Hydroxyurea Optimisation in Sickle Cell Disease (PHOENIX-NG)

Pharmacogenetics and Model-Informed Optimisation of Hydroxyurea Therapy in Sickle Cell Disease Patients of Nigerian Descent

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Hydroxyurea (HU)

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Ochuko M. Orherhe, M.Phil.; Phone Number: +2348051589453; Email: oorherhe@oauife.edu.ng
• Study Contact Backup: Name: Babatunde A Adeagbo, PhD; Phone Number: +2348069019643; Email: badeagbo@oauife.edu.ng

Study Locations

• Nigeria
  • Osun State
    • Ile-Ife, Osun State, Nigeria, 220282
      • Obafemi Awolowo University Teaching Hospital Complex
      • Contact: Olusola J Olarewaju; Phone Number: +2348030698673; Email: olarewajuolusolajoseph@gmail.com
      • Contact: Rahman Bolarinwa; Phone Number: +2348037115854; Email: rbolarin@oauife.edu.ng
      • Principal Investigator: Ochuko M Orherhe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study 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.

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 months

Collaborators and Investigators

• Sponsor: Ochuko Orherhe
• Collaborators: Obafemi Awolowo University Teaching Hospital; Obafemi Awolowo University; Consortium for Advanced Research Training in Africa (CARTA)

Study record dates

Study Major Dates

• Study Start (Estimated): May 8, 2026
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: April 15, 2026
• First Submitted That Met QC Criteria: April 15, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hydroxyurea; Pharmacogenetics; Genetic Polymorphism; Clinical Outcomes; Modelling
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Organic Chemicals; Amides; Urea; Hydroxyurea
• Other Study ID Numbers: ERC/2024/07/12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Each study participant will be assigned a study ID. The hard copies of data collection materials will use the study ID only as identifiers and not the personal identifying information. The code linking the data to the patient's personal information will only be available to the me, the principal investigator. However, in the event that a discovery is made in a study particpant that requires medical attention, the attending physician (who are the facility contacts and patients' medical doctors) will be communicated and individual participant data shared with them.