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

Ware, Russell E.; Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy; Aygün, Banu; Wu, Song; Howard, Thad A.; Sparreboom, Alex

doi:10.1182/blood-2011-07-364190

Cited by 147 publications

(255 citation statements)

References 36 publications

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“…The mean concentrations obtained 2.5 h after ingestion of hydroxyurea in doses of 500 mg, 1000 mg, and 1500 mg per day were 98.31, 190.88, and 302.71 µM, respectively, compatible with the pharmacokinetics of the drug, whose maximum concentration (Cmax) is 793.75 µM for a dose of 2000 mg/day with maximum time (Tmax) of 1.22 h (Ware et al, 2011;Rodriguez et al, 1998). However, it should be noted that there are phenotypic differences in drug metabolism; in rapid metabolizers, Cmax is achieved 15 to 30 min after ingestion, whereas in poor metabolizers Cmax is achieved 60 to 120 min after ingestion (Ware et al, 2011;Rodriguez et al, 1998).…”

Section: Discussionmentioning

confidence: 82%

“…However, it should be noted that there are phenotypic differences in drug metabolism; in rapid metabolizers, Cmax is achieved 15 to 30 min after ingestion, whereas in poor metabolizers Cmax is achieved 60 to 120 min after ingestion (Ware et al, 2011;Rodriguez et al, 1998). Therefore, for therapeutic monitoring of patients treated with HU, the ideal collection time would be 30 min and 1.5 h after drug intake.…”

Section: Discussionmentioning

confidence: 99%

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Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Elias

Carvalho

Soares

et al. 2014

Braz. J. Pharm. Sci.

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Sickle cell anemia (SCA) is a recessively inherited disease characterized by chronic hemolytic anemia, chronic inflammation, and acute episodes of hemolysis. Hydroxyurea (HU) is widely used to increase the levels of fetal hemoglobin (HbF). The objective of this study was to standardize and validate a method for the quantification of HU in human plasma by using ultra high performance liquid chromatography (UPLC) in order to determine the plasma HU levels in adult patients with SCA who had been treated with HU. We used an analytical reverse phase column (Nucleosil C18) with a mobile phase consisting of acetonitrile/water (16.7/83.3). The retention times of HU, urea, and methylurea were 6.7, 7.7, and 11.4 min, respectively. All parameters of the validation process were defined. To determine the precision and accuracy of quality controls, HU in plasma was used at concentrations of 100, 740, and 1600 µM, with methylurea as the internal standard. Linearity was assessed in the range of 50-1600 µM HU in plasma, obtaining a correlation coefficient of 0.99. The method was accurate and precise and can be used for the quantitative determination of HU for therapeutic monitoring of patients with SCA treated with HU.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Elias

Carvalho

Soares

et al. 2014

Braz. J. Pharm. Sci.

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“…In this study, HU treated patients had a high level of TNF-α. Considering the fact that patients assigned to HU are those with a relatively severe type of disease [40], the observed high levels of TNF-α could be a mere reflection of the well-known heterogeneous biological effects of HU treatment in SCD [41]. Fig.…”

Section: Discussionmentioning

confidence: 99%

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

Daak

Elderdery

Elbashir

et al. 2015

Blood Cells, Molecules, and Diseases

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Chronic inflammation and reduced blood levels of omega-3 fatty acids (n−3) are known characteristics of sickle cell disease (SCD).The anti-inflammatory properties of n−3 fatty acids are well recognized. Omega-3 treated (n = 24), hydroxyurea (HU) treated (n = 18), and n−3 untreated (n = 21) homozygous SCD patients (HbSS) and healthy (HbAA) controls (n = 25) matched for age (5-16 years), gender and socioeconomic status were studied. According to age (5-10) or (11-16) years, two or three capsules containing 277.8 mg docosahexaenoic (DHA) and 39.0 mg eicosapentaenoic (EPA) or high oleic acid placebo (41%) were assigned to n − 3 treated and n − 3 untreated groups, respectively. Hydroxyurea treated group was on dosage more than 20 mg/kg/day. The effect of supplementation on systemic and blood cell markers of inflammation was investigated. The n− 3 treated group had higher levels of DHA and EPA (p b 0.001) and lower white blood cell count and monocyte integrin (p b 0.05) compared with the n−3 untreated. No difference was detected between the two groups regarding C-reactive protein, granulocytes integrin and selectin, plasma tumour necrosis factor-α and interleukin-10. The n−3 treated group had lowered nuclear factor-kappa B (NF-κB) gene expression compared to n−3 untreated and HU treated groups (p b 0.05). This study provides evidence that supplementation with n− 3 fatty acids may ameliorate inflammation and blood cell adhesion in patients with SCD.

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“…The most important one is A118G (Asn40Asp-rs1799971) on the OPRM1 gene [1,18], and the second one is G322A (Val158Met-rs4680) on the COMT gene [2]. When present both at the homozygous state, these two SNPs are associated with the lowest pharmacological efficacy of morphine [19].…”

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confidence: 99%

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

Joly¹,

Gagnieu²,

Bardel³

et al. 2012

American J Hematol

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10. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Much of sickle cell disease (SCD) morbidity is due to recurrent painful crises mainly treated by codeine and morphine. However, surprisingly, there are no genotypic data that relate to the frequency of the main opiate-related SNPs in SCD populations [4]. One may argue that the allelic frequencies for African-Americans (AA) are known and that, since SCD patients are mostly of AA origins, their allelic frequencies should be the same. Obviously, this remark is true but we thought it was important to consider the particular subgroup of SCD patients to ensure that some SNPs were not under-or over-represented because of a founder effect. We, thus, decided to perform, in a cohort of 139 SCD patients, a quite extensive genotyping of these SNPs (Table I) with a haplotypic interpretation for those located on the same locus (Table II).Codeine is a pro-drug inactive by itself until it is metabolized into morphine by the CYP2D6 pathway. After oral or parenteral administration, morphine is partially metabolized by the CYP3A pathway (CYP3A4 and CYP3A5 genes) and by the UGT2B7 enzyme. Independently, an increased ABCB1 activity (a well-known drug efflux protein) is also expected to decrease the bioavailability of both morphine (brain efflux) and codeine (gut efflux) [10]. Very logically, the most frequent polymorphisms that modify the enzymatic activity were chosen for each pathway. For the CYP3A pathway, we genotyped two SNPs associated with a lower CYP3A activity: rs2740574 (A-392G 5 *1B allele) on the CYP3A4 gene (wild-type *1A) and rs776746 (A6986G 5 *3 allele) on the CYP3A5 gene (wild-type *1) [11]. For the UGT2B7 gene, we genotyped two SNPs associated with a lower glucuronidation of morphine and codeine: rs7438135 (A-840G) and rs73823859 (G-79A) [12,13]. For the CYP2D6 gene, we searched: (i) two polymorphisms associated with a null activity: rs892097 (G1846A 5 *4 allele) and the whole gene deletion (*5 allele), (ii) a SNP associated with an intermediate activity and very prevalent in the African population: rs28371706 (C1023T 5 *17 allele), and (iii) a gene duplication associated with an enhanced activity [8,14]. For the ABCB1 gene, we genotyped three SNPs associated with a variation (decrease or increase) of the efflux activity for many drugs: rs1128503 (C1236T) on exon 12, rs2032582 (G2677T) on exon 21 and rs1045642 (C3435T) on exon 26 [15]. Interestingly, the mutant T nucleotide for rs1045642 has been associated with a better morphine pain relief in two independent studies [16,17]. By taking these three SNPs together, some authors have defined the three main ABCB1 haplotypes [6,7]: (i) the *1 allele (C/G/C) which is the wild-type allele, (ii) the *2 allele (T/T/T), and (iii) the *2Kr allele (C/G/T).Two SNPs are mainly responsible for a lower analgesic effect of opioids. The most important one is A118G (Asn40Asp-rs1799971) on the OPRM1 gene [1,18], and the second one is G322A (Val158Met-rs4680) on the C...

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

Abstract: Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA

Cited by 147 publications

References 36 publications

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

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