A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL CR ) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49 ⅐ (CL CR /57) liter/h (57 was the mean population value of CL CR ); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h ؊1 ; bioavailability was 0.825; and lag time was 0.382 h. The CL CR was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.

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.

The objectives of the current work were to develop a predictive population pharmacokinetic (PK)/pharmacodynamic (PD) model for the testosterone (TST) effects of triptorelin (TRP) administered in sustained-release (SR) formulations to patients with prostate cancer and determine the minimal required triptorelin serum concentration (C TRP_min ) to keep the testosterone levels of the patients below or equal to the level of castration (TST Յ0.5 ng/ml). A total of eight healthy male volunteers and 74 patients with prostate cancer received one or two doses of triptorelin injected subcutaneously or intramuscularly. Five different triptorelin formulations were tested. Pharmacokinetic (serum concentration of triptorelin) and pharmacodynamic (TST levels in serum) data were analyzed by using the population approach with NONMEM software (http://www.iconplc. com/technology/products/nonmem/). The PK/PD model was constructed by assembling the agonist nature of triptorelin with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible for the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of K D , the receptor equilibrium dissociation constant of triptorelin, and C TRP_min to keep 95% of the patients castrated were 0.931 and 0.0609 ng/ml, respectively. The semimechanistic nature of the model renders the predictions of the effect of triptorelin on TST possible regardless the type of SR formulation administered, while exploring different designs during the development of new delivery systems.

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