Pharmacokinetic-pharmacodynamic Model Research Articles

Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Sutimlimab, a humanized monoclonal antibody targeting the classical complement pathway, is approved in the US, Japan, and EU for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for Phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome (hemoglobin [Hb] levels). Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and non-linear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (Vc) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on Vc and maximal non-linear clearance. There were no PK differences between healthy participants and patients. Following graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (Emax) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that Emax was attained with the approved dosing (6.5 g in patients <75 kg, and 7.5 g in patients {greater than or equal to}75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dL was projected, consistent with Phase 3 study observations. Significance Statement The final validated population PK and PK/PD models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg, and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.

Pharmacokinetic-pharmacodynamic (PK/PD) modeling to study the hepatoprotective effect of Perilla Folium on the acute hepatic injury rats

Ethnopharmacological relevancePerilla Folium (PF), is a traditional medicinal material with the homology of medicine and food in China and has been widely used due to its rich nutritional content and medicinal value. The hepatoprotective effects of PF extract include their protection against acute hepatic injury, tert-butylhydroperoxide (t-BHP) induced oxidative damage, and Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced hepatic injury have been well studied. However, there are few reports on the pharmacokinetics studies of PF extract in acute hepatic injury model rats, and the anti-hepatic injury activity of PF is still unclear. Aim of the studyThe differences in the plasma pharmacokinetic of 21 active compounds between the normal and model groups were compared， and established pharmacokinetics/pharmacodynamics (PK/PD) modeling was to analyze the hepatoprotective effects of PF. Materials and methodsThe acute hepatic injury model was induced with an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN), and the plasma pharmacokinetics of 21 active compounds of PF were analyzed in the normal and model groups using ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The correlation between plasma components and hepatoprotective effects indicators (the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH)) in the model group was also investigated and established a Pharmacokinetic/pharmacodynamic (PK/PD) correlation analysis of the hepatoprotective effects of PF. ResultsThe results revealed that organic acid compounds possessed the characteristics of faster absorption, shorter peak time and slower metabolism, while the flavonoid compounds had slower absorption and longer peak time, and the pharmacokinetics of various components were significantly affected after modeling. The results of PK/PD modeling analysis demonstrated that the plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long. ConclusionsThe plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long in vivo.

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin.

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8mg/kg/day from 0.5 to 2years old, 9.2mg/kg/day from 3 to 6years old, 9.4mg/kg/day from 7 to 12years old, and 8.2mg/kg/day from 13 to 18years old, taken in half for 2-5days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.

High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.

Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.

LC-MS/MS quantification of ropivacaine and local analgesic and adverse effects of Long-acting Ropivacaine Injection based on pharmacokinetic-pharmacodynamic modelling in Bama minipigs

The local analgesic efficacy and adverse effects of a new Long-acting Ropivacaine formulation were examined based on pharmacokinetic-pharmacodynamic (PK-PD) modelling in Bama minipigs. 24 Bama minipigs, 12 males and 12 females, were randomly and equally divided into the following treatment groups: normal saline injection, drug vehicle injection, Long-acting Ropivacaine Injection and Ropivacaine Hydrochloride Injection. After routine disinfection, a skin incision about 3 cm long and 3 cm deep was produced in the leg of each pig, and mechanical withdrawal threshold (MWT) measured at various times pre- and post-injection as an index of analgesia against incision pain. Plasma ropivacaine concentrations were also measured at the same times using a novel liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method. Minipigs were sacrificed 24 h post-injection and hearts collected for drug concentration measurements by LC-MS/MS. The LC-MS/MS method demonstrated high sensitivity, linearity and precision. The Long-acting Ropivacaine formulation produced a longer analgesic effect (∼12 h) at a lower plasma concentration than Ropivacaine Hydrochloride (∼4h), suggesting a better side-effects profile. A PK-PD model revealed a direct relationship between plasma ropivacaine concentration and MWT, with peak analgesia at about 1000 ng/mL and behaved good prediction ability. Long-acting Ropivacaine Injection is a superior local anaesthetic-analgesic treatment due to longer-lasting efficacy at lower concentrations compared to Ropivacaine Hydrochloride, which will reduce the risk of side effects such as cardiotoxicity.

A pharmacokinetic-pharmacodynamic model based on the SSA-1DCNN-Attention network and the semicompartment method

ABSTRACT To solve the problem of inaccurate prediction caused by the lack of representativeness of samples due to the small sample size of the collected clinical data when using machine learning methods to predict drug concentration in plasma and describe the hysteresis phenomenon of drug effect lagging behind plasma drug concentration, this paper proposes a pharmacokinetic-pharmacodynamic (PK-PD) model based on the SSA-1DCNN-Attention network and the semicompartment method. First, a one-dimensional convolutional neural network (1DCNN) is established, and the attention mechanism is introduced to determine the importance of each physiological and biochemical parameter. The sparrow search algorithm (SSA) is used to optimize the parameters of the network to improve the prediction accuracy after data enhancement through the synthetic minority oversampling technique (SMOTE) method. After constructing the time-concentration relationship of the drug through the SSA-1DCNN-Attention network, the concentration-effect relationship of the drug is established by using the semicompartment method to synchronize the drug effect with the concentration. At last, the phenobarbital (PHB) combined with Cynanchum otophyllum saponins to treat epilepsy was taken as an example to validate the proposed method.

Pharmacokinetic-pharmacodynamic model of urinary δ-aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria.

Givosiran, an RNA interference-based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I-III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA-induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ-aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035-5mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5-mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) recommended as first-line treatment for patients with locally advanced/metastatic EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose [10 mg/kg for exposures equivalent to (≈)80 mg], combined with doses of savolitinib (0-15 mg/kg, ≈0-600 mg once daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various time points to follow the time course of drug exposure in addition to phosphorylated MET and EGFR (pMET and pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant antitumor activity, reaching ∼84% TGI, and osimertinib (10 mg/kg) showed no significant antitumor activity (34% TGI, P > 0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related antitumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination antitumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

A Pharmacokinetic-Pharmacodynamic Model Predicts Uracil-tegafur Effect on Tumor Shrinkage and Myelosuppression in a Colorectal Cancer Rat Model.

Oral 5-fluorouracil (5-FU)-based prodrugs, used in cancer chemotherapeutic regimens, exhibit large inter- and intra-patient variability in plasma 5-FU concentrations, contributing to treatment failure. Although dosage determination criteria according to plasma drug concentrations are required, the relationship between pharmacokinetics and drug response after multiple oral 5-FU derivative administrations remain unknown. We evaluated the pharmacokinetics and pharmacodynamics/toxicodynamics of uracil-tegafur (UFT) after multiple administrations in colorectal cancer (CRC) model rats, and applied a pharmacometric approach to describe the time-course alterations of plasma 5-FU concentrations and tumor shrinkage. CRC was induced in rats using 1,2-dimethylhydrazine and dextran sulfate sodium. UFT (30 mg/kg as tegafur) was administered to CRC rats for 14 days. Plasma 5-FU exposure levels increased with the dosing time, and large variations were observed in tumor 5-FU concentrations (32.0-125.8% with coefficient of variation). Although severe hematological toxicities were not observed, a weak correlation was observed between blood platelet count and the plasma 5-FU concentration (r=0.439, p=0.176). A simple pharmacokinetic-pharmacodynamic model was developed comprising of a small number of parameters and successfully describing plasma 5-FU levels and tumor shrinkage after multiple UFT administrations. A pharmacometric model approach can help establish the dose-determination criteria based on plasma 5-FU concentration of UFT-based regimens, and contribute to improvement of clinical outcomes.

The dose regimen formulation of doxycycline hydrochloride and florfenicol injection based on ex vivo pharmacokinetic-pharmacodynamic modeling against the Actinobacillus pleuropneumoniae in pigs

Doxycycline hydrochloride and florfenicol combination (DoxHcl&FF) is an effective treatment for respiratory diseases. In the study, our objective was to evaluate the activity of DoxHcl&FF against Actinobacillus pleuropneumoniae (APP) in porcine pulmonary epithelial lining fluid (PELF) and the optimal dosage scheme to avoid the development of resistance. The DoxHcl&FF was administered intramuscularly (IM) at 20 mg/kg, and the PELF was collected at different time points. The minimum inhibitory concentration (MIC) and time-mortality curves were also included in the study. Based on the sigmoid Emax equation and dose equations, the study integrated the in vivo pharmacokinetic data of infected pigs and ex vivo pharmacodynamic data to obtain the area under concentration time curve (AUC0-24h)/MIC values in PELF and achieve bacteriostatic activity, bactericidal activity and the virtual eradication of bacteria. The study showed that the combination of DoxHcl and FF caused no significant changes in PK parameters. The peak concentration (Cmax) of FF in healthy and diseased pigs was 8.87 ± 0.08 μg/mL and 8.67 ± 0.07 μg/mL, the AUC0-24h were 172.75 ± 2.52 h·μg/mL and 180.22 ± 3.13 h·μg/mL, the Cmax of DoxHcl was 7.91 ± 0.09 μg/mL and 7.99 ± 0.05 μg/mL, and the AUC0-24h was 129.96 ± 3.70 h·μg/mL and 169.82 ± 4.38 h·μg/mL. DoxHcl&FF showed strong concentration-dependent tendencies. The bacteriostatic, bactericidal, and elimination activity were calculated as 5.61, 18.83 and 32.68 h, and the doses were 1.37 (bacteriostatic), 4.59 (bactericidal) and 7.99 (elimination) mg/kg. These findings indicated that the calculated recommended dose could assist in achieving more precise administration, increasing the effectiveness of DoxHcl&FF treatment for APP infections.

Delivering on the promise of protein degraders.

Over the past 3 years, the first bivalent protein degraders intentionally designed for targeted protein degradation (TPD) have advanced to clinical trials, with an initial focus on established targets. Most of these clinical candidates are designed for oral administration, and many discovery efforts appear to be similarly focused. As we look towards the future, we propose that an oral-centric discovery paradigm will overly constrain the chemical designs that are considered and limit the potential to drug novel targets. In this Perspective, we summarize the current state of the bivalent degrader modality and propose threecategories of degrader designs, based on their likely route of administration and requirement for drug delivery technologies. We then describe a vision for how parenteral drug delivery, implemented early in research and supported by pharmacokinetic-pharmacodynamic modelling, can enable exploration of a broader drug design space, expand the scope of accessible targets and deliver on the promise of protein degraders as a therapeutic modality.

Population pharmacokinetic-pharmacodynamic model of dexmedetomidine in elderly patients undergoing sedation after abdominal aortic surgery

Background. Dexmedetomidine (DEX) is a widely used sedative agent for treating post-surgery patients. It also acts on hemodynamic parameters like heart rate or cardiac output. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of DEX using bispectral index (BIS) and cardiac output (CO) as a response. Methodology and results. 21 mechanically ventilated elderly cardiac patients undergoing abdominal aortic surgery were enrolled in the study. DEX was given to maintain moderate or deep sedation. Genotypes of ADR2A*55 were identified using real-time PCR-HRM. Data were analyzed using nonlinear mixed-effect modelling. A two-compartment model described DEX pharmacokinetics. The sigmoid Emax and linear models were used to describe BIS and CO measurements. The typical value of EC50 for DEX effects on BIS was 3.62 ng/ml, and the slope between CO and DEX concentrations was 0.819 (L/min)/(ng/ml). We were unable to show the effects of considered covariates on DEX pharmacodynamics. Conclusions. WE proposed the PK/PD model of DEX to understand better the BIS and CO changes observed after surgery. The measured CI values were in the reference range showing that the used doses of DEX ensured stable cardiac function in the studied patients.

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study.

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic-pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8h after treatment initiation.

A population pharmacokinetic-pharmacodynamic model evaluating efficacy of nalbuphine extended-release in patients with prurigo nodularis.

Population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models were used to describe the exposure-response (E-R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's 'average'; itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-h recall. Simulations based on the model E-R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7-day average of the 24-h WI-NRS by at least 30% from baseline in most of the analysis population. Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A maximum effect ( ) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). The PK-PD model predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of , respectively. Exposures associated with 80% of were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID. Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

A personalised taper-to-target strategy with adalimumab in Crohn's disease

In The Lancet Gastroenterology & Hepatology, Reinier C A van Linschoten and colleagues report the results of the LADI trial. 1 van Linschoten RCA Jansen FM Pauwels RWM et al. Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023; (published online Jan 31.)https://doi.org/10.1016/S2468-1253(22)00434-4 Google Scholar This trial is an excellent opportunity to explore adalimumab exposure–response relationships in patients with Crohn's disease. Surprisingly, no population pharmacokinetic–pharmacodynamic model of adalimumab in patients with Crohn's disease has been published since the approval of the type II variation by the European Medicines Agency in 2007. However, a pharmacokinetic–pharmacodynamic model was developed by marketing authorisation holder AbbVie, describing the temporal relation between adalimumab dose, adalimumab serum concentrations, and the Crohn's Disease Activity Index (CDAI). 2 European Medicines AgencyScientific discussion Humira—emea/h/c/481-482/ii/33. https://www.ema.europa.eu/en/documents/scientific-discussion-variation/humira-h-c-481-ii-33-epar-scientific-discussion-variation_en.pdfDate: 2007 Date accessed: January 15, 2023 Google Scholar Unfortunately, the model code was not shared, preventing model-informed design of the LADI trial through simulating dose-tapering scenarios and their effect on disease severity. 3 Bauer RJ Hooker AC Mentre F Tutorial for $DESIGN in NONMEM: clinical trial evaluation and optimization. CPT Pharmacometrics Syst Pharmacol. 2021; 10: 1452-1465 Crossref PubMed Scopus (0) Google Scholar Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trialThe individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. Full-Text PDF

Overview Of Drug Evaluation By Method; Analgesic Activity, Anticancer Activity, Antidireutics Activity, Antiobesity Activity, Hyperglycemic Activity

The pharmacological medicine and pharmacodynamics of medication area unit totally different in adult and medical specialty populations, the latter being significantly heterogeneous. These variations in pharmacological medicine and pharmacodynamics justify specific studies however raise variety of moral and sensible problems. the most sensible difficulties to avoid whereas performing arts clinical studies in kids area unit the invasiveness of the procedures and also the obstacles to patient enlisting. The invasiveness associated with pain/anxiety and blood loss precludes the performance of classical pharmacokinetic studies in kids in several instances, significantly in neonates and infants. Population approaches, that believe pharmacokinetic-pharmacodynamic modelling, area unit significantly appealing in medical specialty populations as a result of these models will address thin knowledge. The connexion of population approaches to investigation of the dose-concentration-effect relationships and to qualitative/quantitative assessment of things which will make a case for interindividual variability has already been emphasised.

Review on Drug Evaluation Methods

The pharmacokinetics and pharmacodynamics of drugs are different in adult and paediatric populations, the latter being particularly heterogeneous. These differences in pharmacokinetics and pharmacodynamics justify specific studies but raise a number of ethical and practical issues. The main practical difficulties to circumvent while performing clinical studies in children are the invasiveness of the procedures and the obstacles to patient recruitment. The invasiveness related to pain/anxiety and blood loss precludes the performance of classical pharmacokinetic studies in children in many instances, particularly in neonates and infants. Population approaches, which rely on pharmacokinetic-pharmacodynamic modelling, are particularly appealing in paediatric populations because these models can cope with sparse data. The relevance of population approaches to investigation of the dose-concentration-effect relationships and to qualitative/quantitative assessment of factors that may explain interindividual variability has already been emphasized.

Dosage exploration of meloxicam according to CYP2C9 genetic polymorphisms based on a population pharmacokinetic-pharmacodynamic model.

Meloxicam, used for treating inflammatory diseases, shows large differences in metabolism according to CYP2C9 genetic polymorphisms; however, there are few studies on dose regimen setting based on quantitative predictions. The aim of this study was to determine the appropriate meloxicam dose regimen for each genotype through population pharmacokinetic-pharmacodynamic modeling of meloxicam by considering CYP2C9 genetic polymorphisms. For modeling, previously reported pharmacokinetic (plasma concentration)-pharmacodynamic (inhibition of thromboxane B2 generation) data of meloxicam were collected for CYP2C9 genetic polymorphisms (n=43). And these data were mainly used in the modeling process. Through simulations of the established models, steady-state pharmacokinetic-pharmacodynamic profiles were obtained according to meloxicam multiple exposures for each CYP2C9 genotype, and predictions were made based on dose regimen changes. Genetic polymorphisms of CYP2C9 were identified as key covariates that significantly affected pharmacokinetic variability of meloxicam between individuals. The developed meloxicam population pharmacokinetic-pharmacodynamic model predicted pharmacokinetic results of the 7.5mg meloxicam administration groups (n=26) for CYP2C9*1/*1 and *1/*3 as an external validation. The results of model simulation revealed that the differences were 2.39-5.42 times for steady-state mean plasma concentrations and 1.21-1.71 times for the degree of inhibition of thromboxane B2 generation following multiple exposures for CYP2C9*1/*1 versus *1/*13, *1/*3, and *3/*3. This suggested that thromboxane B2 inhibition following increased plasma exposure to meloxicam differed significantly according to CYP2C9 genetic polymorphisms. The dose of meloxicam in CYP2C9*1/*13, *1/*3, and *3/*3 was randomly adjusted to 1.6-15 mg to approximate the mean thromboxane B2 inhibition for CYP2C9*1/*1 at steady state, the dose intervals varied from 24 h to 48 h. The results suggested that clinical dose adjustment of meloxicam would be necessary to account for CYP2C9 genetic polymorphisms and reduce side effects. This study suggests a clearer direction for setting up clinical therapy based on personalized medicine and quantitative predictions for meloxicam.

Direct bioanalysis or indirect calculation of target engagement and free drug exposure: do we apply double standards?

Analysis of "free" drug/target concentrations is important to set up appropriate pharmacokinetic-pharmacodynamic models, to evaluate active-drug exposure and target engagement. Such "free-analyte" determination could be done by direct bioanalysis using an appropriate "free-analyte" assay. Development of "free" assays is often considered challenging from a technological and regulatory perspective. The application of a "total-total" approach, where the "free-analyte" concentration is determined mathematically, is considered a more convenient option. In this perspective, we examine and discuss the challenges of this "total-total" approach, from the affinity data, the importance of applying an appropriate "total" assay, the impact of additional binding partners and the variability of the total drug/target assays and their impact on the quality and variability of the final "free-analyte" dataset.

Population Pharmacokinetic-Pharmacodynamic Modeling of Carvedilol to Evaluate the Effect of Cytochrome P450 2D6 Genotype on the Heart Rate Reduction.

Carvedilol is a beta-adrenergic receptor antagonist primarily metabolized by cytochromes P450 (CYP) 2D6. This study established a carvedilol population pharmacokinetic (PK)-pharmacodynamic (PD) model to describe the effects of CYP2D6 genetic polymorphisms on the inter-individual variability of PK and PD. The PK-PD model was developed from a clinical study conducted on 21 healthy subjects divided into three CYP2D6 phenotype groups, with six subjects in the extensive metabolizer (EM, *1/*1, *1/*2), seven in the intermediate metabolizer-1 (IM-1, *1/*10, *2/*10), and eight in the intermediate metabolizer-2 (IM-2, *10/*10) groups. The PK-PD model was sequentially developed, and the isoproterenol-induced heart rate changes were used to establish the PD model. A direct effect response and inhibitory Emax model were used to develop a carvedilol PK-PD model. The carvedilol PK was well described by a two-compartment model with zero-order absorption, lag time, and first-order elimination. The carvedilol clearance in the CYP2D6*10/*10 group decreased by 32.8% compared with the other groups. The inhibitory concentration of carvedilol estimated from the final PK-PD model was 16.5 ng/mL regardless of the CYP2D6 phenotype. The PK-PD model revealed that the CYP2D6 genetic polymorphisms were contributed to the inter-individual variability of carvedilol PK, but not PD.