Hydroxyurea treatment of sickle cell disease: towards a personalized model-based approach

Abstract

Hydroxyurea is a commonly used drug for the treatment of sickle cell disease. Several studies have demonstrated the efficacy of hydroxyurea in ameliorating disease pathophysiology. However, a lack of consensus on optimal dosing and the need for ongoing toxicity monitoring for myelosuppression limits its utilization. Pharmacokinetic (PK) and pharmacodynamic (PD) studies describe drug-body interactions, and hydroxyurea PK-PD studies have reported wide inter-patient variability. This variability can be explained by a mathematical model taking into consideration different sources of variation such as genetics, epigenetics, phenotypes, and demographics. A PK-PD model provides us with a tool to capture these variant responses of patients to a given drug. The development of an integrated population PK-PD model that can predict individual patient responses and identify optimal dosing would maximize efficacy, limit toxicity, and increase utilization. In this review, we discuss various treatment challenges associated with hydroxyurea. We summarize existing population PK-PD models of hydroxyurea, the gap in the existing models, and the gap in the mechanistic understanding. Lastly, we address how mathematical modeling can be applied to improve our understanding of hydroxyurea’s mechanism of action and to tackle the challenge of inter-patient variability, dose optimization, and non-adherence.

Keywords

Sickle cell disease / hydroxyurea / fetal hemoglobin / pharmacokinetics / pharmacodynamics

References

[1] BrawleyOW,EdwardsLR.National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease..Ann Intern Med2008;148:932-8

[2] BunnHF.Pathogenesis and treatment of sickle cell disease..N Engl J Med1997;337:762-9

[3] SteinbergMH.Management of sickle cell disease..N Engl J Med1999;340:1021-30

[4] ReesDC,GladwinMT.Sickle-cell disease..Lancet2010;376:2018-31

[5] FrenettePS.Sickle cell disease: old discoveries, new concepts, and future promise..J Clin Invest2007;117:850-8.Fi PMCID:PMC1838946

[6] StuartMJ.Sickle-cell disease..Lancet2004;364:1343-60

[7] SerjeantGR.Sickle-cell disease..Lancet1997;350:725-30

[8] FaivreC,BarbolosiD.Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients..Br J Cancer2017;116:344-8 PMCID:PMC5294490

[9] HouyN.Administration of temozolomide: Comparison of conventional and metronomic chemotherapy regimens..J Theor Biol2018;446:71-8

[10] JayachandranD,HannemannRE,RamkrishnaD.Optimal chemotherapy for leukemia: a model-based strategy for individualized treatment..PLoS One2014;9:e109623 PMCID:PMC4195683

[11] JayachandranD,RundellA.Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization..PLoS One2015;10:e0133244 PMCID:PMC4520687

[12] AjmeraI,LaibeC,ChelliahV.The impact of mathematical modeling on the understanding of diabetes and related complications..CPT Pharmacometrics Syst Pharmacol2013;2:e54 PMCID:PMC3731829

[13] WodarzD.Mathematical models of HIV pathogenesis and treatment..Bioessays2002;24:1178-87

[14] YawnBP,Afenyi-AnnanAN.Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members..JAMA2014;312:1033-48

[15] TelenMJ,VercellottiGM.Therapeutic strategies for sickle cell disease: towards a multi-agent approach..Nat Rev Drug Discov2019;18:139-58 PMCID:PMC6645400

[16] RaiP.Drug Therapies for the Management of Sickle Cell Disease..F1000Res2020;9:592 PMCID:PMC7388199

[17] CharacheS,MooreRD.Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia..Medicine (Baltimore)1996;75:300-26

[18] EatonWA.Treating sickle cell disease by targeting HbS polymerization..Blood2017;129:2719-26 PMCID:PMC5437829

[19] TracewellWG,VaughanWP,GwiltPR.Population pharmacokinetics of hydroxyurea in cancer patients..Cancer Chemother Pharmacol1995;35:417-22

[20] VillaniP,RegazziMB,LoriF.Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type I..J Clin Pharmacol1996;36:117-21

[21] SteinbergMH,BartonFB,CharacheS.Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea..Blood1997;89:1078-88

[22] DaviesSC.The role of hydroxyurea in the management of sickle cell disease..Blood Reviews2003;17:99-109

[23] ZhangD,ManwaniD.Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology..Blood2016;127:801-9 PMCID:PMC4760086

[24] AnsariJ.Ischemia-Reperfusion Injury in Sickle Cell Disease: From Basics to Therapeutics..Am J Pathol2019;189:706-18 PMCID:PMC6446225

[25] SteinbergMH,CastroO.The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up..Am J Hematol2010;85:403-8 PMCID:PMC2879711

[26] HankinsJS,NottageK.From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia..Medicine (Baltimore)2014;93:e215 PMCID:PMC4603125

[27] CharacheS,MooreRD.Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia..Blood1992;79:2555-65

[28] ZimmermanSA,DavisJS.Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease..Blood2004;103:2039-45

[29] EsteppJH,KangG.A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy..Am J Hematol2017;92:1333-9 PMCID:PMC5675769

[30] EsteppJH,JohnsonM,HowardSC.Improved hydroxyurea effect with the use of text messaging in children with sickle cell anemia..Pediatr Blood Cancer2014;61:2031-6

[31] CharacheS,MooreRD.Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia..N Engl J Med1995;332:1317-22

[32] WareRE,MortierNA.Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia..Blood2011;118:4985-91 PMCID:PMC3208303

[33] PauleI,HabibiA.Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen..Orphanet J Rare Dis2011;6:30 PMCID:PMC3118100

[34] WiczlingP,PanepintoJA.Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease..J Clin Pharmacol2014;54:1016-22

[35] EsteppJH,ThornburgCD.Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia..J Clin Pharmacol2016;56:298-306 PMCID:PMC4892120

[36] ThornburgCD,TelenM.Adherence to hydroxyurea therapy in children with sickle cell anemia..J Pediatr2010;156:415-9 PMCID:PMC3901082

[37] BrandowAM.Hydroxyurea use in sickle cell disease: the battle with low prescription rates, poor patient compliance and fears of toxicities..Expert Rev Hematol2010;3:255-60 PMCID:PMC3793890

[38] WalkerAL,SparreboomA.Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters..Exp Hematol2011;39:446-56 PMCID:PMC4739778

[39] WalkerAL,FinkelsteinD,SparreboomA.Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics..Am J Physiol Cell Physiol2013;305:C1223-9 PMCID:PMC3882360

[40] ColvinM.The Enzymatic Reduction of Hydroxyurea to Urea by Mouse Liver..Cancer Res1970;30:1516-9

[41] AndraeU.Evidence for the involvement of cytochrome P-450-dependent monooxygenase(s) in the formation of genotoxic metabolites from N-hydroxyurea..Biochem Biophys Res Commun1984;118:409-15

[42] HuangJ,KingSB.Catalase-mediated nitric oxide formation from hydroxyurea..J Med Chem2004;47:3495-501

[43] CokicVP,Beleslin-CokicBB.Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase..J Clin Invest2003;111:231-9 PMCID:PMC151872

[44] IkutaT,CappelliniMD.Mechanism for fetal globin gene expression: role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway..Proc Natl Acad Sci U S A2001;98:1847-52 PMCID:PMC29345

[45] PaceBS,SangermanJ.p38 MAP kinase activation mediates γ-globin gene induction in erythroid progenitors..Exp Hematol2003;31:1089-96

[46] StrouseJJ.Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children..Pediatr Blood Cancer2012;59:365-71 PMCID:PMC3374046

[47] RodriguezGI,WeissGR.A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea..Blood1998;91:1533-41

[48] GwiltPR.Pharmacokinetics and pharmacodynamics of hydroxyurea..Clin Pharmacokinet1998;34:347-58

[49] FabriciusE.Determination of hydroxyurea in mammalian tissues and blood..Rev Eur Etud Clin Biol1971;16:679-83

[50] AdamsonRH,HessSM.The distribution, excretion and metabolism of hydroxyurea-C14..J Pharmacol Exp Ther1965;150:322-34

[51] KovacicP.Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications..Med Hypotheses2011;76:24-31

[52] DiPiroJT.Concepts in clinical pharmacokinetics..ASHP2010;

[53] MouldDR.Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods..CPT Pharmacometrics Syst Pharmacol2013;2:e38 PMCID:PMC3636497

[54] DongM,MizunoT,VinksAA.Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia..Br J Clin Pharmacol2016;81:742-52 PMCID:PMC4799926

[55] McGannPT,DongM.Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia..Am J Hematol2019;94:871-9 PMCID:PMC6639795

[56] DaynekaNL,JuskoWJ.Comparison of four basic models of indirect pharmacodynamic responses..J Pharmacokinet Biopharm1993;21:457-78 PMCID:PMC4207304

[57] MaQ,FarrellJJ.Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea..Pharmacogenomics J2007;7:386-94

[58] GladwinMT,OgnibeneFP.Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease..Br J Haematol2002;116:436-44

[59] NahavandiM,WycheMQ,WinterWP.Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea..Br J Haematol2002;119:855-7

[60] CokicVP,StojilkovicSS,SchechterAN.Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells..Blood2008;111:1117-23 PMCID:PMC2214757

[61] LouTF,MackieA,PaceBS.Hydroxyurea generates nitric oxide in human erythroid cells: mechanisms for gamma-globin gene activation..Exp Biol Med (Maywood)2009;234:1374-82 PMCID:PMC3827858

[62] MabaeraR,ConineSJ.A cell stress signaling model of fetal hemoglobin induction: what doesn’t kill red blood cells may make them stronger..Exp Hematol2008;36:1057-72

[63] WittO,RönndahlG.Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin..Blood2003;101:2001-7

[64] RamakrishnanV.Regulation of γ-globin gene expression involves signaling through the p38 MAPK/CREB1 pathway..Blood Cells Mol Dis2011;47:12-22 PMCID:PMC3695476

[65] ChouYC,LaiZS,ChaoYS.Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells..Mol Cell Biol2015;35:2541-53 PMCID:PMC4475914

[66] BrowningDD,YeRD.Activation of p38 mitogen-activated protein kinase by lipopolysaccharide in human neutrophils requires nitric oxide-dependent cGMP accumulation..J Biol Chem1999;274:537-42

[67] BrowningDD,MartyC.Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase..J Biol Chem2000;275:2811-6

[68] SankaranVG,XuJ.Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A..Science2008;322:1839-42

[69] ZhouD,SunCW,TownesTM.KLF1 regulates BCL11A expression and γ- to β-globin gene switching..Nat Genet2010;42:742-4

[70] XuJ,NiM.Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6..Genes Dev2010;24:783-98 PMCID:PMC2854393

[71] GriecoAJ,GreenNS,BouhassiraEE.Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1..PLoS One2015;10:e0129431 PMCID:PMC4459969

[72] AlmeidaCB,JangJE.Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice..Blood2012;120:2879-88 PMCID:PMC3466969

[73] AlmeidaCB,LeonardoFC.Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea..Blood2015;126:711-20