Pharmacokinetic Principles Research Articles

Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments

The present part II review highlights pharmacokinetic drug–drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug–drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using β-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., β-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered.

Plasma levels, tissue distribution, and excretion of radioactivity after single-dose administration of ( 3H)-oleic acid added to D-004, a lipid extract of the fruit of Roystonea regia, in rats

Background: D-004, a lipid extract of the fruit of Roystonea regia, contains a mixture of fatty acids—mainly oleic, lauric, palmitic, and myristic acids, with oleic acid being among the most abundant—that has been found to reduce the risk for prostatic hyperplasia (PH) induced with testosterone (T) in rats. The pharmacokinetic profile of D-004 has not been reported. Objective: The objective of this study in rats was to assess plasma levels, tissue distribution, and excretion of total radioactivity (TR) after single-dose administration of oral D-004 radiolabeled with ( 3H)-oleic acid, as a surrogate for the pharmacokinetics of D-004. Methods: This experimental study was conducted at the Pharmacology Department, Center of Natural Products, National Center for Scientific Research, Havana, Cuba. Single doses of suspensions of ( 3H)-oleic acid 0.16 μCi/mg mixed with D-004 400 mg/kg (radioactive dose/animal 7.2 μCi) were given orally to male Wistar rats weighing 150 to 200 g assigned to the treated or control group. Three rats were euthanized at each of the following times: 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 48, 72, 96, and 144 hours after study drug administration. After administration, the rats euthanized at the last experimental time point were housed individually in metabolism cages. Urine and feces samples were collected daily. At each time point, blood samples were drawn and plasma samples were obtained using centrifugation. After euthanization, tissue samples (liver, lungs, spleen, brain, kidneys, adipose tissue, muscle, stomach, small and large intestines, adrenal glands, heart, testes, prostate, and seminal vesicles) were quickly removed, washed, blotted, and homogenized. Plasma (100 μL), tissue aliquots (100 mg), feces (10 mg), and urine (100μL) were dissolved and TR was measured. Samples were assayed in duplicate. Results were expressed in μgEq of radio-labeled oleic acid per milliliter of plasma or urine or gram of tissue or feces. Plasma, tissue, feces, and urine samples of rats that did not receive ( 3H)-oleic acid were used as controls. Excretion was expressed as the percentage of the radioactivity excreted via each route with respect to the total radioactive dose administered to each rat. Results: A total of 50 rats were included in the experiment (mean age, 4 weeks; mean weight, 310 g). Absorption was rapid; mean C max was 195.56 (31.12) μgEq/mL, and mean T max was 2 hours. Thereafter, a biphasic decay of TR was found: a rapid first phase (t 1/2α, 1.33 hours), followed by a slower second elimination phase (t 1/2β, 36.07 hours). Radioactivity was rapidly and broadly distributed throughout the tissues, with more accumulating in the prostate than elsewhere. In the first 8 hours, accumulation of TR was greatest in the prostate, followed by the liver, small intestine, and plasma. Subsequently, TR increased in the small intestine, while it decreased in the liver and plasma. In contrast, over the periods of 24 and 144 hours after administration, TR increased in the adipose tissue, while it decreased in the other tissues and plasma. During those intervals, TR was greatest in the prostate, followed by adipose tissue. Mean peak radioactivity in the prostate (562.41 μgEq/g) was reached at 4 hours and decreased slowly thereafter. The prostate had the highest values of t 1/2β and cumulative AUC compared with the other tissues and plasma. Mean (SD) TR was similar in feces (33.48% [4.90%]) and urine (28.96% [5.32%]), with total excretion being 62.40% (5.90%) of the administered dose. Conclusions: In this experimental study, after single-dose administration of oral D-004 radiolabeled with ( 3H)-oleic acid in rats, TR was rapidly and widely distributed across the tissues, with the prostate having the highest accumulation of radioactivity. Excretion of TR was limited, with similar amounts being excreted in feces and urine. The broad distribution of radiolabeled oleic acid and/or its metabolites suggests (SD) pharmacokinetic rationale for the effectiveness of D-004 in reducing the risk for PH induced with T in rats.

CEDIA® Mycophenolic Acid Assay Compared With HPLC-UV in Specimens From Transplant Recipients

Routine monitoring of mycophenolic acid (MPA) has been accepted as an essential tool in the management of this therapy in transplant recipients. The availability of simple, sensitive assays that measure MPA in plasma permits individualization of dosing regimens according to pharmacokinetic principles. We report the results of an evaluation of the CEDIA Mycophenolic Acid Immunoassay (Microgenics Corporation, Fremont, California) for the measurement of plasma MPA concentrations in a range of transplant indications and compare its performance and specificity to an established HPLC/UV method. Precision and accuracy were determined both within and between runs using the quality control materials provided with the CEDIA MPA assay, which produced within run (n = 21) coefficients of variation (CV%) and biases of less than 5%. The between run analyses, performed over consecutive days following daily calibration of the assay, showed CVs and biases of less than 7%. Routine patient samples (n = 298) from 142 patients of varying transplant type were analyzed using the CEDIA MPA kit and HPLC/UV methods. Regression analysis of the patient samples gave an equation of CEDIA = 1.18 HPLC/UV + 0.45 (r = 0.83). According to the manufacturer's product information, there is 192% cross reactivity with the active mycophenolate acyl glucuronide. The data presented suggest that the CEDIA MPA immunoassay, run on the Hitachi 911 analyzer, over-estimates plasma MPA concentrations with a magnitude that is influenced by transplant type. Hence, users must interpret the immunoassay results with caution and not assume that the metabolite fraction is constant in recipients of the same organ type or in different organ transplant populations.

Estimation of Pharmacokinetic Parameters Based on the Patient-Adjusted Population Data

Population pharmacokinetic data, adjusted for patient characteristics, are recommended for the design of initial dosage regimens of some therapeutically monitored drugs in patients for whom patient-specific data are not available. However, despite widespread use by clinicians such as pharmacists, a clear understanding of the principles of population pharmacokinetics, including data collection and analysis and its limitations, is often lacking. This article describes the 2 main methods of obtaining population kinetic data, namely the two-stage method and nonlinear mixed effect model, and their applications to the pharmacokinetic-based design of dosage regimens. Additionally, some numerical examples are provided to assist the reader in understanding the material. The author uses these tools in a pharmacokinetics course taught to PharmD students.

Intraperitoneal chemotherapy for ovarian cancer

Intraperitoneal chemotherapy for ovarian cancer is based on sound pharmacological principles and is technically feasible. There is mounting evidence, bolstered by a recent randomized trial, that in certain patients, this route of delivery may be superior to traditional intravenous chemotherapy. This review explores the background and pharmacokinetic principles of intraperitoneal chemotherapy, the recent evidence supporting an intraperitoneal approach, and some of the logistical and technical challenges involved. Intraperitoneal chemotherapy has been evaluated in several settings. Most phase I and II data came from second-line treatment of ovarian cancer, and there have been a few series, including one recent phase III trial, exploring intraperitoneal consolidation. The greatest impact among recent studies will be from a large, intergroup phase III trial evaluating intraperitoneal therapy in the front-line setting. This study will probably change the dialogue of standard treatment for optimally cytoreduced, advanced epithelial ovarian cancer. Based on recent findings, intraperitoneal chemotherapy should be considered for the front-line treatment of women with minimal residual advanced ovarian cancer. Efforts should continue to facilitate the integration of intraperitoneal treatment into mainstream practice, and future trials should be designed to address lingering controversy surrounding this route of treatment.

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in healthy volunteers. Three doses of either 750 mg or 1000 mg levofloxacin were administered intravenously to 4 healthy adult subjects (750 mg) to 20 healthy adult subjects divided into five groups of 4 subjects (1000 mg). Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Levofloxacin was measured in plasma, BAL fluid and alveolar cells (ACs) using a sensitive and specific combined high-performance liquid chromatographic tandem mass spectrometric technique (HPLC/MS/MS). Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. The maximum plasma drug concentration to minimum inhibitory concentration ratio ( C max/MIC 90) and the area under the drug concentration curve to minimum inhibitory concentration ratio (AUC/MIC 90) during the dosing interval were calculated for potential respiratory pathogens with MIC 90 values from 0.03 μg/mL to 2 μg/mL. In the 1000 mg dose group, the C max (mean ± standard deviation (S.D.)), AUC 0–8 h and half-life were: for plasma, 9.2 ± 1.9 μg/mL, 103.6 μg h/mL and 7.45 h; for ELF, 25.8 ± 7.9 μg/mL, 279.1 μg h/mL and 8.10 h; and for ACs, 51.8 ± 26.2 μg/mL, 507.5 μg h/mL and 14.32 h. In the 750 mg dose group, the C max values in plasma, ELF and ACs were 5.7 ± 0.4, 28.0 ± 23.6 and 34.2 ± 18.7 μg/mL, respectively. Levofloxacin concentrations were significantly higher in ELF and ACs than in plasma at all time points. For pathogens commonly associated with community-acquired pneumonia, C max/MIC 90 ratios in ELF ranged from 12.9 for Mycoplasma pneumoniae to 859 for Haemophilus influenzae, and AUC/MIC 90 ratios ranged from 139 to 9303, respectively. The C max/MIC 90 ratios in ACs ranged from 25.9 for M. pneumoniae to 1727 for H. influenzae, and AUC/MIC 90 ratios ranged from 254 to 16 917, respectively. The C max/MIC 90 and AUC/MIC 90 ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of community-acquired respiratory pathogens.

Optimizing Antimicrobial Therapy for Gram-Positive Bloodstream Infections in Patients on Hemodialysis

Infections with gram-positive organisms are highly prevalent in hemodialysis patients and are a major cause of morbidity and mortality in this population. Antimicrobial therapy is widely used to treat these infections, and prolonged therapy with these agents is often necessary. Extensive use of antimicrobials in hemodialysis patients has resulted in a growing threat of resistance, especially among gram-positive bacteria such as Enterococcus spp and Staphylococcus aureus. Vancomycin-resistant enterococci and S. aureus isolates with reduced susceptibility to vancomycin are increasingly being reported in hemodialysis patients. Additionally, resistance of these organisms to newer agents, such as linezolid and daptomycin, has been documented. Appropriate utilization of antimicrobial therapy to treat these organisms requires an understanding of the pharmacokinetic and pharmacodynamic principles to optimize therapy and avoid adverse drug events. The pharmacokinetic and pharmacodynamic profile of antimicrobial agents can be significantly altered in patients with chronic kidney disease. This review will describe mechanisms of antimicrobial resistance among common gram-positive organisms. The pharmacokinetic and pharmacodynamic principles of cephalosporins, vancomycin, aminoglycosides, linezolid, and daptomycin and applications for use of these agents in the treatment of patients with bloodstream infections on hemodialysis are discussed.

The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations

Levodopa is the most efficacious treatment in the management of Parkinson’s disease. Unfortunately, chronic use of traditional levodopa/dopa decarboxylase inhibitor formulations is associated with the development of complications, such as wearing-off and dyskinesia. In an attempt to avoid these complications, some physicians delay the introduction of levodopa or employ levodopa-sparing strategies; however, these strategies are frequently suboptimal for patients. As most patients require the superior efficacy of levodopa during the course of their disease, an appreciation of the changing response to levodopa over time and an understanding of the pharmacokinetic principles underlying the development of complications such as wearing-off is essential in the long-term management of the patient.

An Overview of TCI and TIVA.

An Overview of TCI and TIVA.

Calculation of red blood cell folate steady state conditions after supplementation with different folate forms and dosages

Maternal red blood cell (RBC) folate levels > 906 nmol/L have been related to the lowest risk of NTD affected pregnancy. While the appearance of folate in RBC has been followed after folic acid supplementation, data on disappearance kinetics are not yet available. The aim of our investigation was to calculate the disappearance kinetics of folate in RBC. Two randomized, placebo-controlled, double blind intervention trials were performed to investigate the appearance of folate in RBC in healthy pregnancy-aged women following different supplementation strategies (I: n=144; 400μg/d folic acid, 416μg/d and 208μg/d (6S)-5-methyltetrahydrofolate for 24 wks; II: n=46; 800μg/d of folic acid for 16 wks). In RBC folate concentrations, no steady state was reached after 24 and 16 wks of intervention, respectively. However, data allow calculating biological half-life (t½) for RBC folate to be about 8 wks. Therefore, taken into account pharmacokinetic principles, steady state conditions for RBC folate should be reached after 5 t½ (40 wks). We propose that the disappearance kinetics of RBC folate can be calculated on the basis of this t½ value. This might be of special interest in case of adding folate or folic acid to oral contraceptives. After pill cessation (to get pregnant), the period of time of RBC folate > 906 nmol/L was estimated to be more than 1 t½ and thus showed protective levels with respect to neural tube defects.

Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns

We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Pharmacodynamic and Pharmacokinetic Considerations in Choosing an Inhaled Corticosteroid

Inhaled corticosteroids are effective in controlling airway inflammation. Their anti-inflammatory effect is primarily topical, at the site of deposition in the airways. Consequently, traditional pharmacodynamic and pharmacokinetic concepts, which rely on measuring blood concentrations of drug, have limited applicability for evaluating the efficacy of topically acting inhaled corticosteroids. Important factors affecting efficacy of inhaled corticosteroids are: (i) intrinsic properties of the drugs, particularly their affinity for the corticosteroid receptor; and (ii) the newer pharmacodynamic concept of deposition characteristics of the drug formulation. Small particle formulations, especially those developed in the metered-dose inhaler with the new hydrofluoroalkane propellant, deposit to a much greater extent in the lung and may consequently have improved clinical efficacy. Lipid conjugation of inhaled corticosteroids within the lung may allow prolonged duration of effect, enabling once-daily administration. Pharmacodynamic and pharmacokinetic principles probably do not play a role in describing upper airway adverse effects occurring with inhaled corticosteroids. These are probably also determined by intrinsic properties of the drug and deposition characteristics. However, pharmacodynamic and pharmacokinetic principles seem to be important in addressing systemic safety concerns with inhaled corticosteroids. Those inhaled corticosteroids with a longer serum half-life, especially if they have higher affinity for the corticosteroid receptor, may be associated with greater systemic effects. A new pharmacokinetic concept suggests that increased protein binding within the systemic circulation and high systemic clearance of an inhaled corticosteroid may reduce the risk for systemic effects. These new pharmacodynamic and pharmacokinetic concepts provide a useful framework for identifying the characteristics of an inhaled corticosteroid with an improved benefit-to-risk profile. Increased lung deposition and reduced deposition in the upper airway should result in an inhaled corticosteroid with favorable clinical efficacy and a decreased risk for topical upper airway adverse effects. An inhaled corticosteroid with high plasma protein binding and rapid clearance might pose much less risk for systemic adverse effects than currently available drugs in this class.

Pharmacokinetics and Safety of Olmesartan Medoxomil in Combination with Glibenclamide in Healthy Volunteers

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. Methods. In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of () olmesartan 20 mg, () olmesartan 20 mg plus glibenclamide 3.5 mg, or () glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to τ = 24 hours (AUCss,τ) or the maximum steady-state concentration (Css,max) of both substances. Mean AUCss,τ values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding Css,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUCss,τ values were 525.7 ng·h/ml for monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The median time to reach Css,max (tmax) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median tmax values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. Conclusion. With the exception of a slight shift of tmax values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds.

Pretransplant Conditioning in Adults and Children: Dose Assurance With Intravenous Busulfan

To provide clinical insights into dosing and administration of IV busulfan, a conditioning agent for hematopoietic stem cell transplantation (HSCT). Review of published literature related to busulfan pretransplant conditioning using MEDLINE. Meeting abstracts, investigational protocols, and pharmaceutical manufacturers' package inserts also were reviewed. Busulfan is an effective myeloablative conditioning agent for HSCT. The IV formulation increases dose assurance and the ability to target a therapeutic window. Therapeutic drug monitoring ensures that targeted blood levels are achieved, especially in children, thereby preventing underdosing, which can lead to disease progression or rejection, as well as overdosing, which can cause an increased risk of toxic side effects. IV busulfan is a convenient, safe, and effective conditioning agent used in HSCT that has a predictable pharmacokinetic profile. An understanding of the pharmacokinetic principles underlying the relationship between the therapeutic window for busulfan and optimal HSCT outcomes will facilitate proper dosing and administration of IV busulfan.

Phase II Study of Fixed Dose Rate Gemcitabine With Cisplatin for Metastatic Adenocarcinoma of the Pancreas

Although gemcitabine remains the standard of care for patients with advanced pancreatic cancer, additional improvements may be realized by combining therapeutic agents with synergistic activity, and optimizing drug delivery using pharmacokinetic principles such as fixed dose rate (FDR) infusion. The objectives of this study were to determine safety and efficacy in patients with metastatic pancreatic cancer treated with FDR gemcitabine in combination with low-dose cisplatin. Chemotherapy-naive patients with metastatic pancreatic adenocarcinoma were treated with a combination of gemcitabine 1,000 mg/m2 at 10 mg/m2/min together with cisplatin 20 mg/m2 on days 1 and 8 of a 21-day cycle. Patient follow-up was performed using computerized tomographic scans and serial CA 19-9 measurements. A total of 51 patients were enrolled onto the study, with a median follow-up time of 215 days. Twenty-two of 40 patients (55.0%) with a baseline serum CA 19-9 level > or = 2x the upper limit of normal demonstrated a > or = 50% biomarker decline during treatment. Nine of 47 patients (19.1%) with measurable disease achieved a partial response, and 28 patients (59.6%) had disease stabilization for at least two treatment cycles. Median time to progression was 3.9 months and median survival was 7.1 months, with an estimated 1-year survival rate of 29%. The most frequently reported grade 3 or 4 adverse events were neutropenia (52.9%) and thrombocytopenia (15.7%). Most patients were switched to an every-other-week dosing schedule. The combination of FDR gemcitabine and cisplatin is well tolerated and appears to be an acceptable, albeit not clearly superior, alternative to other gemcitabine/platinum regimens for the treatment of metastatic pancreatic cancer.

How to design injection protocols for multiple detector-row CT angiography (MDCTA)

The basis of the development of optimal injection protocols for multiple detector-row CT-angiography is knowledge of the physiological and pharmacokinetic principles of arterial enhancement. This article reviews the key rules of early arterial contrast medium dynamics: (1) Arterial enhancement is directly proportional to the iodine administration rate (iodine flux), and can be controlled by the injection flow rate and the iodine concentration of the contrast medium; (2) Arterial enhancement continuously increases over time with longer injection durations, due to the cumulative effects of bolus broadening and recirculation; (3) The strength of an individual's enhancement response to intravenously administered CM depends primarily on the patient's cardiac output and correlates inversely with body weight. In CTA, any of the following strategies can be employed alone, or in combination, to achieve adequate arterial enhancement in spite of short acquisition times: Increasing the injection rate, using higher concentration CM or increasing the injection duration (and scanning delay) relative to the scan time. Both injection volumes and flow rates should be adjusted to body weight, at least for patients < or =60 kg and > or =90kg BW. Rationally designed injection protocols based on physiological concepts allow optimal CM utilisation and take full advantage of the technical capabilities offered by modern MDCT scanners.

Proton Pump Inhibitor Formulary Considerations in the Acutely III: Part 1: Pharmacology, Pharmacodynamics, and Available Formulations

To review important proton pump inhibitor (PPI) pharmacologic, pharmacokinetic, and pharmacodynamic principles in acutely ill patients, compare PPI formulation options for patients unable to swallow a tablet or capsule, and provide clinicians with guidance when making hospital formulary decisions with this class of agents. MEDLINE (1966-May 2005) and the Cochrane Library databases were searched using the key words proton pump inhibitor, acid suppression, peptic ulcer disease, gastrointestinal bleeding, stress ulcer prophylaxis, and critical illness. Bibliographies of cited references were reviewed, and a manual search of abstracts from recent gastroenterology, critical care, and surgery scientific meetings was completed. All articles identified from the data sources were evaluated, and all information deemed relevant was included for this review. PPIs have become a mainstay for acute acid suppression in hospitalized patients over other therapeutic options. Various commercially available PPI products are available for administration, either enterally or parenterally, to patients unable to swallow a tablet or capsule. Newer oral PPI formulations offer numerous advantages over older products. The results of studies comparing the pharmacokinetics and pharmacodynamics of different PPI dosage forms and routes of administration are among the factors to consider when making formulary decisions. While the introduction of new PPI products has expanded the therapeutic options for acid suppression in acutely ill patients, a number of unresolved questions remain surrounding the interchangeability of these products, the clinical significance of one PPI formulation over the other, and how oral/enteral PPI therapy should be used as step-down therapy after parenteral PPI therapy.

Systemic Therapy for Pancreatic Cancer

Pancreatic adenocarcinoma is typically diagnosed at an advanced stage, at which point systemic therapy becomes the primary modality of treatment. Although gemcitabine monotherapy has remained the standard of care for the past decade, a number of large studies conducted over the past several years have suggested that some advantages may be derived from the use of combination therapy, such as the addition of a platinum agent to gemcitabine. The application of pharmacokinetic principles to drug delivery may confer additional benefit as well. Furthermore, with an increasing understanding of the cellular and stromal events that govern pancreatic tumor maintenance, molecularly targeted agents are under active investigation and may prove to serve a critical role in our therapeutic armamentarium. The combination of standard cytotoxic agents and these newer targeted compounds offers promise that we will be able to make significant inroads in improving clinical outcomes for patients with advanced pancreatic cancer.

Back to Basics: Understanding Drugs in Children: Pharmacokinetic Maturation

1. Maria Tetelbaum, MD* 2. Yaron Finkelstein, MD* 3. Alejandro A. Nava-Ocampo, MD* 4. Gideon Koren, MD* 1. *Division of Clinical Pharmacology & Toxicology, Department of Pediatrics and Population Health Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada After completing this article, readers should be able to: 1. Recognize age-related changes in pharmacokinetics and pharmacodynamics of drugs. 2. Describe the dynamics of rational drug dosing for neonates and children. 3. Identify areas of challenge where more drug research is needed during development. Rapid age-related physiologic changes in the pediatric age group, especially during the first postnatal year, affect the absorption, distribution, metabolism, and elimination of drugs. This article reviews pharmacokinetic principles in neonates, infants, and children to help pediatricians understand the rationale for drug therapy and toxicity in these patients. Drugs are administered through a wide range of routes (Table 1). General pharmacokinetic and pharmacodynamic principles can be defined by grouping them in two major routes: intravascular and extravascular. Extravascular administration entails absorption, distribution, metabolism, and excretion. Bioavailability is the fraction of drug reaching the systemic circulation following its administration by any route. Because drugs administrated intravenously do not require an absorption process, their bioavailability is 100%. | Intravascular | || | Extravascular | | Less Common: | Table 1. Primary Routes of Drug Absorption in Children ### Oral Administration Among the extravascular routes, oral administration commonly is used not only because it is painless, but also because technology involved in oral formulations is relatively less costly and requires fewer pharmaceutical processes. However, in some cases, the choice of administration route depends on the site of action, the desired plasma drug concentrations, and the time at which a certain drug concentration must be achieved. Bioavailability after oral administration naturally is less than after intravenous administration. The primary factors affecting oral bioavailability are listed in Table 2. | Physicochemical Factors | || | Physiologic Factors |

The future of therapeutic drug monitoring in clinical practice

Therapeutic drug monitoring (TDM) for psychotropic drugs offers the possibility to optimize psychiatric pharmacotherapy by tailoring the dosage of the administered drugs according to the characteristics of the individual patient. Thus, TDM may increase efficiency of therapy and reduce costs, and it makes a contribution to ensure patient safety. However, there is growing evidence that current use of TDM in routine psychiatric care is far from optimal so that its potential benefits can not fully come to fruition. Several studies have demonstrated a considerable amount of inappropriate TDM ordering, particularly blood sample taking too early after start of medication and change of dose, respectively, before steady state has been reached. Moreover, considerable discrepancies were apparent between the laboratory's recommendations and the actual clinical decision making on dose adjustments. In view of the potential benefits that TDM could have for medical and economic treatment outcome, there is the need for measures to improve its implementation in clinical routine. In addition to intensified physician education about the fundamental principles of drug pharmacokinetics, there are several possible strategies, which have turned out to be effective in other fields of medicine, including clinical pharmacokinetic services actively involved in the treatment process and use of computerized systems.