ABSTRACT
The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2) = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure.
Subject(s)
Anemia, Sickle Cell/metabolism , Antisickling Agents/pharmacokinetics , Hydroxyurea/pharmacokinetics , Models, Biological , Administration, Oral , Adolescent , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/urine , Antisickling Agents/blood , Antisickling Agents/urine , Area Under Curve , Child , Child, Preschool , Female , Humans , Hydroxyurea/blood , Hydroxyurea/urine , MaleABSTRACT
Hydroxyurea (HU) is useful for treating sickle cell anemia because of its ability to reduce some of the severe clinical events such as painful crises and acute chest syndrome. It may also reduce the need for blood transfusions and frequent hospitalizations and reduce mortality. Nevertheless, no consistent recommendations regarding its therapeutic schedule are defined. Our aim was to improve and validate a high performance liquid chromatography (HPLC) technique to measure HU and to study HU levels in serum and urine of sickle cell anemia patients and relate this to treatment efficacy and compliance. Thirty-seven patients received 1,128 +/- 333 mg of HU per day (8.0 to 28.0 mg/kg/day). Plasma and/or urine were sampled and HU was measured using an HPLC method coupled with UV detection. We validated a specific, sensitive assay with good reproducibility and linearity, and showed a positive relationship between plasma HU concentrations and time elapsed between oral HU intake and sampling. We observed plasma HU concentrations were positively correlated with change in mean corpuscular volume (MCV) before and during the treatment. No correlation was obtained between HU concentration and Hb F level.
Subject(s)
Anemia, Sickle Cell/drug therapy , Antisickling Agents/analysis , Antisickling Agents/therapeutic use , Chromatography, High Pressure Liquid/methods , Hydroxyurea/analysis , Hydroxyurea/therapeutic use , Adult , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/urine , Antisickling Agents/blood , Antisickling Agents/urine , Female , Fetal Hemoglobin/analysis , Humans , Hydroxyurea/blood , Hydroxyurea/urine , Male , Middle AgedABSTRACT
Efaproxiral (2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylpropionic acid, formerly referred to as RSR13) is prohibited in sports according to the World Anti-Doping Agency (WADA). The drug as well as structurally related compounds and a stable isotope-labeled derivative have been synthesized to elucidate the fragmentation pathway of efaproxiral, using electrospray ionization (ESI) and tandem mass spectrometry by employing a novel linear ion trap--orbitrap hybrid mass spectrometer--in positive and negative ionization modes. The elimination of 2-methyl acrylic acid (-86 u) has been identified as a major fragmentation process in both charge states. Negative ionization and collision-induced dissociation (CID) caused an additional release of carbon dioxide (-44 u), and positive ionization the loss of formic acid (-46 u). Efaproxiral was incorporated into an existing screening procedure for doping controls using solid-phase extraction (SPE) followed by liquid chromatography-tandem mass spectrometry, enabling a limit of detection of 2.5 ng/ml and interday precisions ranging from 7.9 to 13.0%.
Subject(s)
Aniline Compounds/urine , Antisickling Agents/urine , Chromatography, Liquid/methods , Doping in Sports , Propionates/urine , Spectrometry, Mass, Electrospray Ionization/methods , Aniline Compounds/chemistry , Aniline Compounds/pharmacokinetics , Antisickling Agents/chemistry , Antisickling Agents/pharmacokinetics , Chromatography, Liquid/standards , Humans , Propionates/chemistry , Propionates/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/standardsABSTRACT
Hydroxyurea is increasingly used in the treatment of sickle cell disease (SCD) although there is little evidence on how best to monitor treatment and compliance. It is also not known why 10-50% patients do not benefit from the drug and whether some of this resistance is because of pharmacokinetic factors. We have developed an assay using mass spectrometry (MS) to measure urinary concentrations of hydroxyurea. We have used this assay to study 12 children and six adults with SCD taking hydroxyurea and found that urinary hydroxyurea was present for at least 12 h following tablet ingestion. Thirty-five urine samples were analysed that were expected to contain hydroxyurea, based on the reported timing of the last dose and hydroxyurea was detected in 29 (83%) of these. There were also marked differences in urinary hydroxyurea concentrations, suggesting pharmacokinetic variability may explain some of the differences in response to hydroxyurea. Urine samples were also analysed by MS for penicillin metabolites and 43 of the 57 (75%) contained phenoxyacetate, suggesting the ingestion of penicillin within the last 12 h. These assays are potentially useful to study hydroxyurea metabolism further, develop optimal dosing regimes and monitor compliance with treatment.