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Hydroxyurea Optimisation in Sickle Cell Disease

ConditionSickle Cell Disease
Trial statusNot yet recruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18+
SponsorOchuko Orherhe

About this trial

The wide interindividual variability in clinical response to hydroxyurea therapy in the management of sickle cell disease has limited its use. These variabilities have been linked to differences in pharmacodynamics, pharmacokinetics, and pharmacogenetics. This study, therefore, aims to enhance understanding of these factors as they relate to hydroxyurea therapy, with the overall goal of developing a precision medicine algorithm.

The study will be a prospective cohort pharmacokinetic study of 100 Nigerian patients with sickle cell disease, including current hydroxyurea users and naive patients. Pharmacodynamic markers will be collected to evaluate response. PopPK and PK-PD models will be developed in Monolix, exposure-response relationships will be analysed in R, and pregnancy, lactation, and paediatrics PBPK models will be developed in Simcyp or PK-SIM to inform dose optimisation.

This study aims to build a pharmacometric model by integrating differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea, which could aid the optimisation of hydroxyurea for sickle cell patients in Nigeria.

The objectives of the study are i. To determine the prevalence of genetic polymorphisms in metabolic enzymes and transporters relevant to the disposition of hydroxyurea in the Nigerian sickle cell disease population, ii. To develop and validate an analytical method for the quantification of hydroxyurea using high-performance liquid chromatography.

iii. To evaluate the influence of genetic and other covariates on hydroxyurea disposition in the Nigerian sickle cell disease population using population pharmacokinetic modelling, iv. To investigate the relationship between hydroxyurea exposure and clinical outcomes (foetal haemoglobin, mean corpuscular volume, reduction in vaso-occlusive crises (VOC), and improved blood count) using pharmacokinetic-pharmacodynamic modelling, v. To develop physiologically-based pharmacokinetic (PBPK) models that could predict hydroxyurea concentrations in special populations of sickle cell disease patients in Nigeria i.e. pregnant women, lactating mothers, breastfed infants, and paediatrics.

vi. To develop a dosing guideline for hydroxyurea therapy in Nigerian sickle cell patients.

Overall, this study will provide scientific knowledge that can enhance clinical decision-making in sickle cell management within the Nigerian population, and the models could serve as a template to optimize hydroxyurea use in this population.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Patients with confirmed diagnosis of sickle cell disease (SCD) (e.g., HbSS, HbSC) and of Nigerian descent.

Patients currently on hydroxyurea therapy or hydroxyurea-naive patients who are willing to commence hydroxyurea therapy.

Patients whose genotypic profile for the major metabolising enzymes has been previously done e.g. CYP2D6.

Patients who consent to be part of the study

Disqualifiers

Patients with severe comorbidities that may significantly alter pharmacokinetics (e.g., advanced renal or hepatic failure)

Patients in acute crisis at the time of sampling.

Patients with documented poor adherence to other medications previously on.

Pregnant females and lactating mothers.

Trial population

The study population for this research comprises patients diagnosed with sickle cell disease (SCD) of Nigerian descent, recruited from selected clinical centres within Nigeria ( Sickle Cell Foundation, Ibadan and the Obafemi Awolowo University Teaching Hospital Complex). They will be consented SCD adult patients who have been on hydroxyurea at least six months before study commencement or who are willing to commence hydroxyurea therapy. In both instances, they will be SCD patients whose genetic profile for the major metabolising enzymes are known.

Trial design

Design model

Cohort

Time perspective

Prospective

Treatments tested in this trial

  • Hydroxyurea (HU)

    Drug

    All study participants are sickle cell disease patients who are currently on hydroxyurea therapy or who would be willing to commence hydroxyurea therapy.

Treatment groups

No treatment groups listed

Trial outcomes

Primary outcomes

1

Increase in foetal haemoglobin

Hydroxyurea exerts its therapeutic effects primarily through the induction of foetal haemoglobin production, thereby inhibiting the polymerization of sickled haemoglobin and ameliorating the pathophysiological sequelae of sickle cell disease. By inhibiting ribonucleotide reductase, hydroxyurea interferes with DNA synthesis, prompting the differentiation of erythroid progenitors into red cells containing elevated levels of foetal haemoglobin.

Time frame
6 months

Secondary outcomes

1

Reduction in frequency of vaso-occlusive crises

The phenotypic expression of the increase in foetal haemoglobin is the overall reduction of the incidences of painful crises due to vaso-occlusion, acute chest syndrome, hospitalizations, and blood transfusions, consequently reducing hospitalisations and morbidity

Time frame
6 months

Other outcomes

Sponsors and contacts

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Ochuko Orherhe

Lead sponsor

Obafemi Awolowo University

Sponsor institution

Consortium for Advanced Research Training in Africa (CARTA)

Collaborator

Obafemi Awolowo University

Collaborator

Obafemi Awolowo University Teaching Hospital

Collaborator

Source ClinicalTrials.gov

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