Pharmacokinetic-pharmacodynamic Parameters Research Articles

A three-arm clinical study to compare pharmacokinetic and pharmacodynamic similarity of the denosumab biosimilar LY06006 with reference denosumab in healthy male subjects

ABSTRACT Background This study aimed to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) similarity, comparable safety, and immunogenicity between LY06006, European Union-sourced denosumab (EU-DEN), and United States-sourced denosumab (US-DEN). Research design and methods In this double-blind, parallel-group, and single-dose study, 300 healthy male subjects were randomized 1:1:1 to receive a 60 mg dose of either LY06006, EU-DEN, or US-DEN subcutaneously. This study lasted for 253 days. Primary PK endpoints included maximum serum concentration (Cmax), area under the concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-inf). Pharmacokinetic equivalence was concluded if the two-sided 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) of primary endpoints were within 80%-125%. Other PK parameters, PD parameters, safety, and immunogenicity assessments were also conducted during the study. Results The 90% CIs for ratios of GLSMR were within the predefined equivalence margin for AUC0-inf (89.0%–111.1%), AUC0-t (89.7%–111.3%), and Cmax (92.3%–106.7%). The PD parameters, safety, and immunogenicity of LY06006 were also comparable to US-DEN and EU-DEN. Conclusion LY06006 was highly similar to US-DEN and EU-DEN in terms of PK, PD, safety and immunogenicity in healthy male subjects. Clinical trial registration www.clinicaltrials.gov identifier is NCT06095427

What is the right gentamicin dose for multiple trauma patients? A Monte Carlo simulation exploration study.

The appropriate dose of gentamicin is important to prevent and treat infections. The study aimed to determine the optimal dose of gentamicin to achieve the probability of pharmacokinetic/pharmacodynamic (PK) targets for efficacy and safety in multiple trauma patients. PK parameters of gentamicin in multiple trauma patients were gathered to develop a one-compartment PK model for prediction. The Monte Carlo simulation method was performed. The 24-h area under the concentration time curve to the minimum inhibitory concentration ratio (AUC24h/MIC) ≥50 was defined for the infection prevention target. AUC24h/MIC ≥110 or the maximum serum concentration to MIC ratio ≥8-10 was for the treatment of serious Gram-negative infection target. The risk of nephrotoxicity was the minimum serum concentration ≥2 mg/L. The optimal dose of gentamicin was determined when the efficacy target was >90% and the risk of nephrotoxicity was lowest. The optimal gentamicin dose to prevent infection when the MIC was <1 mg/L was 6-7 mg/kg/day. A higher dose of gentamicin up to 10 mg/kg/day could not reach the target for treating serious Gram-negative infection when the expected MIC was ≥1 mg/L. The probability of nephrotoxicity was minimal at 0.2-4% with gentamicin doses of 5-10 mg/kg/day for 3 days. Once daily gentamicin doses of 6-7 mg/kg are recommended to prevent infections in patients with multiple trauma. Gentamicin monotherapy could not be recommended for serious infections. Further clinical studies are required to confirm our results.

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review.

The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.

Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2'-de-N-Methylaplysinopsin.

Chagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic–pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations.

A Review of Population Pharmacokinetic Analyses of Linezolid.

In recent years, many studies on population pharmacokinetics of linezolid have been conducted. This comprehensive review aimed to summarize population pharmacokinetic models of linezolid, by focusing on dosage optimization to maximize the probability of attaining a certain pharmacokinetic-pharmacodynamic parameter in special populations. We searched the PubMed and EMBASE databases for population pharmacokinetic analyses of linezolid using a parametric non-linear mixed-effect approach, including both observational and prospective trials. Of the 32 studies, 26 were performed in adults, four in children, and one in both adults and children. High between-subject variability was determined in the majority of the models, which was in line with the variability of linezolid concentrations previously detected in observational studies. Some studies found that patients with renal impairment, hepatic failure, advanced age, or low body weight had higher exposure and adverse reactions rates. In contrast, lower concentrations and therapeutic failure were associated with obese patients, young patients, and patients who had undergone renal replacement techniques. In critically ill patients, the inter-individual and intra-individual variability was even greater, suggesting that this population is at an even higher risk of underexposure and overexposure. Therapeutic drug monitoring may be warranted in a large proportion of patients given that the Monte Carlo simulations demonstrated that the one-size-fits-all labeled dosing of 600 mg every 12 h could lead to toxicity or therapeutic failure for high values of the minimum inhibitory concentration of the target pathogen. Further research on covariates, including renal function, hepatic function, and drug–drug interactions related to P-glycoprotein could help to explain variability and improve linezolid dosing regimens.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01125-2.

A Scientific Approach and Perception for Clinical Practice in India

The rate and extent of absorption of a drug from its dosage form is referred to as bioavailability. While bioequivalence between two drug products is attained if their extent and rate of absorption do not relatively differ when administered at the same dose. A bioequivalence study comprises of two or more bioavailability studies which are performed by i) Measurement of active drug substance or its metabolites in the biological fluid; ii) Comparative pharmacodynamic studies in humans; iii) Comparative clinical trials; iv) Comparative in-vitro dissolution studies. The rationale of the study is the monitoring of the pharmacokinetic-pharmacodynamic parameters (AUC, Cmax) after administration of the tested drug. This study is not an experimental study but a form of data analysis and reporting of comparative bioavailability studies. The study data obtained is required to be equipped with applications of new drug products as notified in Schedule Y. Cumulatively, it aids in the development of pharmaceutical preparations in the pharmaceutical industry. This review article aims to illustrate the systematic overview of BA/BE study with an emphasis on its experimental aspects like study design, volunteer selection, dosing regimen, sample collection procedures along with a detailed insight on Informed Consent Document, Case Report Form, Trial Master file and the Protocol which collectively form the backbone of the clinical study.

Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 Inhibitors TBA-7371, PBTZ169, and OPC-167832.

ABSTRACTMultiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

Assessment of the clinical validity of an adjusted Marsh pharmacokinetic model using an effect-site rate constant (ke0) of 1.21 min-1

Introduction: The first commercially available target-controlled infusion pump, the “Diprifusor”, employed a “Marsh” pharmacokinetic-pharmacodynamic parameter set, and this model (the Diprifusor-Marsh model) is also available in several of today’s pumps. However, it is unsuited for effect-site, target-controlled infusions (Ce TCI) because it assumes slow transfer between blood and the effect-site (ke0 = 0.26 min-1). We hypothesised that a faster ke0 of 1.21 min-1 (Adjusted-Marsh model) for Ce-TCI would result in hypnotic effects equivalent to that of the Schnider parameter set (Schnider model). Methods: We replicated a previously published study that demonstrated the Diprifusor-Marsh model’s unsuitability for Ce-TCI. We randomised 40 unpremedicated young adults into two groups to receive Ce-TCI, employing either the Schnider model or the Adjusted-Marsh model. We infused propofol at 3 000 mg.hour-1, while running a pharmacokinetic simulation and recording the electroencephalographic bispectral index (BIS) electronically. At loss of consciousness (LOC), indicated by a syringe-drop, we converted the infusion to Ce-TCI, targeting the effect-site concentration (Ce) observed at LOC, for 20 minutes. We regarded a difference of 10 BIS-units as clinically important. Results: There were no statistically significant differences between the group medians regarding time-to-LOC, induction-dose, BIS at LOC and Ce-target. BIS decreased monotonically in both groups from a median of 78.5 at LOC to a steady-state median (25–27) at 15 minutes. The BIS of the Adjusted-Marsh model group closely followed the BIS of the Schnider model group. At steady state, the median BIS difference (95% CI) was -0.3 (-5.7 to 5.3), which was within the predefined interval for declaring equivalence. The Schnider model group’s mean BIS at steady state did not differ from that of the previous study’s Schnider model group. Conclusion: Reasons for the progressive BIS decrease to lower than expected values include delayed response-times by the BIS monitor, Ce overshoot explained by front-end kinetics, neural inertia and the choice of surrogate LOC indicator. We conclude that Ce-TCI using the Adjusted-Marsh parameter set results in equivalent hypnotic effects to those of the Schnider model, with the proviso that this may apply only to young adults of normal body habitus.

Determination of Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Parameters of Doxycycline against Edwardsiella ictaluri in Yellow Catfish (Pelteobagrus fulvidraco)

This study aimed to examine the pharmacokinetics of doxycycline (DC) in yellow catfish (Pelteobagrus fulvidraco) and to calculate related pharmacokinetic–pharmacodynamic (PK/PD) parameters of DC against Edwardsiella ictaluri. The minimum inhibitory concentration of DC against E. ictaluri was determined to be 500 µg/L. As the increase of oral dose from 10 to 40 mg/kg, the area under the concentration vs. time curve from 0 to 96 h (AUC0–96) values were considerably increased in gill, kidney, muscle and skin, and plasma, except in liver. Cmax values exhibited a similar dose-dependent increase trend in plasma and tissues except in liver, but other PK parameters had no apparent dose-dependence. The PK/PD parameter of the ratio of AUC0–96 to minimum inhibitory concentration (AUC0–96h/MIC) was markedly increased in plasma and tissues dose-dependently except in liver, but %T > MIC values were increased only moderately at some dose groups. After receiving the same dose with disparate time intervals from 96 to 12 h, the AUC0–96h/MIC was distinctly increased in plasma and tissues, but the %T > MIC had a decreasing trend. When administering 20 mg/kg with a time interval of 96 h, the AUC0–96h/MIC values were consistently >173.03 h and the %T > MIC values were above 99.47% in plasma and all tissues. These results suggest that administration of DC at 20 mg/kg every 96 h is a preferable regimen in yellow catfish.

Microfluidic Devices: A New Paradigm in Toxicity Studies

In recent years, great emphasis has been placed on non-animal toxicological methods (e.g.in vitro models,in silico or −omics data) as alternative strategies to reduce animal-testing, in line with the 3R principle. These methods help in the rapid and accurate estimation of preclinical efficacy and safety associated with discovery of new drugs, and reduction of failure rates in clinical trials. Currently, the in vitro studies have been in a transformation or replacement from two-dimensional cell cultures to three-dimensional cell cultures that can mimic the physiology of tissues, organs, and organism. In this context, organ-on-a-chip systems have been developed by integration of three-dimensional culture models with emerging microfluidic technologies. The organ-on-a-chip systems provide a good understanding of dose-response and toxicity mechanisms in drug development process, since impact of xenobiotics on human body can be predicted in a satisfactory level. Besides, these systems may support assessment of pharmacokinetic-pharmacodynamic parameters as well as detection of drug resistance. Models can be generated as “disease-models-on-a-chip” or with healthy cells to evaluate response to xenobiotic under test. In this study, we will focus on microfluidic systems being used in organ-on-a-chip systems and emphasize their potential for toxicity studies in which micro-environments of examples including liver,kidney,brain,lung,heart,and intestines and their physiological properties as reflected to organ-on-a-chip models.

Defining the Role of Novel β-Lactam Agents That Target Carbapenem-Resistant Gram-Negative Organisms.

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Pharmacokinetic–pharmacodynamic modeling to study the anti-dysmenorrhea effect of Guizhi Fuling capsule on primary dysmenorrhea rats

BackgroundPrimary dysmenorrhea (PDM) is one of the most common gynaecological disorders among women, which seriously affects women's life quality due to its high incidence rate. Guizhi Fuling capsule (GZFLC), a well-known traditional Chinese medical prescription, has been widely used to treat gynecological blood stasis syndromes such as PDM. However, its mechanisms of action and combination were still unknown. PurposeThe aim of this study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model to assess time-concentration-effect relationships for anti-dysmenorrhea effect of GZFLC and provide better understanding for mechanisms of action and combination of GZFLC. Study design and methodsThe PDM rats model was induced by oxytocin exposure following estradiol benzoate pretreatment. Gallic acid (GA), amygdalin (AMY), albiflorin (ALB), prunasin (PA) and cinnamic acid (CA) were evaluated as bioactive ingredients for investigating PK processes. GA, AMY, ALB and PA exhibited appropriate PK parameters and were selected as the PK markers to map the anti-dysmenorrhea effect of GZFLC. A PK-PD model was established on the basis of GA, AMY, ALB and PA plasma concentrations vs. the values of two ratios (PGE2/PGF2α and 6-Keto-PGF1α/TXB2), by a two-compartment PK model with a simple Emax model to explain the time delay between the drug plasma concentrations of PK markers and the anti-dysmenorrhea effect. ResultsThe PDM rat model has been successfully established. Compared with the normal treated group, the bioactive ingredients in PDM treated group exhibited significant changing trends of PK behaviors, such as better absorption and distribution, slower elimination and delays in reaching the maximum concentration (Tmax). The analysis of PK-PD parameters indicated that the active metabolites and prototypes of bioactive ingredients in GZFLC were inclined to regulate the activity of prostacyclin synthetase and thromboxane synthetase to control the production of TXA2 and PGI2 so as to treat PDM. As the main effective medicinal materials for the treatment of PDM in GZFLC prescription Persicae Semen, Moutan Cortex and Paeonia lactiflora Pall, Persicae Semen played the most important role, while the role of Paeonia lactiflora Pall was the weakest. ConclusionThe PK-PD model results provided scientific basis for clarifying compatibility mechanisms of GZFLC prescription and a better understanding for biosynthetic mechanisms of four prostaglandins (PGE2, PGF2α, 6-Keto-PGF1α and TXB2) in the treatment of PDM by GZFLC. Investigations on the relationship between the effects and the bioactive ingredients are of benefit to explore the mechanisms of action and combination for traditional Chinese medical prescriptions (TCP) and facilitate the development of future clinical applications of TCP.

Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations.

Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem-relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of β-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to>1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two-compartment, linear model and do not appear to be altered by the co-administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V d) and elimination half-life (t ½) of~18L and 1.2-2.1h, respectively, are similar to imipenem. Likewise, vaborbactam's V d and t½ of~18L and 1.3-2.0h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem-relebactam and meropenem-vaborbactam against various Gram-negative β-lactamase-producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion β-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated urinary tract infections, including acute pyelonephritis. Imipenem-relebactam is currently in two phase III clinical trials for the treatment of imipenem-resistant bacterial infections, as well as hospital-associated bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). A phase III clinical trial has reported superiority of meropenem-vaborbactam over piperacillin-tazobactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem-vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against β-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials. Potential roles in therapy for these agents include the treatment of suspected or documented infections caused by resistant Gram-negative bacilli-producing ESBL, KPC, and/or AmpC β-lactamases. The usage of these agents in patients with CRE infections will likely become the standard of care. Finally, increased activity of imipenem-relebactam against P. aeruginosa may be of clinical benefit to patients with suspected or documented P. aeruginosa infections.

Antimicrobial treatment of infrequent bacterial species isolated in children

This section summarizes the empirical antimicrobial treatment according to the less frequent bacterial species responsible for infection whether community-acquired or nosocomial. It specifies their role in diseases and the recommended antibiotics, taking into account their natural and most common acquired resistance and the pharmacokinetic-pharmacodynamic parameters. The advice of an infectious disease specialist or bacteriologist is recommended.

A systematic review of the pharmacokinetic and pharmacodynamic interactions of herbal medicine with warfarin.

ObjectivesThe aim of this study was to systematically review data regarding pharmacokinetic (PK)-pharmacodynamic (PD) parameters from randomized controlled trials relating to interactions between herbal medicines and warfarin.MethodsThree electronic databases were searched to identify relevant trials. Two reviewers independently performed the study selection and data extraction. The risk of bias and reporting quality were also assessed independently by two reviewers using the Cochrane risk of bias tool and the consolidated standards of reporting trials (CONSORT). Outcomes were measured for all reported PK-PD parameters and adverse events.ResultsNine randomized controlled trials met our inclusion criteria. Most of the included studies were unclear regarding the risk of bias and had a low quality of methodology. Using CONSORT, the reporting percentages for the articles ranged from 36.5% to 61.5% and the mean percentage for all articles was 45.6%. St John’s wort and echinacea affected the PK parameters of warfarin. Ginseng, ginger, garlic, and cranberry had no significant effect on the PK parameters. American ginseng altered the PD parameters of warfarin. St John’s wort, ginseng, Korea red ginseng, ginkgo, ginger, garlic, aged garlic, and echincea did not significantly alter the PD parameters. Studies of ginkgo and cranberry showed conflicting results on the PK parameters and PD parameters, respectively. The incidence of adverse events in all trials was low and no major adverse events were reported.ConclusionsIt was difficult to determine whether ten herbal medicines had significant effects on the PK-PD parameters of warfarin. Low quality of evidence, different compounds within and different compositions of the herbs, and methodological limitations of the crossover study, which is a clinical study in which subjects receive a sequence of different interventions, made it difficult to form conclusions. Additional studies that remedy these vulnerabilities are necessary to verify these results.

Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio≥400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC≥400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24h, whereas AATL was calculated by subtracting AUTL from AUC24 . Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8μg/mL. Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15μg/mL, this level should ideally not be exceeded.

Rapid Quantitative Pharmacodynamic Imaging with Bayesian Estimation.

We recently described rapid quantitative pharmacodynamic imaging, a novel method for estimating sensitivity of a biological system to a drug. We tested its accuracy in simulated biological signals with varying receptor sensitivity and varying levels of random noise, and presented initial proof-of-concept data from functional MRI (fMRI) studies in primate brain. However, the initial simulation testing used a simple iterative approach to estimate pharmacokinetic-pharmacodynamic (PKPD) parameters, an approach that was computationally efficient but returned parameters only from a small, discrete set of values chosen a priori. Here we revisit the simulation testing using a Bayesian method to estimate the PKPD parameters. This improved accuracy compared to our previous method, and noise without intentional signal was never interpreted as signal. We also reanalyze the fMRI proof-of-concept data. The success with the simulated data, and with the limited fMRI data, is a necessary first step toward further testing of rapid quantitative pharmacodynamic imaging.

Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections.

BackgroundTeicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration–time curve (AUC)/minimum inhibitory concentration (MIC) was identified as a pharmacokinetic–pharmacodynamic (PK–PD) parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK–PD are needed, a PK–PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) infections has not yet been performed. Thus, this study examined patients with MRSA infections, who were administered with teicoplanin in order to determine the target AUC/MIC ratio.MethodsThis study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring (TDM) of teicoplanin therapy in 46 patients with MRSA infections at Kagoshima University Hospital. Serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a Bayesian PK estimation to estimate AUC for 24 hours (AUC24). The MIC value for teicoplanin was determined using a standardized agar dilution method. The effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment.ResultsThe estimated AUC24/MIC ratios with and without bacteriological responses were 926.6±425.2 µg·h/mL (n=34) and 642.2±193.9 µg·h/mL, respectively (n=12; P<0.05). On the basis of a logistic regression analysis, AUC24/MIC ratios of 500 µg·h/mL, 700 µg·h/mL, and 900 µg·h/mL gave probabilities of treatment success of 0.50, 0.72, and 0.87, respectively. Furthermore, using the Kaplan–Meier curve analysis, an AUC24/MIC ratio of ≥900 led to a significantly stronger bacteriological response than an AUC24/MIC ratio of <900.ConclusionThese results suggest that an AUC24/MIC ratio of ≥900 µg·h/mL is required to ensure a sufficient bacteriological response.

Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.

Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

Ketofol dosing simulations for procedural sedation.

Propofol mixed with racemic ketamine (or "ketofol") is popular for short procedural sedation and analgesia, yet the optimal combination is unknown. We aimed to determine a ketofol dosing regimen for short procedural sedation and analgesia of 5- to 20-minute duration in healthy patients (2-20 y). Pharmacokinetic-pharmacodynamic parameters were used to simulate drug concentration and effect profiles over time for different ketamine-to-propofol ratios (1:1-1:10). The target effect was a Children's Hospital of Wisconsin Sedation Scale score of less than 2. Combined effects were additive, with a propofol EC50 of 1.54 μg/mL (concentration required to produce hypnosis in 50% of patients), a ketamine EC50 of 0.44 μg/mL, and a slope of 5.3. Emergence threshold concentrations for propofol were 2.0 μg/mL in children and 1.8 μg/mL in adults as well as 0.5 μg/mL for ketamine (children and adults). The EC50 for propofol antiemesis was 0.343 μg/mL. A ketamine-to-propofol ratio of 1:3 was the best combination for intermittent dosing, achieving a rapid onset of a Children's Hospital of Wisconsin Sedation Scale score of less than 2 within 1 minute and a time to emergence of 9 to 19 minutes in all ages after a 10-minute sedation. The optimal ketofol dosing in children (2-11 y) was 0.1 mL/kg initially followed by 0.05 mL/kg at 2 minutes and then 0.025 mL/kg for the subsequent doses. The adults (12-20 y) received 0.05 mL/kg of ketofol initially followed by 0.025 mL/kg for the subsequent doses. These regimens maintain a propofol antiemesis for 30 to 40 minutes after the last dose. We suggest an optimal ratio of racemic ketamine to propofol of 1:3 for boluses during short procedures (5-20 minutes). A short ketofol infusion, ratio 1:4, is a suitable alternative to intermittent boluses. Ratios greater than 1:3 result in delayed recovery after 20 minutes.