Multidose optimization simulation of erythropoietin treatment in preterm infants

All preterm infants develop anemia in the first few weeks of life as a result of multiple physiologic, pathophysiologic, and iatrogenic events (1). Among neonates most critically ill, anemia is greatly exacerbated by frequent physician-ordered laboratory tests (2–4). As treatment for anemia, as many as 80% of very-low-birth-weight infants (VLBW) (weighing less than 1,500 g at birth) and 95% of extremely-low-birth-weight infants (weighing less than 1,000 g at birth) receive one or more red blood cell transfusions (RBCTx (5)). The efficacy of RBCTx, measured in terms of improving tissue oxygenation, is not always apparent. Moreover, RBCTx as given to preterm infants are expensive and can be associated with complications that include microbial infections, retinopathy of prematurity, and electrolyte perturbations (6). The hormone erythropoietin (Epo) stimulates red blood cell (RBC) production and has been investigated as an alternative therapy for the treatment and prevention of neonatal anemia. A meta-analysis of 27 Epo clinical trials in VLBW and extremely-low-birth-weight infants in which the goal was to reduce RBCTx concluded that the effect of Epo in reducing RBCTx in preterm infants was too limited to be of clinical importance (6). However, this conclusion may be challenged for several reasons. First, there are difficulties in combining many clinical trials into a meta-analysis because of the heterogeneity of studies employing different Epo doses and schedules, different routes of Epo administration, different RBCTx criteria, different definitions of success, and different enrollment criteria. Second, the empirical choice of dosing used in some Epo clinical trials is limited because the trials were not designed to recognize the individual responsiveness to Epo treatment (different pharmacodynamics (PD)). An attractive alternative approach to the design of Epo clinical trials in preterm infants is a personalized medicine approach in which Epo’s complex pharmacokinetics (PK) and PD are more fully considered. This powerful PK/PD approach is attractive because it considers how individual infants respond to Epo. Thus, this approach can be used to develop an optimized Epo dosing regimen that both (a) targets subsets of infants predicted to be the most responsive to treatment with Epo and (b) identifies those unlikely to respond. Unfortunately, compared with the extensive Epo PK/PD studies in adults, only limited Epo PK/PD data exist in this difficult-to-study infant patient group. The mechanism of action for the clearance of Epo in both adults and infants has been identified as nonlinear, Epo receptor (EpoR)-mediated endocytosis (5,7–9) followed by lysosomal degradation(10). Determining preterm infants’ PD response to Epo is experimentally demanding because it requires an accurate, real-time evaluation of hemoglobin (Hb) production, a procedure that is greatly impacted by the numerous phlebotomies and RBCTx very premature infants receive (1). Recently, our research group overcame these problems using a mass balance approach to determine Hb production in 14 critically ill VLBW preterm infants studied for factors impacting endogenous erythropoiesis. This approach required meticulous accounting for Hb transfused and Hb removed by phlebotomy for RBC losses caused by senescence and for expanding blood volume as a consequence of growth (11). The sample size was not specifically determined for the present study because this study represents a secondary analysis of data from a yet-to-be published study whose aims/hypothesis required a sample size of 24 VLBW infants.