Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer.

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

A physiologically based pharmacokinetic/pharmacodynamic model to determine dosage regimens and withdrawal intervals of aditoprim against Streptococcus suis.

Introduction: Streptococcus suis (S. suis) is a zoonotic pathogen threatening public health. Aditoprim (ADP), a novel veterinary medicine, exhibits an antibacterial effect against S. suis. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was used to determine the dosage regimens of ADP against S. suis and withdrawal intervals. Methods: The PBPK model of ADP injection can predict drug concentrations in plasma, liver, kidney, muscle, and fat. A semi-mechanistic pharmacodynamic (PD) model, including susceptible subpopulation and resistant subpopulation, is successfully developed by a nonlinear mixed-effect model to evaluate antibacterial effects. An integrated PBPK/PD model is conducted to predict the time-course of bacterial count change and resistance development under different ADP dosages. Results: ADP injection, administrated at 20 mg/kg with 12 intervals for 3 consecutive days, can exert an excellent antibacterial effect while avoiding resistance emergence. The withdrawal interval at the recommended dosage regimen is determined as 18 days to ensure food safety. Discussion: This study suggests that the PBPK/PD model can be applied as an effective tool for the antibacterial effect and safety evaluation of novel veterinary drugs.

Intranasal vitamin B12 administration in elderly patients: A randomized controlled comparison of two dosage regimens.

AIM: Vitamin B12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B12 dosage regimens in elderly vitamin B12-deficient patients. METHODS: Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 µg cobalamin. Total vitamin B12, holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90. RESULTS: Both dosage regimens resulted in a rapid increase of vitamin B12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B12 of 717 pmol/L after 90 days. CONCLUSIONS: Intranasal vitamin B12 administration is an effective and suitable way to replenish and sustain vitamin B12 levels in elderly patients.

Evaluation of effectiveness, hyperkalaemia, and hepatotoxicity of trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii pneumonia in paediatric patients: A single-centre retrospective study.

BACKGROUND: American guidelines recommend trimethoprim-sulphamethoxazole (TMP-SMX) for preventing Pneumocystis jirovecii pneumonia (PJP) in paediatric patients at doses of 5-10 mg/kg/d of the TMP component, administered either daily, three times weekly, or twice weekly. However, limited studies describe the effectiveness and safety of these prophylactic regimens. Our study aimed to assess the clinical effectiveness and incidence of adverse events associated with each TMP-SMX regimen in paediatric patients, and to identify risk factors for adverse events. METHODS: We collected data regarding the onset of PJP, hyperkalaemia, and hepatotoxicity in patients aged 0-18 years who underwent prophylaxis with TMP-SMX from July 2018 to June 2023. RESULTS: A total of 215 paediatric patients met the inclusion criteria. No patients developed PJP. Hyperkalaemia occurred in 14.7%, patients receiving TMP-SMX daily, 15.4% receiving it three times weekly, and 15.5% receiving it twice weekly. Hepatotoxicity was most frequent in patients receiving TMP-SMX twice weekly (19%), followed by those receiving it three times weekly (7.7%), and daily (5.9%). Younger patients were significantly more prone to developing hyperkalaemia or hepatotoxicity. Patients aged <1 year had the highest incidences of hyperkalaemia (56.5%), and those aged 1-2 years had the highest incidence of hepatotoxicity (25%). CONCLUSIONS: No patient developed PJP under various dosage prophylactic regimens of TMP-SMX. However, our findings suggest the need to monitor potassium levels and hepatic function in patients undergoing any of the three TMP-SMX regimens. In particular, patients aged <1 year old and 1-2 years old face a higher risk of hyperkalaemia and hepatotoxicity, respectively.

Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.

Concurrent determination of anti-microbial and anti-inflammatory drugs in lachrymal fluid and tissue by LC-MS/MS: A potential treatment for microbial keratitis and its PK-PD evaluation.

Unforeseen surfacing of microbial keratitis (MKT) over the years has led to a requisite for promising treatment strategy involving combination of antifungal and antibacterial agents. Subsequently, symptoms associated with MKT including inflammation and watery eyes require treatment with anti-inflammatory agents. Thus, a requirement of functional clinical treatment strategy involving combination of anti-inflammatory corticosteroids (Betamethasone) with antifungal polyene (Amphotericin B, AmB) and antibacterials macrolide (Azithromycin, AZT) and aminoglycoside (Neomycin, NEO). In the ensuing pursuit, a sensitive and fast simultaneous LC-MS/MS method of four drastically different analytes in rabbit tear fluid and cornea was developed and validated as per US-FDA guidelines. The gradient LC set-up was used with C18 column and flow rate of 0.55 mL/min along with short run time of 7 min. The calibration curves showed good linearity over the concentration range of 0.07-300 ng/mL, 1.00-400 ng/mL, 3.00-600 ng/mL and 8.00-900 ng/mL for AZT, AmB, NEO and BEM respectively. The bioanalytical method requires only 10 µL of ocular sample and analytes were extracted with fast protein precipitation with acidic methanol. Finally, the developed method was validated for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. PK-PD indices and dosing frequency was predicted using Phoenix WinNonlin Software, based on single dose ocular pharmacokinetics and MIC values of AmB, AZT and NEO. According to the PK-PD simulation, S. aureus and E. coli required 6 and 12 instillations of AZT per 24 h, respectively whereas 12 instillation of NEO requires per 24 h for S. aureus. The result suggests that to minimize antimicrobial resistance; drug, dose and dosing schedule depend upon the pathogen as well as the strain.

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.

Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9.

Effect of growth hormone administration on ameliorating pregnancy outcome in women with advanced maternal age and exploration of its optimized utilization.

Background: Age-related fertility decay is a great challenge for clinicians. Growth hormone (GH) supplementation has been studied as an adjuvant since late 1980s. However, it has not come to a consensus on the GH administration due to the ambiguous efficacy among studies with different enrolled population and dosage regime. Methods: A self-controlled retrospective study was conducted on women with advanced maternal age who underwent at least a previous cycle without GH (GH-) and a subsequent cycle with GH co-treatment (GH+). The ovarian stimulation parameters and outcomes were compared between the two cycles and logistical analysis was applied to further explore the association between GH administration protocol as well as other clinical parameters and cumulative live birth in GH+cycle. Results: A total of 150 women aged 35-43 were included. The number of oocytes retrieved, MII oocytes, 2PNs, transferrable embryos and good-quality embryos in GH+ significantly increased (p < 0.001). The proportion of cycles with no transferrable embryos was significantly reduced in GH+ cycle compared with previous GH- cycle (3 vs. 32; p < 0.001). GH co-treatment cycles showed significantly higher clinical pregnancy rates (43.75% vs. 6.06%; 38.35% vs. 12.04%, p < 0.001), live birth rates (29.17% vs. 0; 27.07% vs. 0, p < 0.001) in both fresh and frozen-thawed embryo transfer cycle. Cumulative live birth rate of the GH+ cycle reached 33.33%. Use of GH prior to Gn stimulation and lasting until the hCG day seemed to achieve a higher successful live birth rate (OR 2.312, 95%CI 1.074-5.163, p=0.032). Conclusion: GH supplementation could ameliorate pregnancy outcome in women with advanced maternal age. Dosage regimen of long-term pretreatment prior to Gn stimulation (4 IU every other day) and 4 IU per day until hCG day may of greater efficacy compared with concurrent administration with Gn. Additionally, it's worthy of exploring whether an individualized dosage regimen based on the IGF or IGFBP level of patient would be more reasonable and effective. More well-designed prospective trials with large sample size and fundamental experiments on the mechanism are required to testify findings above.

Population Pharmacokinetic Modeling of Zaltoprofen in Healthy Adults: Exploring the Dosage Regimen.

Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications.

Evaluation of Dosing Guidelines for Gentamicin in Neonates and Children.

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children's Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8-12 mg/L for neonates and 15-20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment.

Fecal microbiota transplantation in the treatment of systemic lupus erythematosus: What we learnt from the explorative clinical trial.

Systemic lupus erythematosus (SLE) is an autoimmune disease with the characterized presence of autoantibodies and resulting in multiple organ damage, which is incurable and can be lethal. The current treatments are limited and less progress has been made in drug discovery for the last few decades. Researches imply that gut dysbiosis exists in both patients and murine models with SLE, taking part in the pathogenesis of SLE through multiple mechanisms such as microbiota translocation and molecular mimicry. Intestinal interventions on the gut microbiome by fecal transplantations to reconstitute the gut-immunity homeostasis serve as a novel therapeutic option for SLE patients. Fecal microbiota transplantation (FMT), which is usually used in intestinal diseases, has been firstly demonstrated to be safe and efficient in recovering gut microbiota structure of SLE patients and reducing lupus activity in our recent clinical trial, which is the first trial testing FMT therapy in SLE treatment. In this paper, we reviewed the results of the single-arm clinical trial and made recommendations on FMT practice in SLE treatment including therapeutic indications, screening items and dosage regimen, trying to provide references for future study and clinical practice. We also came up with the unanswered questions that need to be solved by the ongoing randomized controlled trial as well as the future expectations for the intestinal intervention strategies of SLE patients.

Population pharmacokinetics of tigecycline in critically ill patients.

Objective: In critically ill patients, the change of pathophysiological status may affect the pharmacokinetic (PK) process of drugs. The purpose of this study was to develop a PK model for tigecycline in critically ill patients, identify the factors influencing the PK and optimiz dosing regimens. Method: The concentration of tigecycline was measured LC-MS/MS. We established population PK model with the non-linear mixed effect model and optimized the dosing regimens by Monte Carlo simulation. Result: A total of 143 blood samples from 54 patients were adequately described by a one-compartment linear model with first-order elimination. In the covariate screening analysis, the APACHEII score and age as significant covariates. The population-typical values of CL and Vd in the final model were 11.30 ± 3.54 L/h and 105.00 ± 4.47 L, respectively. The PTA value of the standard dose regimen (100 mg loading dose followed by a 50 mg maintenance dose at q12 h) was 40.96% with an MIC of 2 mg/L in patients with HAP, the ideal effect can be achieved by increasing the dosage. No dose adjustment was needed for Klebsiella pneumoniae for AUC0-24/MIC targets of 4.5 and 6.96, and the three dose regimens almost all reached 90%. A target AUC0-24/MIC of ≥17.9 reached 100% in patients with cSSSI in the three tigecycline dose regimens, considering MIC ≤ 0.25 mg/L. Conclusion: The final model indicated that APACHEII score and age could affect the Cl and Vd of tigecycline, respectively. The standard dose regimen of tigecycline was often not able to obtain satisfactory therapeutic effects for critically ill patients. For patients with HAP and cIAI caused by one of three pathogens, the efficacy rate can be improved by increasing the dose, but for cSSSI infections caused by Acinetobacter baumannii and K. pneumoniae, it is recommended to change the drug or use a combination of drugs.

Evaluation of delaying effects of different short-term dosage regimens of topical ciprofloxacin on corneal ulcer healing in an avian model.

BACKGROUND: Knowledge on possible delaying effects of topical ciprofloxacin on corneal ulcer healing is scarce in avian patients. OBJECTIVES: The study evaluates effects of different dosage regimens of topical ciprofloxacin on healing of corneal ulcer in an avian model. METHODS: One hundred and fifty adult layers were randomly allocated into two equal categories each consisted of 5 groups (n = 15): 1, negative control (NC, normal cornea); 2, positive control (PC) (birds with experimental corneal ulcer); and 3, 4 and 5, birds with corneal injury that received ciprofloxacin 0.3% topically q6h, q8h and q12h, respectively for 3 (category 1) or 5 days (category 2). Corneas were excised for histopathological evaluation and determination of MMP-9 expression. RESULTS: While no significant difference was observed in daily-measured fluorescein-stained ulcer size among ciprofloxacin-treated birds and PC group in category 1, birds in PC group of category 2 had significantly smaller ulcers as compared to antibiotic-treated birds at the end of experiment (p < 0.01 for all cases). Histopathological evaluations at the end of the experiment showed no significant difference among PC and ciprofloxacin-treated birds of both categories for almost all of the assayed parameters. Over expression of MMP-9 mRNA was observed in PC group after 3 and 5 days of ulcer induction compared to NC groups. Its expression in ciprofloxacin-treated birds of both categories remained close to PC groups. CONCLUSIONS: While ciprofloxacin administration for 3 days does not affect ulcer healing, it delays healing process at the end of 5 days of treatments in an avian model of corneal ulcer injury. This delaying effect is not associated with a drastic change in MMP-9 expression.

New Data for Nebivolol after In Silico PK Study: Focus on Young Patients and Dosage Regimen.

Nebivolol (NEB) is a highly selective ß1 receptor antagonist with a distinct pharmacological profile. This drug is approved for the treatment of hypertension in the US, and hypertension and heart failure in Europe. Here, we review observations based on age dependence and explore new drug regimens with in-silico studies, to achieve better efficacy and safety. The clinical data were obtained from six published literature reports. Then the data were used for model building, evaluation, and simulation. A two-compartment model with first-order absorption, lag time, linear elimination, and the following covariates: age and genotype were the ones best describing our population. Simulation of different dose regimens resulted in an increase chance of efficacy and safety when the dose regimen was altered to 6 mg every 36 h. It is worth noting that our population in this study constituted of young and healthy individuals. Studies regarding the effects of NEB according to age are scarce; however, they are needed to further improve efficacy and safety, and reduce adverse effects.

Population Pharmacokinetics and Dosing Regimen of Lithium in Chinese Patients With Bipolar Disorder.

Background: Lithium is an effective medication approved for the treatment of bipolar disorder (BD). It has a narrow therapeutic index (TI) and requires therapeutic drug monitoring. This study aimed to conduct a population pharmacokinetics (PPK) analysis of lithium and investigate the appropriateness of the dosing regimen according to different patient characteristics. Methods: A total of 476 lithium concentrations from 268 patients with bipolar disorder were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to investigate the influence of covariates, such as weight, creatinine clearance, and daily doses of lithium concentrations, and to determine the individualized dosing regimens for patients. Results: Lithium PK was described by a one-compartment model with first-order absorption and elimination processes. The typical estimated apparent clearance was 0.909 L/h-1 with 16.4% between-subject variability in the 62 kg patients with 116 ml/min creatinine clearance and 600 mg daily doses. To achieve a target trough concentration (0.4-0.8 mmol/L) in the maintenance phase, the regimen of 500 mg than 750 mg daily dose was recommended for patients with renal insufficiency and weighing 100 kg. Conclusion: A PPK model for lithium was developed to determine the influence of patient characteristics on lithium pharmacokinetics. Weight, creatinine clearance, and total daily dose of lithium can affect the drug's clearance. These results demonstrate the nonlinear renal excretion of lithium; hence, dosage adjustments are recommended for patients with renal insufficiency.

Plasma and Intrapulmonary Pharmacokinetics, and Dosage Regimen Optimization of Linezolid for Treatment of Gram-Positive Cocci Infections in Patients with Pulmonary Infection After Cerebral Hemorrhage.

Purpose: The objective of this study was to perform pharmacokinetics/pharmacodynamics (PK/PD) analysis of linezolid in patients with intracerebral hemorrhage and to provide suggestions regarding dosing and treatment regimens. Patients and Methods: Ten patients with cerebral hemorrhage and pulmonary infection were enrolled in this study. Plasma and sputum samples were obtained at specific time points after the seventh infusion. Linezolid concentration was measured using HPLC, and PK parameters were calculated using the non-compartmental model. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) in response to different dosing regimens (1200 mg/900 mg/600 mg/300 mg, q12h) were calculated based on the ratio of area under the curve to minimum inhibitory concentration (AUC/MIC). Results: The Cmax and AUC of linezolid were 12.89 µg/mL and 70.42 h·µg/mL for plasma, and 16.48 µg/mL and 92.95 h·µg/mL for sputum. The average penetration rate of linezolid in sputum, as represented by the ratio of AUC, was 131.99%. In response to the conventional dosing regimen (600mg, q12h), the PTA in the plasma or sputum was >90% only when MIC was ≤1 mg/L. Linezolid had the highest CFR against Streptococcus pneumoniae, followed by Enterococcus faecalis and Enterococcus faecium, with the lowest value for MRSA. Conclusion: This was the first study to evaluate PK/PD of linezolid in plasma and in the lungs of patients with cerebral hemorrhage and may assist in selecting appropriate dosing regimens for linezolid in these patients.

Pharmacodynamic Parameters of Pharmacokinetic/Pharmacodynamic (PK/PD) Integration Models.

Pharmacokinetic/pharmacodynamic (PK/PD) integration models are used to investigate the antimicrobial activity characteristics of drugs targeting pathogenic bacteria through comprehensive analysis of the interactions between PK and PD parameters. PK/PD models have been widely applied in the development of new drugs, optimization of the dosage regimen, and prevention and treatment of drug-resistant bacteria. In PK/PD analysis, minimal inhibitory concentration (MIC) is the most commonly applied PD parameter. However, accurately determining MIC is challenging and this can influence the therapeutic effect. Therefore, it is necessary to optimize PD indices to generate more rational results. Researchers have attempted to optimize PD parameters using mutant prevention concentration (MPC)-based PK/PD models, multiple PD parameter-based PK/PD models, kill rate-based PK/PD models, and others. In this review, we discuss progress on PD parameters for PK/PD models to provide a valuable reference for drug development, determining the dosage regimen, and preventing drug-resistant mutations.

Optimization and Validation of Dosage Regimen for Ceftiofur against Pasteurella multocida in Swine by Physiological Based Pharmacokinetic-Pharmacodynamic Model.

Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against P. multocida by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against P. multocida was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC0-24 h/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC24 h/MIC and AUC 72 h/MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.

Application of Semi-Mechanistic Pharmacokinetic and Pharmacodynamic Model in Antimicrobial Resistance.

Antimicrobial resistance is a major public health issue. The pharmacokinetic/pharmacodynamic (PK/PD) model is an essential tool to optimize dosage regimens and alleviate the emergence of resistance. The semi-mechanistic PK/PD model is a mathematical quantitative tool to capture the relationship between dose, exposure, and response, in terms of the mechanism. Understanding the different resistant mechanisms of bacteria to various antibacterials and presenting this as mathematical equations, the semi-mechanistic PK/PD model can capture and simulate the progress of bacterial growth and the variation in susceptibility. In this review, we outline the bacterial growth model and antibacterial effect model, including different resistant mechanisms, such as persisting resistance, adaptive resistance, and pre-existing resistance, of antibacterials against bacteria. The application of the semi-mechanistic PK/PD model, such as the determination of PK/PD breakpoints, combination therapy, and dosage optimization, are also summarized. Additionally, it is important to integrate the PD effect, such as the inoculum effect and host response, in order to develop a comprehensive mechanism model. In conclusion, with the semi-mechanistic PK/PD model, the dosage regimen can be reasonably determined, which can suppress bacterial growth and resistance development.

Simulated Intravenous versus Inhaled Tobramycin with or without Intravenous Ceftazidime Evaluated against Hypermutable Pseudomonas aeruginosa via a Dynamic Biofilm Model and Mechanism-Based Modeling.

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ). Two hypermutable P. aeruginosa isolates, CW30 (MICCAZ, 0.5 mg/liter; MICTOB, 2 mg/liter) and CW8 (MICCAZ, 2 mg/liter; MICTOB, 8 mg/liter), were investigated for 120 h in dynamic in vitro biofilm studies. Treatments were intravenous ceftazidime, 9 g/day (33% lung fluid penetration); intravenous tobramycin, 10 mg/kg of body every 24 h (50% lung fluid penetration); inhaled tobramycin, 300 mg every 12 h; and both ceftazidime-tobramycin combinations. Total and less susceptible planktonic and biofilm bacteria were quantified over 120 h. Mechanism-based modeling was performed. All monotherapies were ineffective for both isolates, with regrowth of planktonic (≥4.7 log10 CFU/ml) and biofilm (>3.8 log10 CFU/cm2) bacteria and resistance amplification by 120 h. Both combination treatments demonstrated synergistic or enhanced bacterial killing of planktonic and biofilm bacteria. With the combination simulating tobramycin inhalation, planktonic bacterial counts of the two isolates at 120 h were 0.47% and 36% of those for the combination with intravenous tobramycin; for biofilm bacteria the corresponding values were 8.2% and 13%. Combination regimens achieved substantial suppression of resistance of planktonic and biofilm bacteria compared to each antibiotic in monotherapy for both isolates. Mechanism-based modeling well described all planktonic and biofilm counts and indicated synergy of the combination regimens despite reduced activity of tobramycin in biofilm. Combination regimens of inhaled tobramycin with ceftazidime hold promise to treat acute exacerbations caused by hypermutable P. aeruginosa strains and warrant further investigation.