Implication of clinical and paraclinical covariates in the pharmacokinetics of high dose MTX (HD-MTX) in patients with osteosarcoma

Abstract

12022 Background: Methotrexate (MTX) is a mainstay in the treatment of ostosarcoma. MTX is characterized by a narrow therapeutic window, combined with high intra- and inter-patient variabilities. In our institute, safe administration of high dose MTX is ensured by using bayesian, adaptive dosing with feedback strategy. In patients with osteosarcoma, up to 20g/patient MTX is administred following an 8h infusion. From the 6th hour, the dose is tailored according to individual pharmacokinetics parameters, determined in real-time from two early sampling times (T3.5, T4.5) and a reference population. This method enables accurate adjustment of most patients around a target Cend of 10−3 M/L. Still, 15–20% of the patients show reduced MTX elimination rate, thus leading to an overlasting hospitalization time with folate rescue required to prevent severe toxicities. In this work, we studied the relevance of clinical or pareaclinical covariates likely to be associated with the MTX clearance so as to identify patients at risk of impaired elimination with subsequent increase in iatrogeny. Methods: This retrospective study was performed on 49 patients treated with HD-MTX. Population PK parameters were computed using Apis and NonMem routines. The second objective was to predict for how long MTX plasma concentration would remain above 0.2 μM/L, the threshold associated with toxicity, upper which folinic acid is required. Finally, simplified sampling strategy for folate rescue protocol was developed. Results: two covariates (creatinemia and ALAT) have been identified as being correlated with MTX clearance. Besides, simulation of the 0.2μM/L threshold reaching showed that it was possible to predict accurately the time most patients can leave the hospital safely. This, would have led to reduce the hospitalization stay by at least one day in 25% of the patients, thus optimizing their life quality while being cost-effective. Conclusions: in this study, we showed that high dose MTX can be administred safely using an adaptive dosing with drug monitoring strategy. Besides, modelling of MTX PK parameters leads to an accurate estimation of the elimination pattern of this drug, thus enabling a planification of the time patients leave the hospital. No significant financial relationships to disclose.

Pharmacokinetic Modelling of Methotrexate from Routine Clinical Data in Patients with Acute Lymphoblastic Leukemia

“…The MTX is characterized by a narrow therapeutic window combined with high-and inter-patient variability (Dupuis et al, 2006). It has been demonstrated that HDMTX toxicity is directly linked to its exposure time and plasma concentration (Balloy et al, 2007).…”