Population Pharmacokinetics And Outcome Prediction Of Methotrexate Treatment In Ectopic Pregnancies

Objectives:1.To investigate the population pharmacokinetics(PPK) of methotrexate(MTX) in Chinese patients with ectopic pregnancies(EPs) using Nonlinear Mixed Effects Model(NONMEM).2.To analyze predictors of success in an novel MTX protocol of EPs and create a cutoff of pretreatment human chorionic gonadotropin(hCG) in the successful MTX treatment of EPs.Materials and Methods:1.A total of 182 serum concentration measurements obtained from the 59 EP patients treated with intramuscular MTX protocols were collected. All samples were determined by fluorescence polarization immunoassay(FPIA). The effect of a variety of developmental and demographic factors on MTX disposition was investigated using NONMEM approach.2.A group of 31 hemodynamicaly stable women, absence of yolk sac and fetal cardiac activity on transvaginal ultrasonography, no desire for surgical treatment, and with no hepatic, hematologic or renal disease, was electively treated with the MTX protocol(overall intramuscular dosage of 1mg·kg-1 divided to 3 doses at 48-hour intervals given as a course). The diagnosis of EP was made by a nonlaparoscopically algorithm.We accessed the size and the volume of the gestational mass, presence of previous EP, total MTX dosage that patients actually accepted and the pretreatment serum hCG levels et al., and investigated their prognostic value for primary outcome of MTX treatment of EPs.Results:1.The final pharmacokinetic parameters were CL(L·h-1)=9.65±3.8, Vc(L)= 27.9±4.2, Q(L·h-1)=1.7, Vp(L)=15.2, ka(h-1)=2.27, where CL is total body clearance, Vc and Vp are apparent volume of distribution in the central and peripheral compartments, ka is absorption rate constant, Q is intercompartmental clearance. Theinterindividual variabilities in CL and ka were 19% and 58%, respectively. 2. Treatment was successful in 24 cases(77.4%). In these cases, the mean±SD log-transformed serum hCG levels before MTX administration were lower when compared to the levels found in cases of therapeutic failure(2.7511±0.3808 vs. 3.1368±0.3272, respectively; P=0.022). The receiver operating characteristic(ROC) curve analysis showed that a pretreatment serum hCG concentration≤1603.44 mIU·mL-1 was a factor indicative of therapeutic success with sensitivity of 87.5% and specificity of 57.1%. Logistic regression analysis revealed the initial serum hCG concentration to be the only factor that contributed to the success rate(P=0.036).Conclusions:1.A PPK model was developed for intramuscular MTX in women with EPs. Validation studies confirmed the stability, internal validity and predictive performance of the model. Clinical application of the model to patient care may permit selection of an appropriate dosage to achieve target MTX concentrations, thus enabling the clinician and clinical pharmacist to achieve the desired therapeutic effect in women with EPs. However, we didn't find any feature having significant effect on CL, which needs further studies.2.In our protocol, the pretreatment serum concentration of hCG is one of the most important prognostic factors associated with MTX success therapy of EP. When the pretreatment hCG level is >1603.44mIU·mL-1, the MTX treatment of EP is at risk of failure.