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Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia
Jane S Hankins1, Lynn W Wynn, Carlo Brugnara
1Comprehensive Sickle Cell Center, St Jude Children's Research Hospital, Memphis, TN 38105, USA. jane.hankins@stjude.org
Insights
This study found that the maximum tolerated dose of magnesium pidolate combined with hydroxycarbamide in sickle cell anaemia patients was 125 mg/kg/d. Gastrointestinal side effects were observed, indicating a need for further efficacy studies.
Area of Science:
- Hematology
- Pharmacology
- Pediatrics
Background:
- Sickle cell anaemia involves red blood cell dehydration, increasing HbS concentration and sickling.
- Erythrocyte magnesium can reduce water loss by regulating membrane transporters.
- Hydroxycarbamide (hydroxyurea) increases fetal hemoglobin (HbF) to reduce sickling.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and toxicity of oral magnesium pidolate combined with hydroxycarbamide in children with sickle cell anaemia (HbSS).
- To evaluate the safety and tolerability of this combination therapy.
Main Methods:
- A phase I clinical trial involving cohorts of children with HbSS on stable hydroxycarbamide doses.
- Oral magnesium pidolate was administered for 6 months, with dose escalation across cohorts.
- Laboratory evaluations and toxicity assessments were conducted regularly.
Main Results:
- The MTD of magnesium pidolate in combination with hydroxycarbamide was established at 125 mg/kg/d.
- Dose-limiting toxicities (grade III diarrhea and abdominal pain) occurred within the first month.
- KCl co-transporter activity decreased after 3 months of magnesium pidolate treatment (P = 0.02).
Conclusions:
- The combination of magnesium pidolate and hydroxycarbamide is tolerable up to 125 mg/kg/d in children with sickle cell anaemia.
- Further phase II studies are warranted to investigate the efficacy of this therapeutic combination.
Abstract:
In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.