PK-PD Model Research Articles

The in vivo study on antioxidant activity of wendan decoction in treating hyperlipidemia: a pharmacokinetic-pharmacodynamic (PK-PD) model.

Background: Wendan Decoction (WDD) is a six-herb Chinese medicine recipe that was first mentioned in about 652 AD. It is frequently used to treat hyperlipidemic patients' clinical complaints. According to reports, oxidative stress has a significant role in hyperlipidemia. Purpose: There has not yet been a thorough pharmacokinetic-pharmacodynamic (PK-PD) examination of the clinical efficacy of WDD in the context of hyperlipemia-related oxidative stress. Therefore, the goal of this research is to explore the antioxidant essence of WDD by developing a PK-PD model, ordering to assure its implication in treating hyperlipidemia in medical practice. Methods: The model rats of foodborne hyperlipidemia were established by feeding with high-fat feed, and the lipid-lowering effect of WDD was explored. The plasma drug concentration of rats at different doses were measured by UPL-MS/MS technology, and PK parameters were calculated using Phoenix WinNonlin 8.1 software. The level of lipid peroxide (LPO) in plasma at different time points was measured by enzyme labeling instrument. Finally, the PK-PD model was established by using Phoenix WinNonlin 8.1 software, to explore the lipid-lowering effect of WDD and the relation between the dynamic changes of chemical components and antioxidant effect. Results: The findings suggested that, WDD can reduce the levels of triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma, and high-density lipoprotein cholesterol (HDL-C) was related to the dosage. Between the peak drug levels and the WDD's maximal therapeutic response, there existed a hysteresis. WDD's effect-concentration curves displayed a counterclockwise delaying loop. Alternatively, among the ten components of WDD, hesperetin, quercetin, naringenin and tangeretin might exert more significant effects in regulating the LPO levels in hyperlipidemic rats. Conclusion: This study can be helpful for other investigators to study the lipid-lowering effect of WDD.

Model-Informed Dose Selection for a Novel Human Immunoglobulin G4 Derived Monoclonal Antibody Targeting Proprotein Convertase Kwashiorkor Type 9: Insights from Population Pharmacokinetics-Pharmacodynamics and Systems Pharmacology.

Monoclonal antibody drugs targeting proprotein convertase kwashiorkor type 9 (PCSK9) have recently demonstrated remarkable success in lipid-lowering therapies. Specifically, antibodies derived from immunoglobulin G1 (IgG1, alirocumab) and IgG2 (evolocumab) have been successfully utilized for this purpose. Recently, a novel recombinant fully human anti-PCSK9 monoclonal antibody, originally derived from IgG4 and designated as SAL003, was developed. This study aimed to explore the pharmacokinetics, efficacy, and safety of SAL003 in both single and multiple administrations. The investigation included both healthy individuals and individuals with hyperlipidemia. To comprehensively grasp the pharmacokinetic (PK) and pharmacodynamic (PD) attributes of SAL003, this study employed population PK-PD (popPK-PD) and mechanistic systems pharmacology (MSP) modeling. These models were employed for predicting low-density lipoprotein cholesterol (LDLc) concentrations and appropriate dosages across diverse potential clinical scenarios. The research results indicated that SAL003 demonstrated comparable pharmacokinetic properties to evolocumab, exhibited notable effectiveness in reducing lipid levels, and was confirmed to be safe and well-tolerated in both healthy individuals and individuals with hyperlipidemia. Notably, SAL003 displayed differing effectiveness between patients and healthy populations. This discrepancy was observed in the popPK-PD model, with a positive population influence on Emax, and the MSP model, indicating elevated PCSK9 clearance and LDLr-related LDLc clearance in the healthy group. Simulation results from the popPK-PD and MSP models indicated a dosage of 140 mg of Q4W and 420 mg of Q8W for phase II/III clinical trials. Reducing the drug dose or extending the dosing intervals may result in treatment failure. Additionally, the simultaneous use of statins led to elevated PCSK9 levels and intensified fluctuations in steady-state LDLc levels during SAL003 treatment.

Machine Learning and Artificial Intelligence in PK-PD Modeling: Fad, Friend, or Foe?

Machine Learning and Artificial Intelligence in PK-PD Modeling: Fad, Friend, or Foe?

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology.

Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection. Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokinetics-pharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD. QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as Tmax, t1/2, MRT, Vd/F, CL/F and PD parameters such as MIC, AUC0-24h/MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 β, IL-6, TNF- α, IL-10, and MCP-1 levels more akin to those of the blank group. These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.

First-Hand Design of a Fractional order PID for Controlling the Depth of Hypnosis during Induction

The integration of information technology and control engineering has significantly increased in the research field of clinical practice, including the management of medication dosing for general anesthesia. To achieve effective drug dosing, it is necessary to have appropriate controllers for closed loop control methods. A multitude of control mechanisms have been devised to manage hypnosis, with most of them based on pharmacokinetic-pharmacodynamic (PK-PD) models. This study presents a novel structure of a fractional order PID controller tuned for inducing hypnosis. The tuning algorithm uses a novel fractional order model instead of the classical PK-PD models. The main goal is to control the Bispectral Index by delivering Propofol during the hypnotic stage of anesthesia. Closed loop simulation results show that the proposed controller manages to ensure little undershoot and time to target for a nominal patient model. Robustness tests are also performed. The analysis shows that the proposed controller is suitable to maintain BIS signal within a safe operating range but fails to meet the time to target requirement for significant patient variability (greater than 2 orders of magnitude). Online adaptation rules are suggested as a solution.

Simultaneous determination of amphotericin B, tobramycin and vancomycin in rabbit ocular biofluids and tissues by LC-MS/MS: An antimicrobial therapy for keratitis and its PK-PD application

A rationale poly-microbial keratitis (PMK) therapy requires quick identification of pathogen (bacteria and fungi) and their efficient treatment. However, majority of healthcare providers are still having trouble finding an effective medicine to treat PMK due to constraints such as antimicrobial resistance, dose and dosing schedule. Thus, a broad spectrum anti-fungal and antibacterial having less resistance in community involving combination therapy such as amphotericin B (AmB), tobramycin (TBR) and vancomycin (VCM) is required. Hence, to characterize the pharmacokinetic (PK) and PK-pharmacodynamic (PD) indices, a rapid and sensitive simultaneous LC-MS/MS bioanalytical method was developed and validated for the quantification of AmB, TBR and VCM in rabbit ocular biofluids and tissues. Chromatographic resolution was achieved on a Zorbax C18 column with a mobile phase composed of acetonitrile and 0.4 % formic acid in deionized water using a gradient mode of elution. The calibration curves showed good linearity over the concentration range of 1.95–500 ng/mL for AmB and TBR, 3.9–800 ng/mL for VCM, respectively. The lower limit of quantification (LLOQ) was found to be 1.95 ng/mL for AmB and TBR, and 4.5 ng/mL for VCM. Analyte extraction was performed by simple protein precipitation method with minimal sample volume of 10 µL. Finally, the developed method was validated for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. The ocular pharmacokinetic profile of commercial AmB, TBR, and VCM formulations was further assessed using the validated method and the PK-PD indices along with dosing frequency was predicted by PK-PD modelling using Phoenix WinNonlin Software.

Power to identify exposure-response relationships in phase IIa pulmonary tuberculosis trials with multi-dimensional bacterial load modeling.

Adequate power to identify an exposure-response relationship in a phase IIa clinical trial for pulmonary tuberculosis (TB) is important for dose selection and design of follow-up studies. Currently, it is not known what response marker provides the pharmacokinetic-pharmacodynamic (PK-PD) model more power to identify an exposure-response relationship. We simulated colony-forming units (CFU) and time-to-positivity (TTP) measurements for four hypothetical drugs with different activity profiles for 14 days. The power to identify exposure-response relationships when analyzing CFU, TTP, or combined CFU + TTP data was determined at 60 total participants, or with 25 out of 60 participants in the lowest and highest dosing groups (unbalanced design). For drugs with moderate bactericidal activity, power was low (<59%), irrespective of the data analyzed. Power was 1.9% to 29.4% higher when analyzing TTP data compared to CFU data. Combined analysis of CFU and TTP further improved the power, on average by 4.2%. For a drug with a medium-high activity, the total sample size needed to achieve 80% power was 136 for CFU, 72 for TTP, and 68 for combined CFU + TTP data. The unbalanced design improved the power by 16% over the balanced design. In conclusion, the power to identify an exposure-response relationship is low for TB drugs with moderate bactericidal activity or with a slow onset of activity. TTP provides the PK-PD model with more power to identify exposure-response relationships compared to CFU, and combined analysis or an unbalanced dosing group study design offers modest further improvement.

Evaluation of anticancer effect of micelle-encapsulated doxorubicin using gamma-distributed delay model

In clinical trials of nanoparticle-based anticancer drug delivery systems, an inexplicable lack of correlation between the function imparted to the nanoparticles and their therapeutic effects is noted. To elucidate the cause of this lack of correlation, we developed a pharmacokinetic-pharmacodynamic (PK-PD) model of tumor growth kinetics in a tumor-bearing rat model injected with polymeric micelle-encapsulated doxorubicin (DOX) using parameters related to tumor accumulation and anticancer activity. DOX was loaded onto a polyethylene glycol-peptide block polymer (PEG-poly(D/F)n: PPDF) via an amide bond to prepare sustained-release polymeric micelles (PPDF-DOX) and folic acid receptor-targeting polymeric micelles (FA-PPDF-DOX). Plasma concentration–time profiles and pharmacokinetic parameters of DOX released from PPDF-DOX into the tumors were examined using microdialysis analysis on the tumors in Walker 256 tumor-bearing rats after PPDF-DOX administration. PPDF-DOX and FA-PPDF-DOX showed delayed tumor accumulation for up to 4 h after injection. Therefore, the analysis was performed using a three-compartment model, incorporating a gamma-distributed delay model between the central and tumor compartments. The PK model was used to simulate eight repeated doses administered every other day. The cumulative area under the curve of FA-PPDF-DOX was 4.2-fold higher than that of PPDF-DOX. The PK-PD model analysis was performed based on intratumoral DOX concentration profiles and changes in tumor diameter. The time efficacy index—a measure of drug efficacy—indicated a 45k-fold higher antitumor effect of FA-PPDF-DOX over that of PPDF-DOX. These results suggest that the active-targeting function versus the effect of sustained-release polymeric micelles may depend on the delayed tumor retention of anticancer drugs.

Analysis of compatibility mechanism of shenxiong glucose injection after multiple dosing based on differences of PK-PD correlation and cytochrome P450 enzyme

Shenxiong glucose injection (SGI) containing a water extract from the roots of Danshen and Ligustrazine hydrochloride, is the main drug used for the prevention and treatment of acute myocardial ischemia (AMI) in China. Based on the characteristics of drug clinical applications, this study aims to uncover the compatibility mechanism of SGI by investigating pharmacokinetic (PK) and pharmacodynamic (PD) differences between Danshen glucose injection (DGI), Ligustrazine glucose injection (LGI) and SGI groups after multiple dosing during the pathological state from the perspective of metabolic enzymes. Compared to the LGI group, the absorption (Cmax) and exposure (AUC) of ligustrazine increased significantly, and the protein expression of CYP1A2, CYP2C11 and CYP3A2 in the SGI group decreased significantly. Furthermore, the PK and PD experimental data for Danshen and ligustrazine in AMI rats were fitted to obtain a PK-PD binding model with three components. PK-PD parameter analysis showed that in the SGI group the IC50 values of ligustrazine and danshensu on AST, CK-MB, cTn-I and the IC50 values of rosmarinic acid on AST and CK-MB were lower than the DGI or LGI group. It is speculated that Danshen inhibited CYP1A2, CYP2C11 and CYP3A2 mediating the metabolism of ligustrazine and decreased the expression of these three isozymes, which further affected the in vivo process of ligustrazine. Moreover, the combination of Danshen and ligustrazine could have better regulating effect on AST, CK-MB and cTn-I. This preliminary study has provided a scientific basis for understanding the compatibility mechanism of SGI from the viewpoint of the regulation of CYP enzymes in the PK-PD model.

Prediction of C-reactive protein dynamics during meropenem treatment in neonates and infants.

C-reactive protein (CRP) is used to determine the effect of antibiotic treatment on sepsis in neonates/infants. We aimed to develop pharmacokinetic-pharmacodynamic (PKPD) model of meropenem and CRP in neonates/infants and evaluate its predictive performance of CRP dynamics. Data from neonates/infants treated with meropenem in 3 previous studies were analysed. To the previously developed meropenem PK models, the addition of turnover, transit or effect compartment, delay differential equation PD models of CRP as a function of meropenem concentration or its cumulative area under the curve (AUC) were evaluated. The percentage of neonates/infants (P0.1 , P0.2 ) in whom the ratio of the fifth day CRP to its peak value was predicted with an error of <0.1 (<0.2) was calculated. A total of 60 meropenem treatment episodes (median [range] gestational age 27.6 [22.6-40.9] weeks, postnatal age 13 [2-89] days) with a total of 351 CRP concentrations (maximum value 65.5 [13-358.4] mg/L) were included. Turnover model of CRP as a function of meropenem cumulative AUC provided the best fit and included CRP at the start of treatment, use of prior antibiotics, study and causative agent Staphylococcus aureus or enterococci as covariates. Using meropenem population predictions and data available at 0, 24, 48, 72 h after the start of treatment, P0.1 (P0.2 ) was 36.4, 36.4, 60.6 and 66.7% (70.0, 66.7, 72.7 and 78.7%), respectively. The developed PKPD model of meropenem and CRP as a function of meropenem cumulative AUC incorporating several patient characteristics predicts CRP dynamics with an error of <0.2 in most neonates/infants.

Population Pharmacokinetic-Pharmacodynamic Modeling of Neutrophil and Platelet Count for Lower-Intensity Therapy of CPX-351 Combined with Venetoclax in Acute Myeloid Leukemia

Background: Improved survival outcomes and a comparable safety profile with CPX-351 (a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio) vs conventional 7+3 chemotherapy in a pivotal phase 3 trial led to the approval of CPX-351 for newly diagnosed therapy-related acute myeloid leukemia (tAML) or AML with myelodysplasia-related changes (AML MRC) in adults and pediatric (aged ≥1 year) patients in the United States and in adults in Europe. The approved induction dose is 1-2 cycles of CPX-351 100 units/m 2 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2) as a 90-minute intravenous infusion on days 1, 3, and 5 (days 1 and 3 for second induction). In this study, we developed a population pharmacokinetic-pharmacodynamic (PK-PD) model of absolute neutrophil count (ANC) and platelet count to determine the optimal dose for a lower-intensity therapy (LiT) of CPX-351 combined with venetoclax. Methods: The CPX-351 population PK-PD analysis was based on data collected from 3 clinical studies (phase 1 study [NCT00389428; J Clin Oncol 2011; 29(8):979-85];phase 2 study [NCT02238925; Cancer Chemother Pharmacol 2019; 84(1):163-73];phase 3 study [NCT01696084; J Clin Oncol 2018; 36(26):2684-92]) in patients with newly diagnosed high-risk/secondary AML. Venetoclax population PK-PD analysis was based on data from a comprehensive safety analysis of venetoclax monotherapy ( Clin Cancer Res 2018; 24(18):4371-9). ANC and platelet data used in the analysis were from 94 patients for CPX-351 and 272 patients for venetoclax. Generalized semi-mechanistic population PK-PD analyses were performed using non-linear mixed-effects modeling to characterize the time-course of ANC and platelet count following administration of CPX-351 and venetoclax monotherapy. The majority of system parameters were shared across the 2 therapies and a limited number of treatment-specific parameters were estimated by fitting CPX-351 and venetoclax PK time-courses simultaneously. An R Shiny app was developed for the simulation of different dosing regimens with favorable safety profiles to guide optimal dose selection for LiT of CPX-351 combined with venetoclax, assuming the 2 drug effects on ANC and platelet count were additive. Results: The generalized PK-PD model included multi-compartment transit models for ANC and platelet count with separate semi-mechanistic compartments to represent proliferating, maturing, and circulating cells. The model fitted CPX-351 and venetoclax PK-PD data with shared system parameters except for the drug-specific parameter IC 50 (concentration producing 50% of maximal inhibition of cell proliferation). For ANC, the estimated IC 50 values for CPX-351 and venetoclax were 295 μM (relative standard error [RSE]: 8.96%) and 120 μM (RSE: 18.0%), respectively; the shared mean transit time (MTT) estimate for ANC maturation was 66.6 h (RSE: 4.95%), and shared maximal inhibition of cell proliferation (I max) was fixed to 1. For platelet count, the estimated IC 50 values for CPX-351 and venetoclax were 0.0109 μM (RSE: 50.2%) and 16.5 μM (RSE: 8.73%); the shared MTT estimate for platelet maturation was 87.2 h (RSE: 9.01%) and shared I max estimate was 0.313 (RSE: 11.2%). Simulations with different doses of CPX-351 in combination with 400 mg venetoclax were performed. The simulated mean nadir ANC were 2.1, 1.5, 1.1, and 0.6 × 10 9/L for CPX-351 doses of 20, 40, 60, and 100 units/m 2, respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. The simulated mean nadir platelet counts were 31.0, 30.3, 30.0, and 29.7 × 10 9/L for CPX-351 doses of 20, 40, 60, and 100 units/m 2, respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. Model-based simulated outcomes of ANC and platelet count were consistent with the observed trial data. C onclusions: A generalized semi-mechanistic population PK-PD model was developed to adequately describe the time-courses of ANC and platelet counts in patients with AML following the administration of CPX-351 and venetoclax monotherapy and was used to infer the impact on ANC and platelet count when given in combination. Model-based simulations supported initial dose selection in the phase 1b study of combined CPX-351 LiT plus venetoclax as first-line treatment for patients with AML who are unfit for intensive chemotherapy (NCT04038437).

Quantifying the Effect of Methotrexate on Adalimumab Response in Psoriasis by Pharmacokinetic–Pharmacodynamic Modeling

Previously, we showed that the combination of methotrexate and adalimumab treatment leads to less antidrug antibody development. In this study, we quantify the pharmacokinetics/pharmacodynamics (PK/PD) of adalimumab and evaluate the influence of methotrexate cotreatment. A population PK-PD model was developed using prospective data from 59 patients with psoriasis (baseline PASI= 12.6) receiving adalimumab over 49 weeks. Typical PK and PD parameters and their corresponding interpatient variability were estimated. We performed a covariate analysis to assess whether interpatient variability could be explained by addition of methotrexate and other covariates. In total, 330 PASIs, 252 adalimumab serum concentrations, and 247 antidrug antibody titers were available. Presence of antidrug antibodies (adalimumab group= 46.7%, adalimumab+ methotrexate group= 38.7%; P= .031) was correlated with increased adalimumab apparent clearance (P < .001). In the PD model, the use of concomitant methotrexate was borderline to significantly correlated with a decreased half-maximal inhibitory concentration (adalimumab concentration for which clinical response score is reduced by half; P < .10). On the basis of our PK-PD model, concomitant use of methotrexate indirectly increases adalimumab concentration, partially through less antidrug antibodies formation, which may result in better efficacy.

Observer design estimating the propofol concentration in PKPD model with feedback control of anesthesia administration

Observer design estimating the propofol concentration in PKPD model with feedback control of anesthesia administration

Pharmacodynamic Models of Indirect Effects and Irreversible Inactivation with Turnover: Applicability to Mechanism-Based Modeling of Gene Silencing and Targeted Protein Degradation

Indirect response (IDR) and turnover with inactivation (TI) comprise two arrays of mechanism-based pharmacodynamic (PD) models widely used to describe delayed drug effects. IDR Model-IV (stimulation of response loss) and TI (irreversible loss) have been described with discerning “signature” profiles; classical IDR-IV response-time profiles display slow declines where peak response shifts later with increasing dose, whereas TI profiles feature steep response declines with earlier-shifting nadirs. Herein, we demonstrate mathematical convergence of IDR-IV and TI models upon implementation with identical linear versus nonlinear pharmacologic effect terms. Time of peak response in IDR-IV can in fact shift earlier or later depending on PK or PD parameters (e.g., kel, Smax) and effect type. A generalized dynamic model linking mRNA and protein turnover is proposed. Applicability of IDR-IV and TI, with either linear or nonlinear terms acting on degradation/catabolism/loss of response, is demonstrated through model-fitting PK-PD effects of three proteolysis-targeting chimeras (PROTACs) and two ligand-conjugated small interfering RNAs (siRNA). This work clarifies mathematical properties, convergence, and expected responses of IDR-IV and TI, demonstrates their applicability for targeted gene-silencing and protein-degrading agents, and illustrates how well-designed in vivo studies covering broad dose ranges with richly sampled time-points can influence PK-PD model structure and parameter resolution.

Population pharmacokinetic-pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study.

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof-of-concept study for using population pharmacokinetic-pharmacodynamic (PK-PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK-PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two-compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one-compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK-PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.

Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis.

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33h (accumulation factor of 2- to 2.6-fold), and fast and almost complete oral absorption (absolute oral bioavailability: 84%), reaching peak plasma and blood concentrations within 2-4h. Ponesimod is highly metabolized, and the parent compound along with its two major (non-clinically active) metabolites are mainly excreted in the feces (recovery: 57.3-79.6%) and to a lesser extent in the urine (recovery: 10.3-18.4%). Additionally, the population PKPD model characterized the ponesimod effects on heart rate: a transient, dose-dependent decrease in heart rate in the first days of dosing, that is mitigated by administering the first doses of ponesimod treatment using a gradual up-titration schedule, before reaching the daily maintenance dose of 20mg. This selected maintenance dose has been shown to be superior in reducing annualized relapse rate (ARR) when compared with teriflunomide in a pivotal phase III study. Furthermore, a dose-dependent reduction of peripheral lymphocyte counts that is sustained with continued daily oral dosing of ponesimod and is rapidly (4-7days) reversible upon drug discontinuation has been characterized with an indirect response model.

Characterization of Pseudomonas aeruginosa resistance to ceftolozane-tazobactam due to ampC and/or ampD mutations observed during treatment using semi-mechanistic PKPD modeling.

A double ampC (AmpCG183D) and ampD (AmpDH157Y) genes mutations have been identified by whole genome sequencing in a Pseudomonas aeruginosa (PaS) that became resistant (PaR) in a patient treated by ceftolozane/tazobactam (C/T). To precisely characterize the respective contributions of these mutations on the decreased susceptibility to C/T and on the parallel increased susceptibility to imipenem (IMI), mutants were generated by homologous recombination in PAO1 reference strain (PAO1- AmpCG183D, PAO1-AmpDH157Y, PAO1-AmpCG183D/AmpDH157Y) and in PaR (PaR-AmpCPaS/AmpDPaS). Sequential time-kill curve experiments were conducted on all strains and analyzed by semi-mechanistic PKPD modeling. A PKPD model with adaptation successfully described the data, allowing discrimination between initial and time-related (adaptive resistance) effects of mutations. With PAO1 and mutant-derived strains, initial EC50 values increased by 1.4, 4.1, and 29-fold after AmpCG183D , AmpDH157Y and AmpCG183D/AmpDH157Y mutations, respectively. EC50 values were increased by 320, 12.4, and 55-fold at the end of the 2 nd experiment. EC50 of PAO1-AmpCG183D/AmpDH157Y was higher than that of single mutants at any time of the experiments. Within the PaR clinical background, reversal of AmpCG183D, and AmpDH157Y mutations led to an important decrease of EC50 value, from 80.5 mg/L to 6.77 mg/L for PaR and PaR-AmpCPaS/AmpDPaS, respectively. The effect of mutations on IMI susceptibility mainly showed that the AmpCG183D mutation prevented the emergence of adaptive resistance. The model successfully described the separate and combined effect of AmpCG183D and AmpDH157Y mutations against C/T and IMI, allowing discrimination and quantification of the initial and time-related effects of mutations. This method could be reproduced in clinical strains to decipher complex resistance mechanisms.

An improved PKPD modeling approach to characterize the pharmacodynamic interaction over time between ceftazidime/avibactam and colistin from in vitro time-kill experiments against multidrug-resistant Klebsiella pneumoniae isolates.

In contrast to the checkerboard method, bactericidal experiments [time-kill curves (TKCs)] allow an assessment of pharmacodynamic (PD) interactions over time. However, TKCs in combination pose interpretation problems. The objective of this study was to characterize the PD interaction over time between ceftazidime/avibactam (CZA) and colistin (CST) using TKC against four multidrug-resistant Klebsiella pneumoniae susceptible to both antibiotics and expressing a widespread carbapenemase determinant KPC-3. In vitro TKCs were performed and analyzed using pharmacokinetic/pharmacodynamic (PKPD) modeling. The general pharmacodynamic interaction model was used to characterize PD interactions between drugs. The 95% confidence intervals (95%CIs) of the expected additivity and of the observed interaction were built using parametric bootstraps and compared to evaluate the in vitro PD interaction over time. Further simulations were conducted to investigate the effect of the combination at varying concentrations typically observed in patients. Regrowth was observed in TKCs at high concentrations of drugs alone [from 4 to 32× minimum inhibitory concentrations (MIC)], while the combination systematically prevented the regrowth at concentrations close to the MIC. Significant synergy or antagonism were observed under specific conditions but overall 95%CIs overlapped widely over time indicating an additive interaction between antibiotics. Moreover, simulations of typical PK profile at standard dosages indicated that the interaction should be additive in clinical conditions. The nature of the PD interaction varied with time and concentration in TKC. Against the four K. pneumoniae isolates, the bactericidal effect of CZA + CST combination was predicted to be additive and to prevent the emergence of resistance at clinical concentrations.

Pharmacokinetic-pharmacodynamic modeling of the active components of Shenkang injection in rats with chronic renal failure and its protective effect on damaged renal cells.

The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic-pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague-Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-β1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: Y=0.031X+0.0091 (R2 =0.9986) for hydroxy saffron yellow pigment A, Y=0.0389X+0.164 (R2 =0.9979) for tanshinol, Y=0.0257X+0.0146 (R2 =0.9973) for rheum emodin, and Y=0.0763X+0.0139 (R2 =0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20min in the Shenkang injection group (p<0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all indexes in the administered group improved and showed significant inhibition of renal cell fibrosis in vitro. This study could provide scientific reference ideas for the clinical rational use of traditional Chinese medicine.

Overcoming Soluble Target Interference in Measurement of Total Bispecific Therapeutic Antibody Concentrations.

The measurement of therapeutic drug concentrations is used to assess drug exposure and the relationship between therapeutic pharmacokinetics (PK) and pharmacodynamics (PD), which help determine the optimal dose for patients. Ligand binding assays (LBAs) are often the method of choice for evaluation of drug concentration and use either the therapeutic target protein or antibodies to the therapeutic as capture and/or detection reagents. Due to the bivalency of antibody therapeutics, heterogeneous states of the drug/target complex can exist in the presence of soluble targets which can complicate measurement of unbound drug. In the case of bispecific antibodies, measurement of drug can be even more complicated and depend upon the levels of both targets to each arm. Measuring the total drug allows for PKPD modeling prediction of human dose projections in addition to overcoming challenges associated with measuring free drug for bispecific antibodies. Here, we present a study in which a sandwich ELISA format was used to measure total anti-KLK5/KLK7 antibody concentrations. This assay utilized a non-blocking anti-idiotype (ID) antibody to one arm of the antibody for capture and an antibody to target bound to the other arm of the antibody for detection. Our qualified assay showed acceptable precision, accuracy, dilutional linearity, and reproducibility and enabled detection of a total bispecific antibody at high levels of two targets. To confirm that our assay was detecting total drug, a subset of samples was evaluated in a generic total LC-MS/MS assay.