RESUMO
In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0-24h values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0-24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.
RESUMO
The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.