Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 1043-1047 ◽  
Author(s):  
Sherri A. Zimmerman ◽  
William H. Schultz ◽  
Shelly Burgett ◽  
Nicole A. Mortier ◽  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Transcranial Doppler ◽  
Maximum Tolerated Dose ◽  
Multicenter Trial ◽  
Clinical Severity ◽  
Phase 2 Trial ◽  
The Right ◽  
Hydroxyurea Therapy ◽  
Flow Velocities

Abstract Hydroxyurea has hematologic and clinical efficacy in sickle cell anemia (SCA), but its effects on transcranial Doppler (TCD) flow velocities remain undefined. Fifty-nine children initiating hydroxyurea therapy for clinical severity had pretreatment baseline TCD measurements; 37 with increased flow velocities (≥ 140 cm/s) were then enrolled in an institutional review board (IRB)–approved prospective phase 2 trial with TCD velocities measured at maximum tolerated dose (MTD) and one year later. At hydroxyurea MTD (mean ± 1 SD = 27.9 ± 2.7 mg/kg per day), significant decreases were observed in the right middle cerebral artery (MCA) (166 ± 27 cm/s to 135 ± 27 cm/s, P < .001) and left (MCA) (168 ± 26 cm/s to 142 ± 27 cm/s, P < .001) velocities. The magnitude of TCD velocity decline was significantly correlated with the maximal baseline TCD value. At hydroxyurea MTD, 14 of 15 children with conditional baseline TCD values improved, while 5 of 6 with abnormal TCD velocities whose families refused transfusions became less than 200 cm/s. TCD changes were sustained at follow-up. These prospective data indicate that hydroxyurea can significantly decrease elevated TCD flow velocities, often into the normal range. A multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values, and ultimately for primary stroke prevention in children with SCA.

scholarly journals Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Transcranial Doppler Peak Systolic Velocities Overestimate The Risk Of Stroke In Sickle Cell Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2240-2240 ◽  
Author(s):  
Titilope Ishola ◽  
Charles T. Quinn
Keyword(s):  
Clinical Practice ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Transcranial Doppler ◽  
Clinical Care ◽  
Pearson Correlation ◽  
Systematic Bias ◽  
Anatomic Site ◽  
The Right

Abstract Background Children with sickle cell anemia (SCA) have a high risk of stroke that can be estimated by transcranial Doppler ultrasonography (TCD). The gold standard TCD measurement to determine the risk of primary stroke is the time-averaged mean of the maximum velocity (TAMMV) in specific intracranial arteries. Peak systolic velocity (PSV), a different TCD measurement, has been proposed as an alternative method for risk stratification, especially for imaging TCD (TCDi) techniques (Jones et al. 2005). Although PSV has been little studied for this purpose, some centers use PSV in addition to TAMMV for the classification of risk of stroke by TCD for clinical care. A systematic bias in the classification of risk of stroke by PSV (higher or lower compared to TAMMV) would substantially affect medical resources and patient outcomes. Objective Describe the test performance characteristics of PSV compared to TAMMV for the classification of risk of stroke in children with SCA and determine the suitability of PSV for classification of TCDs in clinical practice. Methods We studied all patients in our center with homozygous HbSS, sickle-β0-thalassemia, or sickle-Hb D disease (all genotypes referred to here as SCA) who were ≥2 years of age and had a clinical TCD (all by TCDi technique) between 1998-2013. For each patient, the single most recent TCD performed >30 days from a transfusion was used, except for patients receiving chronic transfusions for whom the TCD before the initiation of chronic transfusions was used. Patients were included only once in this analysis. The highest TAMMV and PSV were recorded for the distal internal carotid artery (DICA), bifurcation and middle cerebral artery on the right and left sides of the brain. The TAMMV in each vessel was classified using modified STOP velocity criteria for TCDi: <155, normal; 155-184, conditional; ≥185 abnormal. The PSV in each vessel was classified using criteria proposed by Jones et al.: <200, normal; 200-249, conditional; ≥250 abnormal. Two overall TCD classifications, using either TAMMV or PSV, were made according to standard STOP methods by considering the worst (most abnormal) classification of any vessel as the overall classification. The primary outcome was the multi-level agreement between overall TCD classification based on TAMMV and PSV as measured by the kappa statistic. Kappa was also calculated for individual vessels to determine if agreement differed by anatomic site. Coefficients of determination (r2) were calculated using Pearson correlation. Results We studied 120 patients with SCA [mean age 12.0 years ± 6.0 (S.D.); 51.1% male]. Fifty-nine (49%) had at least one prior transfusion that was given a mean of 588 (median 387) days before the TCD (none ≤40 days). The distribution of overall TCD classification by simultaneous TAMMV and PSV is shown in the Figure (Panel A). The distribution of classifications by TAMMV, compared to PSV, better approximates the expected distribution in a screening population. Classifications by PSV were skewed higher, giving more conditional and abnormal results, when compared to classification by TAMMV (P<0.0001). Kappa was 0.488 (P<0.001) for overall TCD classification, indicating only moderate agreement between the TAMMV and PSV methods. Agreement between TAMMV and PSV classification was highest (“substantial”) in the right and left DICA (k: 0.657–0.717, P<0.001). Agreement was only moderate in all other vessels (k: 0.428–0.539, P<0.001). Compared to TAMMV, use of PSV resulted in misclassification of 28% of overall TCD interpretations (Figure, Panel B); 32 studies (27%) were up-coded (27 normal to conditional; 5 conditional to abnormal). Only 1 study was down-coded (abnormal to conditional). Considering TAMMV and PSV as continuous variables, TAMMV accounted for 84.2-90.2% (r2) of the variation in PSV across different vessels; so, approximately 10-15% of the variability in PSV is not explained by TAMMV. Conclusions The use of PSV (rather than TAMMV) to classify TCDs overestimates the risk of stroke for almost one-third of children with SCA. This systematic bias will unnecessarily increase anxiety, the frequency of follow-up testing, and use of chronic transfusions for primary stroke prophylaxis. PSV should not be used for primary classification of TCDs in clinical practice. Jones A et al. Can peak systolic velocities be used for prediction of stroke in sickle cell anemia? Pediatr Radiol. 2005;35:66-72. Disclosures: No relevant conflicts of interest to declare.

Pharmacokinetics-Based Individualized Dosing Strategy to Predict Maximum Tolerated Dose of Hydroxyurea in Children with Sickle Cell Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 982-982
Author(s):  
Patrick T. McGann ◽  
Min Dong ◽  
Russell E. Ware ◽  
Alexander A Vinks
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Serum Concentrations ◽  
Individualized Dosing ◽  
Clinical Benefits ◽  
Dosing Strategy ◽  
Sampling Times ◽  
Hydroxyurea Therapy

Abstract Background: Hydroxyurea is the primary disease-modifying therapy for adults and children with sickle cell anemia (SCA). Recent NHLBI guidelines include a recommendation for expanded hydroxyurea use, particularly for young children. The laboratory and clinical benefits of hydroxyurea therapy are optimized when escalated to maximum tolerated dose (MTD), but the process of dose escalation requires expertise and frequent laboratory tests. The time to reach MTD using traditional empirical escalation usually takes >6 months, which can delay the laboratory and clinical benefits. In addition, all children with good adherence at MTD will respond to hydroxyurea, but with substantial interpatient variability in both the MTD itself and the %HbF levels achieved, suggesting important individual differences in pharmacokinetics (PK) that contribute to this phenotypic variability. Objective: The primary objective of this study was to develop an individualized Bayesian adaptive dosing strategy to reduce the time required to reach hydroxyurea MTD for children with SCA. Achieving this objective required the development of a population PK model and identification of the most informative sampling times for Bayesian estimation order to reduce the number of observations required for robust estimation of hydroxyurea PK parameters for individual patients. Methods: PK data at baseline from 96 children with SCA enrolled in the prospective Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175) were used to develop a population PK model using nonlinear mixed effects modeling (NONMEM 7.2). Patient demographics and clinical chemistry measurements were included for covariate analyses. The final model was validated by bootstrap analysis and visual predictive check. To identify the optimal sampling times and number of samples required to robustly estimate individual PK parameters and total hydroxyurea exposure (AUC), a D-optimal design analysis was performed using the final PK model with constraints of clinical feasibility. Results: Hydroxyurea PK profiles were best described by a one compartment model with Michaelis Menten elimination and a transit absorption model. Hydroxyurea serum concentrations showed substantial interpatient variability with AUC on Day 1 ranging from 40.0 to 149.2 mg*h/L. The average AUC at MTD (mean ± SD) was 115.7 ± 34.0 mg*h/L, so this value was chosen as the target hydroxyurea AUC for the final PK model-based approach. Of the tested covariates, body weight and cystatin C were identified as significant predictors of hydroxyurea clearance, but neither serum creatinine nor estimated creatinine clearance was identified as predictors of hydroxyurea clearance. D-optimal design indicated that three serum concentrations collected at 15-20 minutes, 50-60 minutes, and 3 hours after oral administration would accurately estimate systemic hydroxyurea exposure. Figure 1 demonstrates an example from a patient, demonstrating the PK profile obtained using the sparse sampling technique (Panel A) and the modeling to predict a dose that would target a AUC of 115 mg*h/L (Panel B). Conclusions: We have established a PK model-based individualized dosing strategy to predict hydroxyurea MTD in children with SCA. Our selective sampling strategy requires only three serum samples to be collected over 3 hours and is therefore more feasible and practical, particularly for very young children, than traditional hydroxyurea PK analysis that requires frequent blood collections over 6-8 hours. This novel Bayesian approach is being prospectively evaluated in the Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). In TREAT, hydroxyurea concentrations are measured using HPLC after a single oral dose of 20 mg/kg, requiring only 3 fingerstick blood samples over 3 hours for accurate assessment of each patient's unique hydroxyurea PK profile. The predicted MTD is then calculated based on the amount of drug required to meet the target AUC. This strategy has the potential to individualize therapy and optimize the dose titration of hydroxyurea therapy for children with SCA, such that the laboratory and clinical benefits at MTD are achieved more quickly. Disclosures Off Label Use: Hydroxyurea is not FDA-approved for children with sickle cell anemia. Ware:Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Eli Lilly: Other: DSMB membership; Bayer Pharmaceuticals: Consultancy.

Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Correlation Between Cerebral Blood Flow Velocities Measured By Magnetic Resonance and Transcranial Doppler Ultrasound in Children with Sickle Cell Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2496-2496
Author(s):  
Monica L. Hulbert ◽  
Dustin K. Ragan ◽  
Hongyu An ◽  
Cihat Eldeniz ◽  
Geetika Khanna ◽  
...  
Keyword(s):  
Blood Flow ◽  
Magnetic Resonance ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Transcranial Doppler ◽  
Arterial Stenosis ◽  
Acquisition Time ◽  
Transfusion Therapy ◽  
Blood Flow Velocities ◽  
Flow Velocities

Abstract Background Transcranial Doppler (TCD) ultrasonography is the standard stroke screening test for children with sickle cell anemia (SCA). However, approximately 10% of children have inadequate ultrasonographic windows for a successful TCD study, and some clinical sites may lack the equipment or personnel to perform TCDs in children. Magnetic resonance imaging (MRI) techniques can also measure blood flow velocities and could substitute for TCD in these clinical scenarios. We tested the hypothesis that MRI-derived middle cerebral artery (MCA) blood flow velocities would correlate with TCD-derived MCA blood flow velocities in children with SCA. Methods Children age 6 years and up with SCA at their baseline state of health underwent TCD and MRI as part of a prospective clinical study. Imaging TCD of the bilateral MCAs to determine time-average mean of maximum blood flow velocities (TCD-CBFV) were performed using clinical ultrasound equipment. MRIs were performed at 3T without sedation. MRI cerebral time-averaged mean blood flow velocities (MR-CBFV) were measured in the MCAs using phase contrast sequences without cardiac cycle gating to shorten acquisition time and reduce ghosting artifacts. TCD- and MR-CBFV of each hemisphere were compared. Silent cerebral infarctions (SCIs) were categorized as present or absent in each hemisphere. Non-parametric tests were used with a level of significance of <0.05. Statistics were performed in SPSS version 21. Results Twenty hemispheres from 15 children had both TCD-CBFV and MR-CBFV measurements. Median age was 9 years (IQR 6.25-10). In these children, two hemispheres had unobtainable TCDs due to skull thickness, and eight hemispheres had MR-CBFV excluded due to patient motion or poor positioning. The median TCD-CBFV was 116 cm/sec (IQR 90.25-124) and none of the included hemispheres had arterial stenosis or TCD-CBFV in the conditional or abnormal range. Eight included hemispheres were from children receiving chronic blood transfusion therapy for primary or secondary stroke prevention. There was a linear relationship between TCD-CBFV and MR-CBFV (Spearman correlation, ρ=0.781, p<0.001, Figure) although MR-CBFV values were lower than TCD-CBFV values (median difference 32.6%, IQR 26.7-42.8). When evaluating only the children not receiving chronic transfusion therapy, MR-CBFV was significantly higher in 8 hemispheres without SCIs (median 80 cm/sec, IQR 77.8-87.8) than in 4 hemispheres with SCIs (median 60 cm/sec, IQR 44.6-72.3, p=0.004). In a multivariate model adjusting for age, MR-CBFV continued to be associated with presence of SCIs (p=0.036). There was no significant difference in TCD-CBFV when analyzed by SCI status (p=0.2), consistent with published studies of TCD-CBFV and SCIs. Conclusions In this small cohort of children with SCA, MR-CBFV correlated significantly with TCD-CBFV, but MR-CBFV values were approximately 30% lower than TCD-CBFV. This may be due to the method of acquiring MR-CBFV via non-gated methodology, which is known to produce lower blood flow velocity estimates. Further work is needed to determine a threshold for high-risk MR-CBFV values before this modality could be used as a substitute for TCD screening. Lower MR-CBFV was associated with SCIs, suggesting a potential role for MR-CBFV in predicting SCI risk. The relationship between MR-CBFV and SCIs should be explored further. Disclosures Hulbert: Pfizer, Inc.: Other: spouse employment. Fields:NeuroPhage Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4985-4991 ◽  
Author(s):  
Russell E. Ware ◽  
Jenny M. Despotovic ◽  
Nicole A. Mortier ◽  
Jonathan M. Flanagan ◽  
Jin He ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Oral Absorption ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Interpatient Variability ◽  
Nucleotide Polymorphisms ◽  
Hydroxyurea Treatment ◽  
Treatment Responses ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.

scholarly journals Hydroxyurea Pharmacokinetics for Predicting Maximum Tolerated Dose in Children with Sickle Cell Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2707-2707
Author(s):  
Patrick T. McGann ◽  
Alex Sparreboom ◽  
Nicole A Mortier ◽  
Banu Aygun ◽  
Thad A Howard ◽  
...  
Keyword(s):  
Oral Dose ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Coefficient Of Variation ◽  
Maximum Concentration ◽  
Maximum Tolerated Dose ◽  
Oral Clearance ◽  
Predictive Equations ◽  
Starting Dose ◽  
Hydroxyurea Therapy

Abstract Background: Hydroxyurea has emerged as the primary disease-modifying therapy for both children and adults with sickle cell anemia (SCA). New guidelines from the National Heart, Lung, and Blood Institute include a recommendation that all children with SCA be offered hydroxyurea as young as nine months of age, regardless of the frequency or severity of clinical complications. The benefits of hydroxyurea are most evident when the dose is escalated to the maximum tolerated dose (MTD); however, a stable MTD may take 8-12 months to achieve. In this era of personalized medicine, individualized pharmacokinetics (PK) profiles can be used to predict appropriate medication dosing. Accordingly, we investigated hydroxyurea PK data in a large cohort of children with SCA at their first oral dose and at MTD, to understand inter-patient variability and to create an accurate dose prediction model for hydroxyurea MTD. Methods: The Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175) is a longitudinal observational study for children with SCA receiving hydroxyurea therapy. Prospective investigation of hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics is a primary study objective. HUSTLE includes two cohorts of children: a “New Cohort” with children initiating hydroxyurea therapy upon enrollment in the study, and an “Old Cohort” with children already taking hydroxyurea upon study entry. Children in the “New Cohort” received their first oral dose of hydroxyurea 20 mg/kg with formal first-dose PK data collection using peripheral blood analysis at baseline (t=0) followed by 15, 30, 60, 120, 240, and 480 minutes. PK analyses were performed at MTD for both the New and Old Cohorts. Hydroxyurea concentration was determined by a previously described color-based method, testing each sample in triplicate with a standard curve ranging from 0 to 1000mM, and sensitivity as low as 8mM. Results: A total of 97 children with SCA who enrolled in the New Cohort had first-dose hydroxyurea PK analysis, 65 of whom also had a paired PK study at MTD. Another 34 samples from the Old Cohort had PK analysis performed at MTD. Abstract 2707. Table 1.Patient samplesPK analysis timepoint# of patientsTmax(hr)Cmax(mg/mL)CL/F (L/hr)t ½ (hr)AUC (mg¥hr/mL)AllBaseline970.82 ± 0.47 (57.1)26.0 ± 6.60 (25.4)6.77 ± 3.14 (46.4)1.64 ± 0.55 (33.3)91.8 ± 23.0 (25.0)AllMTD990.80 ± 0.52 (65.1)31.2 ± 8.08 (25.9)7.27 ± 2.99 (41.2)1.94 ± 0.87 (44.6)115 ± 24.1 (20.9)PairedBaseline650.82 ± 0.46 (56.4)25.3 ± 5.56 (22.0)7.11 ± 3.16 (44.4)1.73 ± 0.49 (28.5)93.1 ± 23.1 (24.8)PairedMTD650.74 ± 0.47 (62.8)31.0 ± 7.82 (25.2)7.40 ± 3.13 (42.3)1.82 ± 0.89 (48.9)114 ± 22.3 (19.5) Baseline (first-dose) hydroxyurea pharmacokinetics revealed substantial interpatient variability, with a coefficient of variation ranging from ~25% for maximum concentration (Cmax) and area-under-the-curve (AUC) to ~50% for time to maximum concentration (Tmax) and apparent oral clearance (CL/F). At MTD, the PK parameters showed an expected increase in Cmax due to the higher average dose, but a convergence toward AUC of ~115 (mg¥hr/mL) with a reduced coefficient of variation. Based on this target AUC, predictive equations were generated that include PK parameters, but the simplest equation for the starting hydroxyurea dose is: Dose (mg) = 400 – [1000 x creatinine] + [21 x weight]. Conclusions: Individual hydroxyurea absorption patterns for young children with SCA can be used to predict MTD. The starting dose can be optimized by using predictive equations that reflect apparent oral clearance instead of body weight alone, and subsequently titrated by marrow suppression. AUC is the most relevant PK parameter, and our data show its variability is consistently lower at MTD, with a target AUC of 115 mg.hr/mL. As the use of hydroxyurea therapy expands, we plan a prospective study to tailor the starting dose using a pharmacometrics model involving weight, renal function, and selected PK parameters to rapidly achieve a safe and stable MTD. Disclosures Off Label Use: Hydroxyurea use for children with sickle cell anemia.

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