AIM: The purpose of this analysis was to construct appropriate models to characterise population pharmacokinetics (PK) for PHA-794428 and PK/pharmacodynamics (PD) for the efficacy biomarker Insulin-like Growth factor-...AIM: The purpose of this analysis was to construct appropriate models to characterise population pharmacokinetics (PK) for PHA-794428 and PK/pharmacodynamics (PD) for the efficacy biomarker Insulin-like Growth factor-1 (IGF-1). METHODS: Fifty-six male healthy volunteers were enrolled into a clinical study. Subjects received in a randomised manner 3 subcutaneous injections over 3 periods: i) 3.6 mg recombinant human growth hormone (rhGH), ii) PHA-794428 0, 3, 10, 30, 60, 100, 300 or 500 μg/kg, and iii) PHA-794428 0, 10, or 30 μg/kg. Both PK and IGF-1 data were collected up to 336 h post-dose. The PK and PK/PD models were constructed in 3 stages: i) the PK model was developed, ii) the PK parameters were fixed during IGF-1 model building, iii) PK and IGF-1 data were analysed simultaneously. RESULTS: PHA-794428 exhibited non-linearity with respect to dose. A one-compartment disposition model with parallel linear and non-linear elimination most appropriately described the PHA-794428 serum concentrations versus time data. The absorption of PHA-794428 was characterised as a first-order process involving two absorption rate constants. The nonlinear elimination, characterised in terms of the maximal elimination capacity (Vmax=91.5 μg/h for 70 kg) and Michaelis-Menten constant (Km=73.9 μg/L) describing the concentration at which elimination is at half Vmax. The non-linear elimination pathway is approximately 10 times higher than the linear route (0.129 L/h). PHA-794428 has a limited distribution in the blood (V=4.4 L), due to its large molecular weight. Serum IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production rate. Drug effect was appropriately characterised by a maximum effect (Emax) model. The maximal IGF-1 production rate could increase up to 8-fold across the dose range studied. The PHA-794428 concentration at half Emax (EC50) is 56.5 ng/mL. A negative feedback loop was incorporated into the PK/IGF-1 model. The maximal inhibition (Imax) of IGF-1 on endogenous GH secretion was set to 100% and IC50, the IGF-1 concentration decreasing GH secretion by 50%, was 382 ng/mL. Placebo effect was negligible. CONCLUSION: Serum data of PHA-794428 and IGF-1 could be adequately described by PK and PK/IGF-1 models, which were successfully used to predict the doses and time course of PK and IGF-1 and study design for the subsequent clinical trials in adult patients with growth hormone deficiency (AGHD). PK/PD modelling and simulation demonstrated that PHA-794428 has a potential to return low IGF-1 levels to within the normal range by weekly dosing.展开更多
The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding ...The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.展开更多
The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. ...The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.展开更多
文摘AIM: The purpose of this analysis was to construct appropriate models to characterise population pharmacokinetics (PK) for PHA-794428 and PK/pharmacodynamics (PD) for the efficacy biomarker Insulin-like Growth factor-1 (IGF-1). METHODS: Fifty-six male healthy volunteers were enrolled into a clinical study. Subjects received in a randomised manner 3 subcutaneous injections over 3 periods: i) 3.6 mg recombinant human growth hormone (rhGH), ii) PHA-794428 0, 3, 10, 30, 60, 100, 300 or 500 μg/kg, and iii) PHA-794428 0, 10, or 30 μg/kg. Both PK and IGF-1 data were collected up to 336 h post-dose. The PK and PK/PD models were constructed in 3 stages: i) the PK model was developed, ii) the PK parameters were fixed during IGF-1 model building, iii) PK and IGF-1 data were analysed simultaneously. RESULTS: PHA-794428 exhibited non-linearity with respect to dose. A one-compartment disposition model with parallel linear and non-linear elimination most appropriately described the PHA-794428 serum concentrations versus time data. The absorption of PHA-794428 was characterised as a first-order process involving two absorption rate constants. The nonlinear elimination, characterised in terms of the maximal elimination capacity (Vmax=91.5 μg/h for 70 kg) and Michaelis-Menten constant (Km=73.9 μg/L) describing the concentration at which elimination is at half Vmax. The non-linear elimination pathway is approximately 10 times higher than the linear route (0.129 L/h). PHA-794428 has a limited distribution in the blood (V=4.4 L), due to its large molecular weight. Serum IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production rate. Drug effect was appropriately characterised by a maximum effect (Emax) model. The maximal IGF-1 production rate could increase up to 8-fold across the dose range studied. The PHA-794428 concentration at half Emax (EC50) is 56.5 ng/mL. A negative feedback loop was incorporated into the PK/IGF-1 model. The maximal inhibition (Imax) of IGF-1 on endogenous GH secretion was set to 100% and IC50, the IGF-1 concentration decreasing GH secretion by 50%, was 382 ng/mL. Placebo effect was negligible. CONCLUSION: Serum data of PHA-794428 and IGF-1 could be adequately described by PK and PK/IGF-1 models, which were successfully used to predict the doses and time course of PK and IGF-1 and study design for the subsequent clinical trials in adult patients with growth hormone deficiency (AGHD). PK/PD modelling and simulation demonstrated that PHA-794428 has a potential to return low IGF-1 levels to within the normal range by weekly dosing.
基金The National Natural Science Foundation of China(No.11171065,81130068)the Natural Science Foundation of Jiangsu Province(No.BK2011058)the Fundamental Research Funds for the Central Universities(No.JKPZ2013015)
文摘The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.
基金The 115th Project of Legionary Medical Treatment and Public Health(Grant No.06G023)
文摘The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.
