The issue of treating
sickle cell disease with drugs that increase
hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of
voxelotor, the only antisickling drug approved since
hydroxyurea in 1998.
Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high
oxygen affinity R (oxy) conformation of
hemoglobin S (HbS). Treatment of sickle cell patients with
voxelotor increases Hb levels and decreases indicators of
hemolysis, but with no indication as yet that it reduces the frequency of
pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood
oxygen dissociation curves and red cell sickling in the absence and presence of
voxelotor under the in vivo conditions of rapid
oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in
oxygen delivery from reduced sickling is largely offset by the increase in
oxygen affinity. The net result is that the drug increases overall
oxygen delivery only at the very lowest
oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in
hemolysis. More importantly, our modeling of in vivo
oxygen dissociation, sickling, and
oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase
oxygen affinity.