Stable-Isotope Dilution HPLC–Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples

Marahatta, Anu; Megaraj, Vandana; McGann, Patrick T.; Ware, Russell E.; Setchell, Kenneth D.R.

doi:10.1373/clinchem.2016.263715

Cited by 33 publications

(21 citation statements)

References 31 publications

(36 reference statements)

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“…33,34 We have since miniaturized the hydroxyurea assay further through the development of a highly sensitive and accurate tandem mass spectrometry-based assay (LC-MS/MS) for the quantitative measurement of hydroxyurea, requiring even smaller volumes of blood. 35 Blood collection occurs using novel Volumetric Absorption Microsampling (VAMS) devices (Neoteryx, LLC, Torrance, CA), which store exactly 10 µL and samples can be collected by nger stick or heel stick, which is much preferred compared to venous sampling, for young children. Figure 3 illustrates the microsampling collection process using these VAMS devices.…”

Section: Microsampling and Measurement Of Hydroxyurea Concentrationsmentioning

confidence: 99%

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia

Meier

Creary

Heeney

et al. 2020

Preprint

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Background : Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the United States and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. Methods : HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the United States, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10μL of blood collected at 3 time-points over 3 hours. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. Discussion: HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. Trial registration: ClinicalTrials.gov, NCT03789591. Registered on December 28, 2018.

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Section: Microsampling and Measurement Of Hydroxyurea Concentrationsmentioning

confidence: 99%

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia

Meier

Creary

Heeney

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…All these qualities are compatible with the plasma concentrations found in adults and infants [25,29]. Even if many HU dosage techniques have been published, only those using mass spectrometry as a detector are specific enough not to interfere with endogenous compounds and allow low concentration quantification [30,31,32].…”

Section: Discussionmentioning

confidence: 98%

Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach

Nazon

Sabo

Becker

et al. 2019

JCM

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Background: Hydroxyurea (HU) is a FDA- and EMA-approved drug that earned an important place in the treatment of patients with severe sickle cell anemia (SCA) by showing its efficacy in many studies. This medication is still underused due to fears of physicians and families and must be optimized. Methods: We analyzed our population and identified HU pharmacokinetic (PK) parameters in order to adapt treatment in the future. Working with a pediatric population, we searched for the most indicative sampling time to reduce the number of samples needed. Results: Nine children treated by HU for severe SCA were included for this PK study. HU quantification was made using a validated gas chromatography/mass spectrometry (GC/MS) method. Biological parameters (of effectiveness and compliance) and clinical data were collected. None of the nine children reached the therapeutic target defined by Dong et al. as an area under the curve (AUC) = 115 h.mg/L; four patients were suspected to be non-compliant. Only two patients had an HbF over 20%. The 2 h sample was predictive of the medication exposure (r2 = 0.887). Conclusions: It is urgent to be more efficient in the treatment of SCA, and pharmacokinetics can be an important asset in SCA patients.

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“…Traditional assays may require large volumes of blood which would be difficult to collect, store and ship. With the recent advances in technology for hydroxyurea concentration measurement 31 , as little as 10 microliter of blood collected using dry blood spot cards or micro-sampling devices would be sufficient for hydroxyurea concentration determination. This type of technology offers great convenience for sample collection, storage and shipment, and therefore is promising for use in areas where SCA is most prevalent but where resources are limited.…”

Section: Discussionmentioning

confidence: 99%

“…With recently developed and novel approaches in sample collection and measurement, plasma volumes as low as 10 μL can be sufficient for determination of hydroxyurea concentration. 31 One of the challenges faced in the development of this Bayesian dosing strategy was the lack of consensus on a hydroxyurea exposure target associated with the likelihood of achieving desired clinical outcomes. As a practical compromise, the average value of the AUC obtained from 69 patients at their MTD in the HUSTLE trial was adopted as the initial exposure target.…”

Section: Application Of Bayesian Approach In Hydroxyurea Dosing Inmentioning

confidence: 99%

Opportunities for model-based precision dosing in the treatment of sickle cell anemia

Dong

Mizuno

Vinks

2017

Blood Cells, Molecules, and Diseases

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Hydroxyurea is the primary pharmacotherapy to prevent complications of sickle cell anemia (SCA). Accumulated clinical experience across multiple age ranges has suggested that the use of an individualized maximum tolerated dose (MTD) will achieve optimal benefit of hydroxyurea treatment. However, the current empirical and trial-and-error approach for dose escalation often results in a lengthy titration process and is not strictly implemented in many clinics. Opportunities exist for pharmacokinetics model-based precision dosing of hydroxyurea to quickly achieve individual MTD. This review intends to introduce the use of a quantitative modeling approach including a Bayesian adaptive control strategy for the precision dosing of hydroxyurea. The rationale and practical considerations for the implementation of this approach are discussed. Future research directions with a focus on integrating specific safety and other clinical outcome endpoints into dose selection decision making are also discussed.

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Stable-Isotope Dilution HPLC–Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples

Cited by 33 publications

References 31 publications

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia

Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach

Opportunities for model-based precision dosing in the treatment of sickle cell anemia

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