Pharmacokinetic-pharmacodynamic modeling of alpha interferon response induced by a Toll-like 7 receptor agonist in mice.

Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.

The influence of labour on the pharmacokinetics of intravenously administered amoxicillin in pregnant women.

AIMS: Many physiological changes take place during pregnancy and labour. These might change the pharmacokinetics of amoxicillin, necessitating adjustment of the dose for prevention of neonatal infections. We investigated the influence of labour on the pharmacokinetics of amoxicillin. METHODS: Pregnant women before and during labour were recruited and treated with amoxicillin intravenously. A postpartum dose was offered. Blood samples were obtained and amoxicillin concentrations were determined using high-pressure liquid chromatography. The pharmacokinetics were characterized by nonlinear mixed-effects modelling using NONMEM. RESULTS: The pharmacokinetics of amoxicillin in 34 patients was best described by a three-compartment model. Moderate interindividual variability was identified in CL, central and peripheral volumes of distribution. The volume of distribution (V) increased with an increasing amount of oedema. Labour influenced the parameter estimate of peripheral volume of distribution (V(2)). V(2) was decreased during labour, and even more in the immediate postpartum period. For all patients the population estimates (mean +/- SE) for CL and V were 21.1 +/- 4.1 l h(-1) (CL), 8.7 +/- 6.6 l (V(1)), 11.8 +/- 7.7 l (V(2)) and 20.5 +/- 15.4 l (V(3)) respectively. CONCLUSIONS: The peripheral distribution volume of amoxicillin in pregnant women during labour and immediately postpartum is decreased. However, these changes are not clinically relevant and do not warrant deviations from the recommended dosing regimen for amoxicillin during labour in healthy pregnant patients.

Population pharmacokinetics of lorazepam and midazolam and their metabolites in intensive care patients on continuous venovenous hemofiltration.

BACKGROUND: The objective is to study the population pharmacokinetics of lorazepam and midazolam in critically ill patients with acute renal failure who are treated with continuous venovenous hemofiltration (CVVH). METHODS: Twenty critically ill patients with acute renal failure on CVVH therapy were administered either lorazepam (n = 10) or midazolam (n = 10) by continuous infusion. CVVH was performed with an ultrafiltrate flow of 2 L/h with filtrate substitution in the predilution or postdilution mode. Blood flow through the 1.9-m 2 cellulose triacetate membrane filter was 180 mL/min. For 48 hours, multiple blood and ultrafiltrate samples were obtained for determination of concentrations of the drug and its metabolites. RESULTS: The pharmacokinetics of lorazepam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 6.4 L/h, and volume of distribution was 376 L. Ultrafiltration clearance was 0.31 L/h, equivalent to approximately 5% of total clearance. Average degree of plasma protein binding was 82.9% for lorazepam, with a sieving coefficient of 0.16 +/- 0.03. For lorazepamglucuronide, degree of plasma protein binding was 39.5%, and sieving coefficient was 0.48 +/- 0.07. The pharmacokinetics of midazolam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 8.5 L/h, and volume of distribution was 157 L. Clearance by ultrafiltration was 0.055 L/h, equivalent to approximately 0.7% of total clearance. Average degree of plasma protein binding was 95.8%, with a sieving coefficient of 0.04 +/- 0.03. For the metabolite 1-hydroxymidazolamglucuronide, average degree of plasma protein binding was 43.4%, with a sieving coefficient of 0.45 +/- 0.06. CONCLUSION: Neither lorazepam nor midazolam is removed efficiently by CVVH. CVVH contributes significantly to the removal of the glucuronide metabolites lorazepamglucuronide and 1-hydroxymidazolamglucuronide.

Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis.

Mechanism-based PK-PD models differ from conventional PK-PD models in that they contain specific expressions to characterize, in a quantitative manner, processes on the causal path between drug administration and effect. This includes target site distribution, target binding and activation, pharmacodynamic interactions, transduction, and homeostatic feedback mechanisms. As the final step, the effects on disease processes and disease progression are considered. Particularly through the incorporation of concepts from receptor theory and dynamical systems analysis, important progress has been made in the field of mechanism-based PK-PD modeling. This has yielded models with much-improved properties for extrapolation and prediction. These models constitute a theoretical basis for rational drug discovery and development.

Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients.

OBJECTIVE: The objective of the present investigation was to develop a population pharmacodynamic model for midazolam- and lorazepam-induced sedation upon long-term continuous infusion in critically ill patients. METHODS: The study was conducted in 59 patients receiving lorazepam and 54 patients receiving midazolam by continuous infusion for at least 24 h. Repeated blood samples were obtained for determination of the concentrations of lorazepam and midazolam. The level of sedation was assessed using a 5-point sedation scale. RESULTS: The pharmacokinetics of lorazepam and midazolam was described with previously proposed pharmacokinetic models. For the pharmacodynamics, the probability that the sedation was equal to or more than a specific score was described using a sigmoid E(max) model. The EC(50) values of lorazepam for the sedation scores equal or larger than 2-5 were 6.1, 57, 184 and 529 ng/ml, respectively. The corresponding values for midazolam were 216, 483, 1,100 and 2,200 ng/ml. Inter-individual variability in the EC(50) values was relatively high with a CV of 68% for lorazepam and 86% for midazolam (p=0.035). No covariates explaining part of the observed inter-individual variability were identified. CONCLUSION: The population pharmacodynamic model shows a similarly wide intra- and inter-individual variability in the pharmacodynamics of both lorazepam and midazolam. Thus, the previously observed differences in "ease of titration" between lorazepam and midazolam are unrelated to pharmacodynamic factors.

Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients.

AIMS: It is well established that there is a wide intra- and interindividual variability in dose requirements for lorazepam and midazolam in intensive care patients. The objective of this study was to compare the population pharmacokinetics of lorazepam and midazolam after long-term continuous infusion in mechanically ventilated critically ill patients. METHODS: Forty-nine critically ill patients randomly received either lorazepam (n = 28) or midazolam (n = 21) by continuous infusion for at least 24 h. Multiple blood samples were obtained for determination of the drug and metabolite concentrations by HPLC. Population pharmacokinetic models were developed using the Non-Linear Mixed Effect Modelling (NONMEM) program. The influence of selected covariates was investigated. The prospective performance of the models was evaluated on the basis of results in separate groups of patients for lorazepam (n = 31) and midazolam (n = 33). RESULTS: The pharmacokinetics of lorazepam were best described by a two-compartment model. Alcohol abuse, positive end expiratory pressure (PEEP) and age were identified as significant covariates. Total body clearance for patients without alcohol abuse was 4.13 - (PEEP - 5) x 0.42 l h-1, and 0.74 l h-1 for patients with alcohol abuse. The volume of distribution was 0.74 l, the steady state volume of distribution was 56 - (age - 58) x 2.1 l and the intercompartmental clearance was 10 l h-1. The proportional residual error was 15% and the median absolute prediction error was 13.6% with a bias of 1.5%. The pharmacokinetics of midazolam were best described by a two-compartment model with alcohol abuse, APACHE score and age as significant covariates. Total body clearance for patients without alcohol abuse was 11.3 - (age - 57) x 0.14 l h-1, and 7.27 - (age -57) x 0.14 l h-1 for patients with alcohol abuse. The volume of distribution was 7.15 l, the steady state volume of distribution was 431 l, and the intercompartmental clearance was 40.8 - (APACHE score - 26) x 2.75 l h-1. The proportional residual error was 31% with an additive residual error of 32 ng ml-1. The median absolute prediction error was 12.9% with a bias of 1.2%. The prospective performance in the lorazepam evaluation group was better with the covariate adjusted model, but in the midazolam evaluation group it was not better than with the simple model. In all models a tendency to overestimate the lower plasma concentrations was observed. CONCLUSIONS: The pharmacokinetics of both lorazepam and midazolam were well described by a two-compartment model. Inclusion of alcohol abuse and age as covariates improved both models. PEEP was identified as an additional covariate for lorazepam, and the APACHE score for midazolam. For both drugs there is a large interindividual variability in their pharmacokinetics when used for long-term sedation in critically ill patients. However, the intra-individual variability is much lower for lorazepam.