A microcomputer program for tobramycin consult services, based on the two-compartment pharmacokinetic model

A microcomputer program has been developed to provide assistance to tobramycin clinical pharmacokinetic consult services. Written for the Apple II Plus computer with 64 K memory, one-disk drive, and a dot matrix graphics printer, this software is user-oriented and simple to operate. The program disk contains complete documentation and referenced instructions. Major sections provide empiric dosing recommendations based on population data and allow determination of dosage from measured serum concentrations. The program keeps a record of previous regimens, allows for the entry of the user's own recommendation, and provides complete flexibility for up to 15 dosage and interval changes. In addition to its dosing information and file management capabilities, the program simulates serum concentration profiles based on user-selected one-compartment, two-compartment, or two-compartment prenephrotoxic models. The program prints a consult sheet with concentration vs. time simulation, patient demographic data, and user-entered recommendations and comments. The program provides extensive disk storage capabilities for patient files, with immediate access to facilitate updating and dosing regimen changes as they occur. In addition to providing improvements in empiric dosing capabilities, pharmacokinetic modeling, and data handling, this computer software has been designed to incorporate pharmacokinetic data derived from important subpopulations into the empiric dosing algorithms. This unique aspect enables the program to provide improved empiric dosing regimens for patients who do not fall under the guidelines for any of the conventional aminoglycoside dosing nomograms.     

Pharmacokinetic- and pharmacodynamic-based antithrombotic dosing recommendations in children

With the increasing incidence of venous thromboembolic events in children, there has also been a concurrent increase in the use of anticoagulants in children. It is imperative that dosing recommendations of anticoagulants be derived from pharmacokinetic- and pharmacodynamic-based data in children and not simply extrapolated from data based on adults. Medications for children are often based on weight or body surface area, and are often distributed and metabolized differently as well. Furthermore, the hemostatic system in neonates and infants differs from that of older children and adults, and targets for therapy may differ. For these reasons, dosing guidelines for all antithrombotic medications should be based on pharmacokinetic and pharmacodynamic data. The authors reviewed pharmacokinetic and pharmacodynamic studies of anticoagulants in children and make dosing recommendations based on study findings.     

Pharmacokinetic- and pharmacodynamic-based antithrombotic dosing recommendations in children

With the increasing incidence of venous thromboembolic events in children, there has also been a concurrent increase in the use of anticoagulants in children. It is imperative that dosing recommendations of anticoagulants be derived from pharmacokinetic- and pharmacodynamic-based data in children and not simply extrapolated from data based on adults. Medications for children are often based on weight or body surface area, and are often distributed and metabolized differently as well. Furthermore, the hemostatic system in neonates and infants differs from that of older children and adults, and targets for therapy may differ. For these reasons, dosing guidelines for all antithrombotic medications should be based on pharmacokinetic and pharmacodynamic data. The authors reviewed pharmacokinetic and pharmacodynamic studies of anticoagulants in children and make dosing recommendations based on study findings.     

Clinical and economic comparison of epoetin alfa and darbepoetin alfa

BACKGROUND: The pharmacoeconomics of erythropoietic therapy for the treatment of anemia is receiving renewed attention due to the current availability of two agents. Epoetin alfa has been the standard of therapy for patients with renal disease and cancer-related anemia for more than a decade. Darbepoetin alfa, an alternative agent, is now approved for anemia resulting from renal disease and cancer chemotherapy. METHODOLOGY: Although direct comparative trials have not been performed with these agents, information published in the last several years regarding their clinical efficacy, safety, and dosing is sufficient, in most cases, to compare costs. With the disclaimer that any efficacy comparison of competing products using published reports has certain limitations, a cost-minimization approach from a provider's perspective was conducted. RESULTS: To provide background for the economic evaluation, pharmacokinetic and pharmacodynamic data for these two agents are discussed. Recent clinical trials in the nephrology and oncology therapeutic areas are summarized, highlighting study designs, dosing regimens, patient entry criteria, study endpoints, and published results. Cost data, based on average wholesale prices (AWP) in 2003, are compared and calculated from available clinical data with an emphasis on efficacy. CONCLUSION: These evaluations largely conclude that epoetin alfa is the better pharmacoeconomic value of the two currently available erythropoietic agents.     

Antifungal agents in neonates: issues and recommendations

Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is best accomplished based on body surface area. Micafungin shows a clear trend toward lower levels in the smallest patients. There are no data on the use of other new antifungal drugs (ravuconazole and anidulafungin) in neonates. In summary, the initial data suggest dosage differences in neonates for some antifungal agents, although the newer agents have not been fully tested for optimal administration in these patients.     

A chart review comparing paregoric to methadone in the treatment of neonatal opioid withdrawal

Neonatal opioid withdrawal often requires treatment but there have been few recent studies of current pharmacological interventions to guide treatment. This retrospective chart review provides an exploratory examination of newborns treated with either methadone or paregoric for opioid withdrawal and outlines dosage ranges and intervals, side effects, and clinical outcomes of the two regimens. The outcome variables examined were time to resolution of withdrawal symptoms, rate of decrease in symptom severity, and length of hospital stay. There were no observed differences in outcome variables between the two treatment groups and side effect profiles were similar. Dosages, dosage intervals, and tapering regimens were consistent with American Academy of Pediatrics recommendations. Although the sample size is small and standardized regimens were not used, this study provides preliminary data about dosing levels and dosing intervals of these two pharmacologic treatment agents. Both groups of infants had favorable outcomes, although given the variation in treatment regimens it is difficult to draw an equation of equivalency. These results are applicable to the design of future studies of pharmacological interventions.     

Cefotaxime dosage in infants and children. Pharmacokinetic and clinical rationale for an extended dosage interval.

Cefotaxime is a third generation cephalosporin antimicrobial agent which has received wide acceptance as a first-line antibiotic for many infections in neonates, infants and children. With an average elimination half-life of about 1 h, cefotaxime is not considered to be a 'long half-life cephalosporin' like ceftriaxone. For this reason, currently accepted dosage regimens for cefotaxime in infants and children employ a dosage of 50 mg/kg every 6 h. Re-examination of the paediatric pharmacokinetic data for cefotaxime and use of simple multiple-dose pharmacokinetic simulation of alternative dosage regimens was performed. From this analysis, regimens administering 75 mg/kg of the drug every 8 h or every 12 h were projected to produce serum cefotaxime concentrations adequate to effectively kill many of the common pathogens against which the drug is currently indicated for use in children. The clinical utility of these alternative dosage regimens was supported by a review of the medical literature and examination of the clinical results from studies in neonates, infants and children where cefotaxime was administered in 2 to 3 divided doses daily. It would appear, therefore, that increasing the cefotaxime dosage to 75 mg/kg administered at 8 h intervals would result in less frequent drug administration which would not be expected to compromise safety and efficacy. Alternative dosage regimens for cefotaxime merit further consideration and clinical evaluation before they become commonly used in paediatric therapeutics.     

Comparative evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.     

Clinical and economic comparison of epoetin alfa and darbepoetin alfa

SUMMARY

Background: The pharmacoeconomics of erythropoietic therapy for the treatment of anemia is receiving renewed attention due to the current availability of two agents. Epoetin alfa has been the standard of therapy for patients with renal disease and cancer-related anemia for more than a decade. Darbepoetin alfa, an alternative agent, is now approved for anemia resulting from renal disease and cancer chemotherapy.

Methodology: Although direct comparative trials have not been performed with these agents, information published in the last several years regarding their clinical efficacy, safety, and dosing is sufficient, in most cases, to compare costs. With the disclaimer that any efficacy comparison of competing products using published reports has certain limitations, a cost-minimization approach from a provider's perspective was conducted.

Results:To provide background for the economic evaluation, pharmacokinetic and pharmacodynamic data for these two agents are discussed. Recent clinical trials in the nephrology and oncology therapeutic areas are summarized, highlighting study designs, dosing regimens, patient entry criteria, study endpoints, and published results. Cost data, based on average wholesale prices (AWP) in 2003, are compared and calculated from available clinical data with an emphasis on efficacy.

Conclusion: These evaluations largely conclude that epoetin alfa is the better pharmacoeconomic value of the two currently available erythropoietic agents.     

Population pharmacokinetics and pharmacodynamics for treatment optimization in clinical oncology

Population pharmacokinetic and pharmacodynamic analysis is an important tool to support optimal treatment in clinical oncology. The population approach is suitable to explain variability between patients and to establish relationships between drug exposure and a relevant pharmacodynamic parameter. This can facilitate the selection of dosing schedules, the development of strategies for dose individualization and the application of therapeutic drug monitoring of anticancer agents. This review discusses the role of population pharmacokinetics and pharmacodynamics in clinical oncology to enhance the efficiency of drug development and to support the development of safe and effective dosing regimens for optimal treatment of cancer patients. An overview of published population studies of investigational anticancer agents and established treatment regimens is presented.     

Comparison of two empirical prolonged infusion dosing regimens for meropenem in patients with septic shock: A two-center pilot study

BackgroundDue to high pharmacokinetic variability, standard doses of meropenem are frequently inadequate in septic patients. Therapeutic drug monitoring of meropenem is not widely available; therefore, improved empiric dosing recommendations are needed.ObjectivesThis study aimed to compare the attainment of pharmacologic targets for two common empirical dosing regimens for meropenem in patients with septic shock.MethodsTwo empiric dosing schemes for meropenem were compared using extended infusions (120 minutes) in 32 patients with septic shock in the intensive care units at two different hospitals. One regimen was 3 × 2 g meropenem/24 h for two days, followed by 3 × 1 g meropenem/24 h; the other regimen was 4 × 1 g meropenem/24 h. Serum meropenem concentrations were measured for the first 72 h of therapy, and pharmacokinetic modelling was performed to define the percentage of time the free drug concentration was above various target MICs for each regimen (%fT_>MIC).ResultsBoth regimens led to a sufficiently high %fT_>MIC for pathogens with target MICs < 4 mg/L. When higher MICs were targeted, the %fT_>MIC of 4 × 1 g meropenem decreased faster than that of 3 × 2 g meropenem. At high MICs of 32 mg/L, both dosing regimens failed to provide appropriate drug concentrations. Renal function was a significant covariate of target attainment.ConclusionsThe results of this study can guide clinicians in their choice of an empirical dosing regimen for meropenem. If pathogens with low MICs (< 4 mg/L) are targeted, both dosing regimens are adequate, whereas more resistant strains require higher doses.     

A reappraisal of current dosing strategies for intravenous fosfomycin in children and neonates

The rising incidence of multi-drug resistant bacterial pathogens has renewed interest in the long-known antibacterial fosfomycin. Not least because of its low toxicological potential, there is good clinical experience with intravenous fosfomycin for various Gram-positive and Gram-negative infections in the treatment of children and neonates. However, the current dosing recommendations for intravenous fosfomycin vary widely in paediatric patients. In the present review, we summarized available plasma pharmacokinetic data derived from neonates or children following intravenous administration of fosfomycin. Subsequently, we used this information for recalculation of different dosing strategies and simulated a variety of clinically applied dosing regimens. The percentage of time above the minimal inhibitory concentration (T>MIC) was calculated for each dosing strategy, as this pharmacokinetic-pharmacodynamic parameter was shown to be most predictive of antimicrobial and clinical success of fosfomycin treatment. Our data corroborate the current practice of selecting the dosage of intravenous fosfomycin primarily on the basis of bodyweight and age in paediatric patients. As with other 'time-dependent' antibacterials, a dosing interval of 6-8 hours should be preferred over 12 hours except for immature neonates. Given a T>MIC target of 40-70%, currently recommended dosing strategies appear to be insufficient in children aged 1-12 years, if pathogens with MICs of ≥32 mg/L are suspected and subjects are presenting with normal renal function. Likewise, the lowest recommended daily dose for neonates and infants (aged up to 12 months) of 100 mg/kg bodyweight of fosfomycin should be considered only for pre-term neonates with a postmenstrual age below 40 weeks.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 1: IV options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome.

Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.     

Therapeutic drug monitoring in pregnancy

ABSTRACT:: Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.     

Regulatory Aspects of Pharmacokinetic Profiling in Special Populations

The clinical efficacy and safety profile of a new medicinal product is established in phase III studies, which are usually restricted to a well defined patient population. This population may not fully represent the population in which the product will be used once it is on the market. Pharmacokinetic studies in special populations are performed to estimate drug exposure in subpopulations of patients with characteristics that may affect drug exposure. The clinical consequences of altered exposure are then assessed, taking pharmacokinetic/pharmacodynamic relationships into consideration. If needed, specific treatment recommendations should be developed.Recommendations regarding pharmacokinetic characterization in special populations are given in a number of European guidelines. The pharmacokinetic characteristics, therapeutic window and intended use of the medicinal product influence the need for pharmacokinetic studies of a new medicinal product. There are a number of methodological issues to be considered when designing pharmacokinetic studies in special populations: the study design, study population and control group, the dosing regimen to be used, the analytes to be measured, and the distribution and range of the factor to be studied. The data should be presented in sufficient detail to enable assessment by regulatory authorities of the conducted analysis and conclusions drawn. Assessment of the data should include an evaluation of how and to what extent the pharmacokinetics in specific subpopulations deviate from the exposure at the therapeutic dose in the clinical efficacy and safety studies, and if there is a need for specific treatment recommendations. Based on the available information on the pharmacokinetic/pharmacodynamic relationships for efficacy and safety and/or the exposure at the therapeutic dose in the phase III population where efficacy and safety have been demonstrated, target criteria (a target exposure range) should be defined. Within the target exposure range, there should be no clinically relevant difference in efficacy and safety. Should the exposure in a specific group fall outside the defined target criteria, appropriate treatment recommendations need to be developed. The aim should be to develop dosing recommendations that will allow the majority of the patients to obtain exposure within the defined target range. If it is not possible to develop suitable dosing recommendations in a subgroup of patients, there may be a need for specific warnings or wordings regarding monitoring of the patients. It may also be an option to exclude that patient group from the indication. The resulting treatment recommendations should ensure safe and effective use of the drug in the entire population for which it has been approved.     

Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.     

New strategies to deliver anticancer drugs to brain tumors

Background: Malignant brain tumors are among the most challenging to treat and at present there are no uniformly successful treatment strategies. Standard treatment regimens consist of maximal surgical resection followed by radiotherapy and chemotherapy. The limited survival advantage attributed to chemotherapy is partially due to low CNS penetration of antineoplastic agents across the blood–brain barrier (BBB). Objective: The objective of this paper is to review recent approaches to delivering anticancer drugs into primary brain tumors. Methods: Both preclinical and clinical strategies to circumvent the BBB are considered that include chemical modification and colloidal carriers. Conclusion: Analysis of the available data indicates that new approaches may be useful for CNS delivery, yet an appreciation of pharmacokinetic issues and improved knowledge of tumor biology will be needed to affect significantly drug delivery to the target site.     

Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the Children's Oncology Group

Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed-effects modeling with the NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites.     

Therapeutic drug monitoring of busulfan in transplantation

Busulfan is the only agent used in myeloablative regimens for hematopoietic stem cell transplantation for which therapeutic drug monitoring (TDM) has been widely used. Studies of oral busulfan (Bu) indicate wide intrapatient and interpatient variations in pharmacokinetic (PK) behavior, particularly in children. Dose adjustments of oral Bu based on TDM to bring exposures within established therapeutic ranges have been shown to reduce toxicity and improve outcomes. Intravenous (IV) Bu is becoming more widely used and has much more predictable PK. Outcomes with IV Bu appear to be superior to those achieved using oral Bu without TDM. However there is still at least a threefold variation in exposures achieved by the same dose of IV Bu in different individuals and a small proportion of patients will experience toxic exposures with current dosing regimens. Therapeutic monitoring with appropriate dose adjustment is therefore recommended for all patients treated with regimens containing high doses of Bu. Giving IV Bu at a fixed rate to adults will narrow the range of exposures but more work is needed to establish the best dosing regimen to bring as many exposures as possible within the target range. Studies of test dosing of IV Bu show that this strategy is more accurate when test and treatment doses are infused at the same rate. Finally, targeting exposures to the upper end of the therapeutic range may provide a safe approach to exploiting dose-intensity for the treatment of some malignancies.