Population Pharmacokinetic and Exposure–Response Analyses of Prasugrel in Pediatric Patients with Sickle Cell Anemia

• Published in: Clinical pharmacokinetics Vol. 57; no. 2; pp. 243 - 254
• Main Authors: Moser, Brian A., LaBell, Elizabeth S., Chigutsa, Emmanuel, Jakubowski, Joseph A., Small, David S.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2018; Springer Nature B.V
• Subjects: Acute coronary syndromes; Adenosine diphosphate; Adolescent; Anemia, Sickle Cell - drug therapy; Blood platelets; Cardiovascular disease; Child; Child, Preschool; Double-Blind Method; Drug dosages; FDA approval; Female; Hemoglobin; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Models, Biological; Original Research Article; Pain; Pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - pharmacokinetics; Population; Prasugrel Hydrochloride - administration & dosage; Prasugrel Hydrochloride - adverse effects; Prasugrel Hydrochloride - pharmacokinetics; Randomized Controlled Trials as Topic; Sickle cell anemia; Sickle cell disease; Studies; United States > US
• DOI: 10.1007/s40262-017-0556-y
• ISSN: 0312-5963; 1179-1926

Background and Objective Prasugrel, a P2Y 12 adenosine diphosphate (ADP) receptor antagonist, inhibits ADP-mediated platelet activation and aggregation in patients with sickle cell anemia (SCA). We developed a population pharmacokinetic (popPK) model in pediatric patients from 2 to <18 years of age with SCA, and performed exposure–response evaluations to characterize the effects of prasugrel in a subset of these patients who weighed 19 kg or more and experienced at least two episodes of vaso-occlusive crises (VOC) in the past year. Methods A three-compartment popPK model adapted from that used in adults with acute coronary syndrome was used to describe the relationship between plasma concentrations of prasugrel’s active metabolite (Pras-AM) and time using data from phase II and III clinical studies in children. A VOC event rate model was developed from the phase III study to explore the exposure–response relationship between Pras-AM exposure and VOC, and included evaluation of covariates. Results The final popPK model for children with SCA provided a reasonable fit to Pras-AM plasma concentrations over time, with estimates of apparent clearance (CL/F) (172 L/h) and apparent volume of distribution (Vd/F) (51.7 L) that were comparable to previous studies in adults. The final model included weight as a covariate on both CL/F and Vd/F, and age as a covariate on CL/F. Analyses of safety (bleeding events requiring medical intervention) and efficacy (VOC event rate) variables showed no apparent relationship to model-predicted Pras-AM exposure quartiles, and no statistically significant effects of intrinsic or extrinsic factors on the VOC event rate were identified in the VOC event rate model. The effect of post hoc exposures on the VOC event rate did not reach statistical significance. Conclusions A popPK model was developed that provided reasonable parameter estimates, goodness-of-fit diagnostics, and visual predictive checks when applied to Pras-AM plasma concentrations in pediatric patients with SCA. Post hoc exposures obtained from this model did not correlate with measures of VOC or bleeding events in this population.