Pharmacokinetics of intravenous immunoglobulin (Gammagard) in bone marrow transplant patients.

The pharmacokinetics of an intravenous immunoglobulin (IVIG), Gammagard (Baxter Healthcare Corp., Glendale, CA), were measured in 31 cytomegalovirus (CMV) antibody negative bone marrow transplant (BMT) patients as part of a multicenter efficacy trial of 2 weekly dose regimens. Since all patients lacked antibody to CMV and received only screened CMV negative blood products, the half-life of the exogenous CMV antibody could be measured with an ELISA assay. The CMV antibody titer was related to the immunoglobulin concentration using a standard curve. Compared with the 22-day half-life in normal subjects, the half-life in BMT patients was approximately 6 days for either the 250 mg/kg or 500 mg/kg dose regimen. The half-life did not change over the subsequent 3 weekly doses. Peak concentrations were 3.5 +/- 1.4 and 2.6 +/- 0.7 mg/mL of IVIG in week 1 as well as 5.5 +/- 2.6 and 3.4 +/- 1.2 mg/mL in week 3 after the 250 mg/kg and 500 mg/kg, respectively. Total body clearance of IVIG was 0.61 and 0.46 mL/kg/hr for the 500 mg/kg and 250 mg/kg, respectively.     

A selective LC/RIA for dexamethasone and its prodrug dexamethasone-21-isonicotinate in biological fluids.

A combined LC/RIA procedure is described for the selective determination of dexamethasone (DEX) and its prodrug dexamethasone-21-isonicotinate (DIN) in plasma. The low affinity of the employed dexamethasone antiserum for DIN (cross-reactivity less than 0.5%) allowed the direct determination of DEX in plasma extracts. For the determination of DIN, both substances of interest were separated by LC, the DIN containing fraction was collected, hydrolysed and the generated DEX was consequently assayed by radioimmunoassay. The assay detection limits were 0.1 ng ml-1 for DEX and 0.75 ng ml-1 for DIN. For both substances, inter- and intra-day variabilities (RSDs) were 6 and 12%, respectively.     

Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma.

The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma. Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the anti-inflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance. The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamic-pituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning. Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.     

A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.     

Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation

Quantitative prediction of unbound drug fraction (f_u) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of f_u values under pathological conditions. The primary objective of this study was to predict f_u values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling f_u in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting f_u in hepatic insufficiency, particularly for albumin-bound drugs.     

Nonlinear Protein Binding: Not What You Think

Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system.     

Enhanced in vitro activity of tigecycline in the presence of chelating agents

The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG–TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens.     

Predicting Pediatric Age-Matched Weight and Body Mass Index

The empirical scaling from adult to pediatric using allometric size adjustments based on body weight continued to be the mainstream method for pediatric dose selection. Due to the flexibility of a polynomial function to conform to the data trend, an empirical function for simulating age-matched weight and body mass index by gender in the pediatric population is developed by using a polynomial function and a constant coefficient to describe the interindividual variability in weight. A polynomial of up to fifth order sufficiently described the pediatric data from the Center for Disease Control (CDC) and the World Health Organization (WHO). The coefficients of variation to describe the variability were within 17%. The percentages of the CDC simulated weights for pediatrics between 0 and 5 years that fell outside the WHO 90% and 95% confidence boundaries were well within the expected percentage values, indicating that the CDC dataset can be used to substitute for the WHO dataset for the purpose of pediatric drug development. To illustrate the utility of this empirical function, the CDC-based age-matched weights were simulated and were used in the prediction of the concentration–time profiles of tenofovir in children based on a population pharmacokinetic model whose parameters were allometrically scaled. We have shown that the resulting 95% prediction interval of tenofovir in newborn to 5 years of age was almost identical whether the weights were simulated based on WHO or CDC dataset. The approach is simple and is broadly applicable in adjusting for pediatric dosages using allometry.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9657-9) contains supplementary material, which is available to authorized users.KEY WORDS: Age, Allometry, BMI, Pediatric, Weight     

A sensitive LC-MS/MS method for the quantification of fluticasone propionate in human plasma

A sensitive and selective LC-(APCI) MS/MS method capable of quantifying fluticasone propionate (FP) at levels down to 10 pg ml(-1) in human plasma is reported. The method was validated over a linear range from 10 to 1000 pg ml(-1) using a previously published solid-phase extraction procedure with a 13C3-labeled internal standard. The inter and intra batch precision (coefficient of variation) and accuracy (% bias) of the quality controls samples (20, 25, 50, 100, 200, 500 and 1000 pg ml(-1)) were less than 15 and 11%, respectively. The method is robust, rapid (analysis time of 2 min), selective and hence is ideally suited for pharmacokinetic investigations involving inhalation of therapeutic doses of FP.     

Population pharmacokinetics of eniporide and its metabolite in healthy subjects and patients with acute myocardial infarction

Eniporide (EMD 96 875) is a novel and selective inhibitor of the Na+-H+ exchange (NHE-1) inhibitor. The study objectives were to identify a structural model for population pharmacokinetic analysis of eniporide and its metabolite (EMD 112 843) using nonlinear mixed-effects modeling after short-term infusion (dose: 2.5-400 mg) in healthy subjects and patients undergoing myocardial reperfusion therapy. Pooled concentrations of eniporide and its metabolite from healthy subjects (n = 153; 4815 observations) and patients (n = 304; 1465 observations) were included in the pharmacokinetic analysis. Population estimates of clearance and volume of distribution of eniporide were 29.2 L/h (24.1% coefficient of variation [CV], healthy), 20.8 L/h (28.0% CV, patients) and 20.4 L (13.1% CV, healthy), 16.9 L (24.9% CV, patients), respectively. Statistical significance was achieved for the effect of age on clearance and creatinine clearance on volume of distribution of eniporide. The impact of the covariates on eniporide pharmacokinetics is minimal to warrant any dosage adjustments in patient population.