was observed in the extensive metaboliser with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

PURPOSE: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA. METHODS: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population). RESULTS: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment. CONCLUSION: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

BACKGROUND: Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients. METHODS: Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation. RESULTS: Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day). CONCLUSIONS: Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.

Pharmacokinetics and target attainment of intravenous posaconazole in critically ill patients during extracorporeal membrane oxygenation.

BACKGROUND: Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. OBJECTIVES: To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. METHODS: Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2-3) and a late (Day 4-7) sampling day. Daily trough concentrations were measured. RESULTS: The median (IQR) AUC0-24, CL and Vd were 34.3 (28.3-37.7) mg·h/L, 8.7 (8.0-10.6) L/h and 389 (314-740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. CONCLUSIONS: ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.

Ultra-performance liquid chromatography for quantification of amphotericin B plasma concentrations after use of liposomal amphotericin B.

OBJECTIVES: Liposomal amphotericin B is widely used to treat life-threatening invasive fungal infections and has replaced conventional amphotericin B deoxycholate due to its more favourable toxicity profile. Despite the fact that liposomal amphotericin B has been licensed for several decades, there is still a paucity of clinical pharmacokinetic data. An assay for the quantification of amphotericin B is necessary to allow the study of its pharmacokinetics. METHODS: A UPLC-photodiode array (PDA) analytical method was developed and validated (linearity, accuracy, precision, dilution integrity, carry-over, selectivity and stability) in accordance with EMA requirements. RESULTS: The analytical method was validated over a concentration range of 0.5-50.0 mg/L. Accuracy ranged from 97.6% to 112.1% and within-day repeatability and between-day reproducibility from 1.0% to 6.6% and from 0.4% to 4.6%, respectively, dependent on the concentration. Originally, the goal was to develop an analytical method to separate the liposomal and free amphotericin B fractions, but this was not achieved. Difficulties and bottlenecks encountered are presented. CONCLUSIONS: A UPLC-PDA analytical method was developed to quantify total amphotericin B in plasma after the use of liposomal amphotericin B.

Development and External Validation of an Online Clinical Prediction Model for Augmented Renal Clearance in Adult Mixed Critically Ill Patients: The Augmented Renal Clearance Predictor.

OBJECTIVES: Augmented renal clearance might lead to subtherapeutic plasma levels of drugs with predominant renal clearance. Early identification of augmented renal clearance remains challenging for the ICU physician. We developed and validated our augmented renal clearance predictor, a clinical prediction model for augmented renal clearance on the next day during ICU stay, and made it available via an online calculator. We compared its predictive performance with that of two existing models for augmented renal clearance. DESIGN: Multicenter retrospective registry-based cohort study. SETTING: Three Belgian tertiary care academic hospitals. PATIENTS: Adult medical, surgical, and cardiac surgery ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Development of the prediction model was based on clinical information available during ICU stay. Out of 33,258 ICU days, we found augmented renal clearance on 19.6% of all ICU days in the development cohort. We retained six clinical variables in our augmented renal clearance predictor: day from ICU admission, age, sex, serum creatinine, trauma, and cardiac surgery. We assessed performance by measuring discrimination, calibration, and net benefit. We externally validated the final model in a single-center population (n = 10,259 ICU days). External validation confirmed good performance with an area under the curve of 0.88 (95% CI 0.87-0.88) and a sensitivity and specificity of 84.1 (95% CI 82.5-85.7) and 76.3 (95% CI 75.4-77.2) at the default threshold probability of 0.2, respectively. CONCLUSIONS: Augmented renal clearance on the next day can be predicted with good performance during ICU stay, using routinely collected clinical information that is readily available at bedside. Our augmented renal clearance predictor is available at www.arcpredictor.com.