Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.

Validation of an HPLC method for estimation of cefotaxime from dried blood spot: alternative to plasma-based PK evaluation in neonates

Aim: Pharmacokinetic evaluation of cefotaxime in neonates is currently a challenge due to the large volume requirement of blood for its analysis by existing methods. A dried blood spot (DBS) based method is the best alternative. Materials & methods: We validated an HPLC method for estimation of cefotaxime from DBS and plasma. Extraction employed a simple procedure using acetonitrile and buffer. Selective separation of cefotaxime was achieved on a C8 column using gradient programming. Results & conclusion: The linearity of the method ranged from 2 to 200 μg/ml with acceptable precision and accuracy for both plasma and DBS. Hematocrit was not affecting the assay accuracy. A strong correlation and interchangeability observed with the plasma method proves its clinical validity for application to PK evaluations.