Intrapulmonary pharmacokinetics of high doses of tigecycline in patients with ventilator-associated pneumonia.

Tigecycline is commonly used for infections by multidrug-resistant bacteria. However, it is not approved for ventilator-associated pneumonia (VAP) as increased mortality has been reported in VAP patients treated with conventional doses. The purpose of this study was to prospectively evaluate the intrapulmonary pharmacokinetics of off-label high-dose tigecycline in patients with VAP. Nine mechanically ventilated patients received tigecycline intravenously (loading dose 200 mg followed by 100 mg every 12 h). After ≥5 doses, two bronchoscopies were performed in each patient on consecutive days and eight blood samples were collected. Tigecycline concentrations in plasma and bronchoalveolar lavage fluid were determined by liquid chromatography. The urea dilution method was used to calculate epithelial lining fluid (ELF) concentrations. A two-compartmental pharmacokinetic (PK) model with linear elimination was used to estimate PK parameters. Mean patient age was 69 ± 11.86 years and mean APACHE II score was 21. The estimated population mean PK parameters (relative standard error) were: clearance, 11.64 L/h (54%); volume of distribution in central compartment, 79.01 L (37%); volume of distribution in peripheral compartment, 92.95 L (17%); intercompartmental clearance, 62.81 L/h (34%); and ELF penetration ratio, 2.41 (40%). Cmax, Cmin, plasma AUC0-12, plasma fAUC0-12 and ELF AUC0-12 were 1.99 ± 1.82 µg/mL, 0.81 ± 1.27 µg/mL, 12.89 ± 17.25 µg•h/mL, 3.24 ± 3.09 µg•h/mL and 7.13 ± 2.61 µg•h/mL, respectively. The increased plasma and ELF AUC0-12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.

Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time.

OBJECTIVES: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. METHODS: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. KEY FINDINGS: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 µm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 µm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 µm × min), no patient below 900 µm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. CONCLUSIONS: TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.

Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

The effect of athletes` hyperhydration on the urinary 'steroid profile' markers in doping control analysis.

The urinary 'steroid profile' in doping control analysis is a powerful tool aimed at detecting intra-individual deviations related to the abuse of endogenous steroids. Factors altering the steroid profile include, among others, the excessive fluid intake leading to low endogenous steroids concentrations compared to an individual's normal values. Cases report the use of hyperhydration by athletes as a masking method during anti-doping urine sample collection. Seven healthy physically active non-smoking Caucasian males were examined for a 72-hour period using water and a commercial sports drink as hyperhydration agents (20 mL/kg body weight). Urine samples were collected and analyzed according to World Anti-Doping Agency (WADA) technical documents. Although, significant differences were observed on the endogenous steroid concentrations under the studied hyperhydration conditions, specific gravity adjustment based on a reference value of 1.020 can eliminate the dilution induced effect. Adjustment methods based on creatinine and urinary flow rate were also examined; however, specific gravity was the optimum method in terms of effectiveness to adjust concentrations close to the baseline steroid profile and practicability. No significant effect on the urinary steroid ratios was observed with variability values within 30% of the mean for the majority of data. Furthermore, no masking on the detection ability of endogenous steroids was observed due to hyperhydration. It can be concluded that any deviation on the endogenous steroid concentrations due to excessive fluid intake can be compensated by the specific gravity adjustment and therefore, hyperhydration is not effective as a masking method on the detection of the abuse of endogenous steroids.

Pharmacokinetics of doripenem in CSF of patients with non-inflamed meninges.

OBJECTIVES: To investigate intact blood-brain barrier (BBB) penetration by doripenem and characterize doripenem pharmacokinetics in CSF using a pharmacokinetic model. PATIENTS AND METHODS: Thirty-eight neurological patients with no active neurological disease or CNS infection received a single 500 mg doripenem dose before pump implantation surgery, or lumbar puncture, for intrathecal baclofen administration. In most cases single CSF and blood samples were collected per patient and analysed for doripenem with HPLC. A two-stage pharmacokinetic analysis was performed to estimate: (i) empirical Bayesian estimates (EBEs) of individual doripenem plasma pharmacokinetic parameters, using plasma doripenem concentrations and literature population priors for a two-compartment model; and (ii) doripenem CSF pharmacokinetic parameters using simulated plasma concentrations from stage (i) as a forcing function. The mean values of the structural model parameters, k(CSF) (distribution rate constant) and PC (CSF/plasma partition coefficient), and the residual variability were estimated. RESULTS: The mean estimates of the parameters were k(CSF)= 0.105 h(-1) and PC= 0.053, corresponding to mean steady-state doripenem CSF concentrations of 0.20 mg/L and 0.40 mg/L for regimens of 3 × 500 mg daily and 3 × 1000 mg daily, respectively, and a mean equilibrium half-life of 6.6 h. The model was validated internally using a visual predictive check (VPC) and bootstrap. Simulating two dosing scenarios gave doripenem levels in the CSF above or close to the literature MIC values. CONCLUSIONS: The present NONMEM software analysis shows that doripenem crosses intact BBB significantly and suggests that the drug should be further evaluated as a candidate to treat certain CNS infections, since drug penetration through BBB is enhanced by meningeal inflammation.

Proper lumping in systems biology models.

An algorithm for automatic order reduction of models defined by large systems of differential equations is presented. The algorithm was developed with systems biology models in mind and the motivation behind it is to develop mechanistic pharmacokinetic/pharmacodynamic models from already available systems biology models. The approach used for model reduction is proper lumping of the system's states and is based on a search through the possible combinations of lumps. To avoid combinatorial explosion, a heuristic, greedy search strategy is employed and comparison with the full exhaustive search provides evidence that it performs well. The method takes advantage of an apparent property of this kind of systems that lumps remain consistent over different levels of order reduction. Advantages of the method presented include: the variables and parameters of the reduced model retain a specific physiological meaning; the algorithm is automatic and easy to use; it can be used for nonlinear models and can handle parameter uncertainty and constraints. The algorithm was applied to a model of NF-B signalling pathways in order to demonstrate its use and performance. Significant reduction was achieved for the example model, while agreement with the original model was proportional to the size of the reduced model, as expected. The results of the model reduction were compared with a published, intuitively reduced model of NF-B signalling pathways and were found to be in agreement, in terms of the identified key species for the system's kinetic behaviour. The method may provide useful insights which are complementary to the intuitive reduction approach, especially in large systems.

Development of a reaction-limited model of dissolution: application to official dissolution tests experiments.

A reaction-limited model for drug dissolution is developed assuming that the reaction at the solid-liquid interface is controlling the rate of dissolution. The dissolution process is considered as a bidirectional chemical reaction of the undissolved drug species with the free solvent molecules, yielding the dissolved species of drug complex with solvent. This reaction was considered in either sink conditions, where it corresponds to the unidirectional case and the entire amount of the drug is dissolved, or reaching chemical equilibrium, which corresponds to saturation of the solution. The model equation was fitted successfully to dissolution data sets of naproxen and nitrofurantoin formulations measured in the paddle and basket apparatuses, respectively, under various experimental conditions. For comparative purposes these data were also analyzed using three functions based on the diffusion layer model. All functions failed to reveal the governing role of saturation solubility in the dissolution process associated with the diffusion layer model when the conditions for the valid estimation of saturation solubility, established theoretically in this study, were met by the experimental set up employed. Overall, the model developed provides an interesting alternative to the classic approaches of drug dissolution modeling, quantifying the case of reaction-limited dissolution of drugs.

Modelling and simulation in drug absorption processes.

Drug absorption is a complex process dependent upon drug properties such as solubility and permeability, formulation factors, and physiological variables including regional permeability differences, pH, luminal and mucosal enzymes, and intestinal motility, among others. Despite this complexity, various qualitative and quantitative approaches have been proposed for the estimation of oral drug absorption. These approaches are reviewed in this article with particular emphasis on drug dissolution modelling, dynamic systems for oral absorption and absorption models based on structure. The regulatory aspects of oral drug absorption and in particular the biopharmaceutic classification of drugs are also discussed. Models for drug dissolution and release describe adequately the in vitro data, and models for oral drug absorption provide reasonable results. The development of in vitro-in vivo correlations based on the official compendia specifications are facilitated using commercial computer packages.

Nonlinear dynamics and chaos theory: concepts and applications relevant to pharmacodynamics.

The theory of nonlinear dynamical systems (chaos theory), which deals with deterministic systems that exhibit a complicated, apparently random-looking behavior, has formed an interdisciplinary area of research and has affected almost every field of science in the last 20 years. Life sciences are one of the most applicable areas for the ideas of chaos because of the complexity of biological systems. It is widely appreciated that chaotic behavior dominates physiological systems. This is suggested by experimental studies and has also been encouraged by very successful modeling. Pharmacodynamics are very tightly associated with complex physiological processes, and the implications of this relation demand that the new approach of nonlinear dynamics should be adopted in greater extent in pharmacodynamic studies. This is necessary not only for the sake of more detailed study, but mainly because nonlinear dynamics suggest a whole new rationale, fundamentally different from the classic approach. In this work the basic principles of dynamical systems are presented and applications of nonlinear dynamics in topics relevant to drug research and especially to pharmacodynamics are reviewed. Special attention is focused on three major fields of physiological systems with great importance in pharmacotherapy, namely cardiovascular, central nervous, and endocrine systems, where tools and concepts from nonlinear dynamics have been applied.

Modeling of supersaturated dissolution data.

A recursion equation which relies on the population growth model of dissolution is used for the analysis of supersaturated dissolution data. The concentration-time data of dissolution experiments are initially transformed to fractions of dose dissolved-generations by adopting an appropriate time interval as the time step of the recursion equation. A computer program is used to derive estimates for the maximum fraction of dose dissolved and the fraction of dose remaining in solution at steady state. Good fittings were observed when this equation was applied to phenytoin and nifedipine supersaturated dissolution data obtained from literature.

An alternative method for the estimation of the terminal slope when a few data points are available.

Phase plane plots are graphical expressions for differential equations plotting the state derivative dc/dt versus the state c. Using these plots, we developed a novel method for the estimation of the terminal slope from time-concentration data. The values of the derivatives used for the construction of the phase plane plots were calculated by two different methods of numerical differentiation. The first method (D1) is based on the classical calculation of slope of the line connecting two successive data points. The alternative method (D2) relies on an initial second-order polynomial interpolation utilizing three successive data points followed by the calculation of the derivative at each one of the concentration values. A forced-through-zero linear regression of the phase plane plot data is used to derive an estimate for the slope. For comparative purposes, the standard approach based on the semilogarithmic plot was also applied. For a hypothetical drug absorbed by first-order process into a one-compartment model, simulated time-concentration data disturbed by a Gaussian zero mean random error with various coefficients of variation were generated. Various sampling schedules, with two, three, four, or five data points, were utilized for the estimation of the terminal slope. Performances of the proposed methods on simulated data were expressed by means of root-mean-squared error, bias, and standard deviation. In all cases, D2 was superior to D1. The D2 method outperforms the standard method in that it furnishes estimates closer to the real values in all cases when two data points and in most cases when three data points were used. All methods behave similarly when four or five data points were used.

Investigation of absorption kinetics by the phase plane method.

PURPOSE: To develop a simple approach for investigating absorption kinetics, which does not require modeling assumption or intravenous data. METHODS: The concentration (C) -time (t) data are plotted as a phase plane plot (dCldt versus C). Errorless C,t data were generated from one and two compartment models employing first-order, zero-order and Michaelis-menten input kinetics, and the phase plane plots were constructed. A simple test based on the ratio of slopes of the separate linear regression analyses of absorption and elimination data of the phase plane plot is proposed to justify or not the presence of zero order input kinetics. Errant data were used to assess the performance of the test developed. Literature data of theophylline and nitroglycerin formulations were analyzed using the phase plane plot. Input rate-time profiles were constructed for one compartment model drugs utilizing the data of the phase plane plot. RESULTS: The geometric forms of the phase plane plots derived form the errorless data of the various pharmacokinetic models were found to be indicative of the absorption kinetics. Very good resulted were obtained when the test for he discernment of absorption kinetics was applied to errant data. Zero-order absorption kinetics were justified (i) for the transdermal absorption of nitroglycerin and (ii) only for a certain period of time, for the gastrointestinal absorption of theophylline. CONCLUSIONS: Investigation of absorption kinetics can be accomplished with the phase plane method. The cumulative character of the classical percent absorbed versus time plots can be misleading in justifying the presence of zero-order input kinetics.

A population growth model of dissolution.

PURPOSE: To develop a new approach for describing drug dissolution which does not require the presuppositions of time continuity and Fick's law of diffusion and which can be applied to both homogeneous and heterogeneous media. METHODS: The mass dissolved is considered to be a function of a discrete time index specifying successive "generations" (n). The recurrence equation: phi n + 1 = phi n + r(1 - phi n)(1 - phi n X0/theta) was derived for the fractions of dose dissolved phi n and phi n+1, between generations n and n + 1, where r is a dimensionless proportionality constant, X0 is the dose and theta is the amount of drug corresponding to the drug's solubility in the dissolution medium. RESULTS: The equation has two steady state solutions, phi ss = 1 when (X0/theta) < or = 1 and phi ss = theta/X0 when (X0/theta) > 1 and the usual behavior encountered in dissolution studies, i.e, a monotonic exponential increase of phi n reaching asymptotically the steady state when either r < theta/X0 < 1 or r < 1 < theta/X0. Good fits were obtained when the model equation was applied to danazol data after appropriate transformation of the time scale to "generations". The dissolution process is controlled by the two dimensionless parameters theta/X0 and r, which were found to be analogous to the fundamental parameters dose and dissolution number, respectively. The model was also used for the prediction of fraction of dose absorbed for highly permeable drugs. CONCLUSIONS: The model does not rely on diffusion principles and therefore it can be applied under both homogeneous and non-homogeneous conditions. This feature will facilitate the correlation of in vitro dissolution data obtained under homogeneous conditions and in vivo observations adhering to the heterogeneous milieu of the GI tract.