Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy.

WHAT IS KNOWN AND OBJECTIVE: Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post-induction CBZ behaviour, as well as for combined therapy with CBZ plus another 'old' antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data 'works', and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post-induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. METHODS: Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. RESULTS AND DISCUSSION: This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient-specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov-Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5- to 3·5-year observation period. No bias in predictions was associated with the time horizons. WHAT IS NEW AND CONCLUSION: Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.

Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosage.

BACKGROUND: Proper use of antiepileptic drugs in the elderly involves knowledge of their pharmacokinetics to ensure a patient-specific balance between efficacy and toxicity. However, populations of epileptic patients on chronic carbamazepine (CBZ) therapy which have been studied have included data of relatively few elderly patients. AIMS: The aim of the present study was to evaluate the population pharmacokinetics of CBZ in elderly patients on chronic monotherapy. METHODS: We have used the non-parametric expectation maximization (NPEM) program in the USC*PACK collection of PC programs to estimate individual and population post-induction pharmacokinetics of CBZ in epileptic elderly patients who received chronic CBZ monotherapy. Age-related changes of CBZ population pharmacokinetics were evaluated from routine therapeutic drug monitoring (TDM) data of 37 elderly and 35 younger patients with epilepsy. As a 'historical control' we used previously published population modelling results from 99 young epileptic patients on chronic CBZ monotherapy. In that control group, TDM was performed in the same pharmacokinetic (PK) laboratory, using the same sampling strategy as in the present study, and the same PK population modelling software was used for data analysis. RESULTS AND CONCLUSIONS: A poor correlation was found between daily CBZ dose and serum concentrations in the elderly patients (r=0.2, P=0.25). Probably statistically significant difference in the median values of the CBZ metabolic rate constant (P<0.001) between elderly and relatively young epileptic patients was found. Our results showed that age-related influences in CBZ pharmacokinetics in elderly patients should be considered in the optimal planning of CBZ dosage regimens. Most elderly patients with epilepsy will usually need CBZ dosages lower than those based on the median population PK parameter values obtained from younger patients. The present population model is also uniquely well suited for the new 'multiple model' design of dosage regimens to hit target therapeutic goals with maximum precision.

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms.

BACKGROUND AND OBJECTIVE: Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride. METHODS: The parametric Iterative Two-stage Bayesian Population Model (IT2B) program followed by the Non-parametric Expectation Maximization Population Model (NPEM2) program was used to determine population pharmacokinetic parameter values of tramadol in 138 postoperative orthopaedic Malaysian patients. All patients had received a 100 mg intravenous dose of tramadol, infused over 2-3 min, as their first postoperative analgesic. Blood was sampled at 0 min and subsequently at 15, 30 min, 1, 2, 4, 8, 16, 20 and 24 h for serum tramadol high-performance liquid chromatography analysis. RESULTS AND DISCUSSION: The one-compartmental model pharmacokinetic parameters--volume of distribution (Vd), elimination rate constant (kel) and the total clearance rates (ClT)--found were: mean Vd = 167.6 +/- 63.84 L; median Vd = 161.48 L; mean kel = 0.1241 +/- 0.056 h(-1); median kel = 0.1138 h(-1); ClT = 19.57 +/- 9.51 L/h; median ClT =18.12 L/h. The interindividual coefficient of variation of ClT (48.56%) was higher than that of Vd (38.09%), indicating the presence of other possible influencing factors on tramadol's ClT such as CYP2D6 polymorphism, gender and age. Overall, NPEM2 suggested more diversity in the population than did IT2B.

Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implications for dosage.

Therapeutic drug monitoring (TDM) of valproate (VAL) is important in the optimization of its therapy. The aim of the present work was to evaluate the ability of TDM using model-based, goal-oriented Bayesian adaptive control for help in planning, monitoring, and adjusting individualized VAL dosing regimens. USC*PACK software and routine TDM data were used to estimate population and individual pharmacokinetics of two commercially available VAL formulations in epileptic adult and pediatric patients on chronic VAL monotherapy. The population parameter values found were in agreement with values reported earlier. A statistically significant (P < 0.001) difference in median values of the absorption rate constant was found between enteric-coated and sustained-release VAL formulations. In our patients (aged 0.25-53 years), VAL clearance declined with age until adult values were reached at about age 10. Because of the large interindividual variability in PK behavior, the median population parameter values gave poor predictions of the observed VAL serum concentrations. In contrast, the Bayesian individualized models gave good predictions for all subjects in all populations. The Bayesian posterior individualized PK models were based on the population models described here and where most patients had two (a peak and a trough) measured serum concentrations. Repeated consultations and adjusted dosage regimens with some patients allowed us to evaluate any possible influence of dose-dependent VAL clearance on the precision of total VAL concentration predictions based on TDM data and the proposed population models. These nonparametric expectation maximization (NPEM) population models thus provide a useful tool for planning an initial dosage regimen of VAL to achieve desired target peak and trough serum concentration goals, coupled with TDM soon thereafter, as a peak-trough pair of serum concentrations, and Bayesian fitting to individualize the PK model for each patient. The nonparametric PK parameter distributions in these NPEM population models also permit their use by the new method of 'multiple model' dosage design, which allows the target goals to be achieved specifically with maximum precision. Software for both types of Bayesian adaptive control is now available to employ these population models in clinical practice.

Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors.

The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.

Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors.

In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42+/-10 and 90+/-7 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73+/-4 vs 95+/-8 ng/ml (P=0.284). For TBC >85 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65 ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101+/-10 ng/ml, mild: 77+/-11 ng/ml, moderate: 61+/-13 ng/ml, severe: 56+/-15 ng/ml (P <0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.

[PK/PD modeling of aminoglycoside nephrotoxicity]. / Un modèle PK/PD de la néphrotoxicité des aminoglycosides.

Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis.

Aminoglycosides are often prescribed as part of the treatment regimen for acute pulmonary exacerbations due to their potent activity and low potential for development of resistance. Preliminary evidence from randomized controlled trials in patients with cystic fibrosis (CF) suggests that once-daily administration of aminoglycosides results in similar efficacy and a low risk for toxicity compared with traditional dosing. The pharmacokinetics of aminoglycosides administered once daily in CF patients are currently not well described. In this study we compare the distribution and elimination patterns of traditional dosing (3.3 mg/kg q8h) versus once-daily dosing (10 mg/kg q24h) of tobramycin in six adult patients with CF. The pharmacokinetics of tobramycin administered either once daily or every 8 h were best described by a two-compartment model. No statistically significant differences in any of the pharmacokinetic parameter values between regimens were noted. The distribution phase half-lives of 32 and 24 min following the q8h and q24h regimens were longer than expected. The use of a one-compartment model requires clinical peak levels to be drawn 2 h after initiation of either a 30 min infusion for multiple daily dosing or a 60 min infusion with once-daily dosing, to ensure completion of the distribution phase. Our data indicate that a dose of 10 mg/kg/day provides post-distributional phase peak concentrations that achieve the desired goal for susceptible organisms (>20 mg/L) and AUC(24) values at the upper end of the desired range (70-100 mg.h/L).

Renal elimination of amikacin and the aging process.

OBJECTIVE: Although amikacin is primarily eliminated via glomerular filtration, drug concentrations are not consistently predicted in all patients. To better describe the relationship between amikacin clearance and both age and renal function, we used a new heuristic approach involving statistical analysis of dependence. DESIGN AND SETTING: Retrospective pharmacokinetic study using data from seven centres in France. PARTICIPANTS: 634 patients with sepsis aged between 18 and 98 years of age who received intravenous amikacin. METHODS: Clearance of amikacin was modelled using the NonParametric EM algorithm for a two-compartment model (NPEM2) with intravenous infusion. RESULTS: A total of 2499 serum amikacin determinations was available for analysis. The relationship between the clearance of amikacin and age was weak. Interestingly, the Z method, which filters data based on dependence criteria, selected data that were best fitted by a polynomial function (r = 0.90; p < 0.001). This representation of the polynomial function was similar to a previously proposed theoretical model describing covariations between the clearance of amikacin and age. However, the polynomial function applied to only 33% of the patients that were selected by the Z method. The correlation between the clearance of amikacin and renal function was also relatively low (r = 0.39). The Z method exhibited a continuous and strong dependence pattern between the clearance of amikacin and age for 49% of the patients. CONCLUSIONS: The Z methodology, which filters data using dependence criteria, confirms that age, renal function and amikacin clearance are strongly related, but only in less than half of a large sample of patients with sepsis without renal pathology. These results suggest that other variables should be taken into account in order to improve the description of the behaviour of amikacin. The Z methodology improved the classical description of relationships between variables, and should be applied to better select pertinent variables in pharmacokinetic studies.

Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation.

OBJECTIVE: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates. This study evaluated the evolution of this variability with gestational age (GA) at birth in relation to renal maturation. METHODS: Population PK values of amikacin were studied in 131 newborns (postnatal age 1 day, GA 24-41 weeks) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per group). PK variables were Kel/Vol, Ks/Vs, Cl/Vol. Cls/ where: Kel = Kslope x GA + Kintercept, Cl = Clslope x GA + Clintercept, and Vol = Vs x body weight. Ki and Cli were held as constants. The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group. RESULTS: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination. Amikacin volume of distribution increased with body weight up to a GA of about 38 weeks and then decreased for highest GA values. However, the PDF for the individual GA groups showed a multimodal PK distribution. Kel, Vol, Vs, Cl, and Cl, standard deviations increased linearly with GA, showing differential renal maturation. The higher the GA, the more interindividual PK variability increased. CONCLUSIONS: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability with high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC ratio of >or=125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC(0-24)/MIC ratio of >or=125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at alpha phase, 0.16 h; and half-life at beta phase, 2.9 h. The overall fractional attainment of achieving an AUC(0-24)/MIC ratio of >or=125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 microg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC(0-24)/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC(0-24)/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

Population pharmacokinetics of intravenous and intramuscular streptomycin in patients with tuberculosis.

STUDY OBJECTIVES: To determine population pharmacokinetic parameters of streptomycin after administration of multiple intramuscular and intravenous doses. DESIGN: Prospective, unblinded clinical study. SETTING: Two medical centers in Denver, Colorado. PATIENTS: Thirty patients with tuberculosis. INTERVENTION: Patients received multiple doses of streptomycin as part of their tuberculosis treatment. They received concurrent drugs based on in vitro susceptibility data. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected over a 10-hour period and assayed by validated high-performance liquid chromatography Concentration-time data were analyzed using population methods. Streptomycin concentrations increased linearly with increasing intravenous doses. The intramuscular doses did not produce as linear a relationship, presumably because of variability in rates of and, potentially, completeness of absorption. Streptomycin elimination decreased with declining renal function. Higher, intermittent doses were well tolerated and appeared to maximize the peak concentration:minimal inhibitory concentration ratio. CONCLUSION: Overall, pharmacokinetic parameters of streptomycin were comparable with those previously published for streptomycin and other aminoglycosides. Higher, intermittent doses maximize pharmacodynamic parameter estimates and might have advantages for treatment of tuberculosis.

Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models.

Amikacin is widely used in the treatment of suspected or confirmed neonatal infections. However, dosage regimens are not well defined in this group of patients because of a wide inter-individual pharmacokinetic variability. An individualized goal-oriented amikacin dosage design was applied using population pharmacokinetic data. A dosing chart was developed for neonates during the first 2 days of life, by using population pharmacokinetic parameter values and USCPACK software. This dosing chart based on gestational age (GA) and body weight gives a once-a-day amikacin dosage regimen involving an injection every 24 h. Validation was performed in 57 neonates less than 2 days old, divided into three GA groups and prospectively treated using the dosing chart. Target peak serum levels of amikacin were obtained in 62-80% of patients after the first dose and in 80-100% after the second dose, and trough concentrations were obtained in 100%. This study has confirmed the need for individualization of amikacin dosage regimens in neonates.

Population pharmacokinetic modelling of carbamazepine by using the iterative Bayesian (IT2B) and the nonparametric EM (NPEM) algorithms: implications for dosage.

OBJECTIVE: To estimate individual and population postinduction pharmacokinetics of carbamazepine (CBZ) in epileptic adult and paediatric patients who received chronic CBZ monotherapy. METHODS: We have used the USC*PACK collection of PC programs for the estimations. The preinduction CBZ metabolism was also estimated in 16 volunteers after a single dose of CBZ (200 mg). We used a linear one-compartmental model with oral absorption and found the pharmacokinetic parameter values of CBZ behaviour to be in good agreement with those reported earlier. RESULTS: Serum CBZ concentrations correlated poorly with daily doses in both the adult and child populations. Because of the diversity within the population, use of the mean population model without knowledge of an individual patient's pharmacokinetic characteristics gives poor prediction. In contrast, the individual Bayesian posterior models gave good prediction for all subjects in the population, due to the removal of the interindividual variability. CONCLUSION: This approach permits one to individualize drug therapy for patients even when only sparse therapeutic drug monitoring (TDM) data are available. Future individual CBZ serum level predictions were acceptable from a clinical point of view (mean absolute error = 13.2 +/- 9.7%). The optimal sampling strategy approach helped to design an optimal cost-effective TDM protocol for CBZ therapy management.

Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials.

A number of new fluoroquinolone antibacterials have been released for clinical use in recent years. These new agents exhibit enhanced activity against Gram-positive organisms while retaining much of the Gram-negative activity of the earlier agents within the same class. The pharmacokinetics of most of these agents are well described including serum pharmacokinetics, tissue and fluid distribution, and pharmacokinetics in renal and hepatic disease. When compared with earlier agents within this class (i.e. ciprofloxacin), the newer agents retain the wide distribution characteristics; however, they exhibit a more prolonged elimination, which, in part, supports single daily administration for these agents. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for ciprofloxacin, levofloxacin, gatifloxacin and sitafloxacin. Drug interactions, particularly with multivalent cations (calcium/aluminium-containing antacids and iron products), remain a problem for the newer agents, resulting in reduced absorption requiring separate administration times to maximise bioavailability. However, the newer agents do not appear to interfere significantly with the cytochrome P450 system, thus minimising the potential for interactions with other drugs metabolised by this system. The pharmacodynamic properties of the fluoroquinolones have been well described. The bactericidal activity is maximised when the ratios of peak plasma drug concentration (Cmax): minimum inhibitory concentrations (MIC) or area under the concentration-time curve (AUC): MIC exceed specific threshold values. Knowledge of the pharmacodynamic relationships allows for appropriate drug selection and enables design of dosage regimens to maximise the bactericidal activity. Therapeutic drug monitoring of the fluoroquinolones may provide a means of optimising the dosage regimen in certain clinical situations (that is, meningitis and hospitalised pneumonias) with the goals of achieving a more predictable therapeutic response and minimising the potential for the development of resistance.

Failure of traditional trough levels to predict tacrolimus concentrations.

The objective of this study was to estimate tacrolimus population parameter values and to evaluate the ability of the maximum a posteriori probability (MAP) Bayesian fitting procedure to predict tacrolimus blood levels, using the traditional strategy of monitoring only trough levels, for dosage individualization in liver transplant patients. Forty patients treated with tacrolimus after liver transplantation were studied during the early posttransplant phase (first 2 weeks). This phase was divided into four time periods (1-4 days, 5-7 days, 8-11 days, 12-14 days). Tacrolimus was administered twice daily. Approximately one determination of a tacrolimus trough level on whole blood was performed each day. The NPEM2 program was used to obtain population pharmacokinetic parameter values. With each individual pharmacokinetic parameter estimated by the MAP Bayesian method for a given period, the authors evaluated the prediction of future levels of tacrolimus for that patient for the next period. This evaluation of Bayesian fitting predictive performance was performed using the USC*PACK clinical software. Mean pharmacokinetic parameter values were in the same general range as previously published values obtained with richer data sets. However, during each period, the percentage of blood levels predicted within 20% did not exceed 40%. The traditional strategy of obtaining only trough whole blood levels does not provide enough dynamic information for the MAP Bayesian fitting procedure (the best method currently available) to be used for adaptive control of drug dosage regimens for oral tacrolimus. The authors suggest modifying the blood concentration monitoring scheme to add at least one other concentration measured during the absorptive or distributive phase to obtain more information about the behavior of the drug. D-Optimal design and similar strategies should be considered.