Software for dosage individualization of voriconazole for immunocompromised patients.

The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVE: We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ. STUDY DESIGN: Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects. RESULTS: Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P < 0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P < 0.001), older age (76 vs 70 years, P < 0.001), and Asian race (49% vs 14%, P < 0.001). CONCLUSIONS: Our model accurately discriminated BRONJ cases from controls among patients on BP therapy.

Quantification by energy dispersive x-ray spectroscopy of alendronate in the diseased jaw bone of patients with bisphosphonate-related jaw osteonecrosis.

OBJECTIVE: Recently, specific in vitro bisphosphonate concentrations have been established for reaching a toxic threshold that could result in the induction of bisphosphonate-related osteonecrosis of the jaw (BRONJ), but these data have not been validated in vivo. The purpose of this study was to quantify the concentration of bisphosphonates (BPs) in the diseased jaw bone of patients experiencing BRONJ. STUDY DESIGN: We hypothesized that if the average natural nitrogen content of mammalian bone is known, the excess of nitrogen in the jaw bone of BRONJ patients is likely to reflect the concentration of amino-BP. To test our hypothesis, jaw bone specimens from patients with BRONJ were acquired after sequestrectomy and analyzed by energy-dispersive X-ray spectroscopy (EDS). RESULTS: The EDS analysis of the bone demonstrated a highly linear correlation between increasing concentrations of BP and the increasing percentage of nitrogen measured at the bone surfaces (R(2) = .9851, P = .0149). CONCLUSIONS: SEM/EDS can be a valuable tool for assessing BP concentration in jaw bone and provides important insight into BP pharmacokinetics and BRONJ.

Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients.

Invasive pulmonary aspergillosis is a life-threatening infection in lung transplant recipients; however, no studies of the pharmacokinetics and pharmacodynamics (PKPD) of echinocandins in transplanted lungs have been reported. We conducted a single-dose prospective study of the intrapulmonary and plasma PKPD of 150 mg of micafungin administered intravenously in 20 adult lung transplant recipients. Epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage performed 3, 5, 8, 18, or 24 h after initiation of infusion. Micafungin concentrations in plasma, ELF, and ACs were determined using high-pressure liquid chromatography. Noncompartmental methods, population analysis, and multiple-dose simulations were used to calculate PKPD parameters. Cmax in plasma, ELF, and ACs was 4.93, 1.38, and 17.41 microg/ml, respectively. The elimination half-life in plasma was 12.1 h. Elevated concentrations in ELF and ACs were sustained during the 24-h sampling period, indicating prolonged compartmental half-lives. The mean micafungin concentration exceeded the MIC90 of Aspergillus fumigatus (0.0156 microg/ml) in plasma (total and free), ELF, and ACs throughout the dosing interval. The area under the time-concentration curve from 0 to 24 h (AUC0-24)/MIC90 ratios in plasma, ELF, and ACs were 5,077, 923.1, and 13,340, respectively. Multiple-dose simulations demonstrated that ELF and AC concentrations of micafungin would continue to increase during 14 days of administration. We conclude that a single 150-mg intravenous dose of micafungin resulted in plasma, ELF, and AC concentrations that exceeded the MIC90 of A. fumigatus for 24 h and that these concentrations would continue to increase during 14 days of administration, supporting its potential activity for prevention and early treatment of pulmonary aspergillosis.

A population pharmacokinetic model of epidural lidocaine in geriatric patients: effects of low-dose dopamine.

The purposes of this study were to develop a population pharmacokinetic (PK) model of epidural lidocaine in geriatric patients, to search for any difference in the PK behavior of epidural lidocaine when dopamine is given concurrently, and to develop a descriptive PK model from which to calculate dosage and infusion regimens of epidural lidocaine to define and achieve desired target goals in either the epidural or the serum compartment. Twenty patients over age 65 years, undergoing peripheral vascular surgery using continuous epidural lidocaine anesthesia, were studied. Ten patients also received an intravenous infusion of placebo (normal saline), whereas 10 other patients received an intravenous infusion of dopamine at 2 mug/kg per minute. Total plasma lidocaine concentrations (gas-chromatographic assay) were measured from arterial samples just before injecting the first epidural dose (baseline) and then at 5, 15, 30, 60, 90, and 120 minutes and hourly thereafter. Samples were also taken when the lidocaine infusion was stopped at the end of the surgery and at 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, and 5 hours after surgery. The nonparametric adaptive grid (BigNPAG) computer program in the MM-USCPACK collection was used for population PK modeling to obtain the entire discrete maximum likelihood joint parameter distribution. The assay error polynomial was determined to be 0.2 + 0.05 C. The structural population PK model was linear and had three compartments, each with first-order transfer kinetics. Lidocaine had a very fast transfer rate constant (Ka part + K20) from the epidural space to the serum compartment. This rate was slowed, by over 41%, by dopamine. The mean rate constant of elimination from the serum compartment (K20) was increased by 9.7% by dopamine. The mean rate constant for drug movement from central to peripheral compartment (K23) was increased by 47% in the patients receiving dopamine. The mean rate constant back from the peripheral to the central compartment (K32) was slowed 46% by dopamine. There was no obvious difference in the apparent volume of distribution of the central compartment between the patients given placebo and the patients receiving dopamine. In this model, there was no specific compartment for lidocaine in the cerebrospinal fluid. Cerebrospinal fluid is probably one of the components of the overall peripheral, nonserum compartment in our model. In this first population model of epidural lidocaine using a statistically consistent method, low-dose dopamine appears to decrease the rate of transfer of lidocaine from the epidural to the serum compartment and to increase both the rate of elimination of lidocaine as well as its transfer between the central (serum) and peripheral compartment presumably by increasing tissue perfusion. Serum lidocaine concentrations were slightly less in the patients receiving dopamine. Dosage requirements (overall hourly weight-adjusted infusion rates) were slightly less for the patients receiving dopamine, consistent with the slower removal of lidocaine from the epidural compartment. This model should be useful to design more optimal and individualized epidural lidocaine infusion regimens to define and achieve desired target goals in the epidural or the serum compartment.

Evaluation and comparison of simple multiple model, richer data multiple model, and sequential interacting multiple model (IMM) Bayesian analyses of gentamicin and vancomycin data collected from patients undergoing cardiothoracic surgery.

This study compared the abilities of three Bayesian algorithms-simple multiple model (SMM) using a single creatinine measurement; richer data multiple model (RMM) using all creatinine measurements; and the sequential interacting multiple model (IMM)-to describe gentamicin and vancomycin concentration-time data from patients within a cardiothoracic surgery unit who had variable renal function. All algorithms start with multiple sets of discrete parameter support points obtained from nonparametric population modeling. The SMM and RMM Bayesian algorithms then estimate their Bayesian posterior probabilities by conventionally assuming that the estimated parameter distributions are fixed and unchanging throughout the period of data analysis. In contrast, the IMM sequential Bayesian algorithm permits parameter estimates to jump from one population model support point to another, as new data are analyzed, if the probability of a different support point fitting the more recent data is more likely. Several initial IMM jump probability settings were examined-0.0001%, 0.1%, 3%, and 10%-and a probability range of 0.0001% to 50%. The data sets comprised 550 gentamicin concentration measurements from 135 patients and 555 vancomycin concentration measurements from 139 patients. The SMM algorithm performed poorly with both antibiotics. Improved precision was obtained with the RMM algorithm. However, the IMM algorithm fitted the data with the highest precision. A 3% jump probability gave the best estimates. In contrast, the IMM 0.0001% to 50% range setting performed poorly, especially for vancomycin. In summary, the IMM algorithm described and tracked drug concentration data well in these clinically unstable patients. Further investigation of this new approach in routine clinical care and optimal dosage design is warranted.

Population pharmacokinetic analysis of nonlinear behavior of piperacillin during intermittent or continuous infusion in patients with cystic fibrosis.

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and R(2) values, and predictive performance was based on bias (mean weighted error [MWE]) and precision (mean weighted square error [MWSE]). A linear pharmacokinetic model could not describe combined intermittent infusion and continuous infusion data well. A good population model fit to the intermittent infusion and continuous infusion data was obtained with the constructed nonlinear models. Maximum a posteriori probability (MAP) Bayesian R(2) values for the nonlinear models were 0.96 to 0.97. Median parameter estimates for the best nonlinear model were as follows: K(m), 58 +/- 75 mg/liter (mean and standard deviation); V(max), 1,904 +/- 1,009 mg/h; volume of distribution of the central compartment, 14.1 +/- 3.0 liters; k(12), 0.63 +/- 0.41 h(-1); and k(21), 0.37 +/- 0.19 h(-1). The median bias (MWE) and precision (MWSE) values for MAP Bayesian estimation with the Michaelis-Menten model were 0.05 and 4.6 mg/liters, respectively. The developed nonlinear pharmacokinetic models can be used to optimize piperacillin therapy administered via continuous infusion in patients with CF and have distinct advantages over conventional linear models.