Indirect Response Research Articles

Quantitative assessment of observed versus predicted responses to selection.

Although artificial-selection experiments seem well suited to testing our ability to predict evolution, the correspondence between predicted and observed responses is often ambiguous due to the lack of uncertainty estimates. We present equations for assessing prediction error in direct and indirect responses to selection that integrate uncertainty in genetic parameters used for prediction and sampling effects during selection. Using these, we analyzed a selection experiment on floral traits replicated in two taxa of the Dalechampia scandens (Euphorbiaceae) species complex for which G-matrices were obtained from a diallel breeding design. After four episodes of bidirectional selection, direct and indirect responses remained within wide prediction intervals, but appeared different from the predictions. Combined analyses with structural-equation models confirmed that responses were asymmetrical and lower than predicted in both species. We show that genetic drift is likely to be a dominant source of uncertainty in typically-dimensioned selection experiments in plants and a major obstacle to predicting short-term evolutionary trajectories.

Delay differential equations based models in NONMEM.

Delay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time. Two of them are based on algorithms already applied elsewhere, while others are extensions of existing ordinary differential equations (ODEs) solvers. The purpose of this tutorial is to introduce basic concepts underlying DDE based models and toshow how they can be developed using NONMEM. The examples include previously published DDE models such as logistic growth, tumor growth inhibition, indirect response with precursor pool, rheumatoid arthritis, and erythropoiesis-stimulating agents. We evaluated the accuracy of NONMEM DDE solvers, their ability to handle stiff problems, and their performance in parameter estimation using both first-order conditional estimation (FOCE) and the expectation-maximization (EM) method. NONMEM control streams and excerpts from datasets are provided for all discussed examples. All DDE solvers provide accurate and precise solutions with the number of significant digits controlled by the error tolerance parameters. For estimation of population parameters, the EM method is more stable than FOCE regardless of the DDE solver.

Description of Resonant Inelastic X-Ray Scattering in Correlated Metals

To fully capitalize on the potential and versatility of resonant inelastic x-ray scattering (RIXS), it is essential to develop the capability to interpret different RIXS contributions through calculations, including the dependence on momentum transfer, from first-principles for correlated materials. Toward that objective, we present new methodology for calculating the full RIXS response of a correlated metal in an unbiased fashion. Through comparison of measurements and calculations that tune the incident photon energy over a wide portion of the Fe L$_3$ absorption resonance of the example material BaFe$_2$As$_2$, we show that the RIXS response in BaFe$_2$As$_2$ is dominated by the direct channel contribution, including the Raman-like response below threshold, which we explain as a consequence of the finite core-hole lifetime broadening. Calculations are initially performed within the first-principles Bethe-Salpeter framework, which we then significantly improve by convolution with an effective spectral function for the intermediate-state excitation. We construct this spectral function, also from first-principles, by employing the cumulant expansion of the Green's function and performing a real-time time dependent density functional theory calculation of the response of the electronic system to the perturbation of the intermediate-state excitation. Importantly, this allows us to evaluate the indirect RIXS response from first-principles, accounting for the full periodicity of the crystal structure and with dependence on the momentum transfer.

Population pharmacokinetic-pharmacodynamic model-based exploration of alternative ustekinumab dosage regimens for patients with Crohn's disease.

In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (~6mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes. Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 μg/g to 694 μg/g (EC50 ). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 μg/g to 214 μg/g (EC50 ). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing. The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.

Abstract 1368: Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors

Abstract BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker. RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose. CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies. ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract. Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1368.

PK/PD modeling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients.

IONIS‐FXIRX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end‐stage renal disease (ESRD). FXI‐LICA (BAY2976217) shares the same RNA sequence as IONIS‐FXIRX but contains a GalNAc‐conjugation that facilitates asialoglycoprotein receptor (ASGPR)‐mediated uptake into hepatocytes. FXI‐LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis. We present a model‐informed bridging approach that facilitates the extrapolation of the dose‐exposure‐FXI relationship from IONIS‐FXIRX to FXI‐LICA in patients with ESRD and, thus, supports the selection of FX‐LICA doses being investigated in patients with ESRD. A two‐compartment pharmacokinetic (PK) model, with mixed first‐ and zero‐order subcutaneous absorption and first‐order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/pharmacodynamic model adequately described the median trends, as well as the interindividual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS‐FXIRX and FXI‐LICA, and in patients with ESRD of IONIS‐FXIRX. The model was then used to predict dose‐dependent steady‐state FXI activity following repeat once‐monthly doses of FXI‐LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in patients with ESRD and healthy volunteers, doses of 40 mg, 80 mg, and 120 mg FXI‐LICA are expected to cover the target range of clinical interest for steady‐state FXI activity in the phase IIb study of FXI‐LICA in patients with ESRD undergoing hemodialysis.

The functions and evolution of xob ‘well’ in Persian: A thetical analysis

This study aims to explore the functions of the Persian xob ‘well’ and its evolution mechanisms. The Discourse Grammar model was mainly employed to analyze the occurrences of xob in the Bijankhān corpus. The data analysis revealed that xob is significantly frequent, especially in semi-formal and informal spoken genres. It also demonstrated that xob has risen from the adjective/adverb xub with several propositional meanings most of which converge on ‘good’. Having evolved from this meaning, the core procedural meaning of xob, i.e., ‘engaging in (positive) epistemic/affective consideration prefatory to continuation’, has developed metatextual functions in the three components of the situation of discourse. To express speaker's attitude and speaker-hearer interaction, xob mainly serves the functions of direct response (signaling acceptance, sufficiency, etc.), indirect response (signaling qualification, concession, etc.), and involvement prompting (signaling attention getting, backchannelling, and soliciting consensus). Meeting the needs of text organization, xob fulfills the dual purposes of framing the text pieces and transition between topics and events. The study also highlights the contribution of cooptation and late grammaticalization to the rise of the discourse markers xob and xeyli/besyār xob ‘very well’. Overall, these findings illustrate the potential of Discourse Grammar to address theticals such as discourse markers.

P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease

Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.

Lactoferrin Retargets Human Adenoviruses to TLR4 to Induce an Abortive NLRP3-Associated Pyroptotic Response in Human Phagocytes.

Despite decades of clinical and preclinical investigations, we still poorly grasp our innate immune response to human adenoviruses (HAdVs) and their vectors. In this study, we explored the impact of lactoferrin on three HAdV types that are being used as vectors for vaccines. Lactoferrin is a secreted globular glycoprotein that influences direct and indirect innate immune response against a range of pathogens following a breach in tissue homeostasis. The mechanism by which lactoferrin complexes increases HAdV uptake and induce maturation of human phagocytes is unknown. We show that lactoferrin redirects HAdV types from species B, C, and D to Toll-like receptor 4 (TLR4) cell surface complexes. TLR4-mediated internalization of the HAdV-lactoferrin complex induced an NLRP3-associated response that consisted of cytokine release and transient disruption of plasma membrane integrity, without causing cell death. These data impact our understanding of HAdV immunogenicity and may provide ways to increase the efficacy of HAdV-based vectors/vaccines.

Direct and indirect effects of altered temperature regimes and phenological mismatches on insect populations.

Climate change is transforming ecosystems by altering species ranges, the composition of communities, and trophic interactions. Here, we synthesize recent reviews and subsequent developments to provide an overview of insect ecological and evolutionary responses to altered temperature regimes. We discuss both direct responses to thermal stress and indirect responses arising from phenological mismatches, altered host quality, and changes in natural enemy activity. Altered temperature regimes can increase exposure to both cold and heat stress and result in phenological and morphological mismatches with adjacent trophic levels. Host plant quality varies in a heterogenous way in response to altered temperatures with both increases and decreases observed. Density-dependent effects, spatial heterogeneity, and rapid evolutionary change provide some resilience to these threats.

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC50/SC50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC50), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Paraneoplastic Disorders of the Central Nervous System

Paraneoplastic neurological syndromes (PNS) are neurological disorders that occur as indirect immune-mediated responses to malignancies. The increased number of patients with PNS correlates with the discovery of an increasing number of novel autoantibodies associated with PNS. The use of immune checkpoint inhibitors that have expanded the range of cancers strongly associated with PNS has likely increased the frequency of PNS diagnoses. This article presents an overview of the pathophysiology, diagnosis, therapy, and prognosis of PNS.

Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.

The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28‐joint disease activity score based on C‐reactive protein (DAS28‐CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure–response models. The analysis incorporated results from three multicenter, placebo‐controlled, double‐blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28‐CRP measurements were modeled by a non‐linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure–response models of effect of peficitinib on duration‐dependent increase in ACR20 response rate and decrease in DAS28‐CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28‐CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28–CRP model. The covariate effects were highly consistent between the two models. Our exposure–response models of peficitinib in RA patients satisfactorily described duration‐dependent improvements in ACR20 response rates and DAS28‐CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment.Clinical trial registrationNCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).

In a belowground multitrophic interaction, Trichoderma harzianum induces maize root herbivore tolerance against Phyllophaga vetula.

Trichoderma spp. are soil fungi that interact with plant roots and associated biota such as other microorganisms and soil fauna. However, information about their interactions with root-feeding insects is limited. Here, interactions between Trichoderma harzianum and the root-feeding insect Phyllophaga vetula, a common insect pest in maize agroecosystems, were examined. Applications of T. harzianum and P. vetula to the root system increased and decreased maize growth, respectively. Induced tolerance against herbivore attack was provided by T. harzianum maintaining a robust and functional root system as evidenced by the increased uptake of Cu, Ca, Mg, Na and K. Herbivore tolerance also coincided with changes in the emission of root volatile terpenes known to induce indirect defense responses and attract natural enemies of the herbivore. More importantly, T. harzianum induced de novo emission of several sesquiterpenes such as β-caryophyllene and δ-cadinene. In addition, single and combined applications of T. harzianum and P. vetula altered the sucrose content of the roots. Finally, T. harzianum produced 6-pentyl-2H-pyran-2-one (6-PP) a volatile compound that may act as an antifeedant-signaling compound mitigating root herbivory by P. vetula. Our results provide novel information about belowground multitrophic plant-microbe-arthropod interactions between T. harzianum and P. vetula in the maize rhizosphere resulting in alterations in maize phenotypic plant responses, inducing root herbivore tolerance.

Memantine Alleviates Acute Lung Injury Via Inhibiting Macrophage Pyroptosis.

Acute lung injury (ALI) is caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis and trauma. Alveolar macrophages are the main and critical leukocytes in the airspace, and through the synthesis and release of various inflammatory mediators critically influence the development of ALI following infection and non-infectious stimuli. There is increasing recognition that inflammation and cell death reciprocally affect each other, which forms an auto-amplification loop of these two factors, and in turn, exaggerates inflammation. Therefore, pharmacological manipulation of alveolar macrophage death signals may serve as a logical therapeutic strategy for ALI. In this study, we demonstrate that memantine, a N-methyl-D-aspartic acid receptor (NMDAR) antagonist, through suppressing Ca2+ influx and subsequent ASC oligomerization inhibits macrophage Nlrp3 inflammasome activation and pyroptosis, therefore, alleviates ALI in septic mice. This finding explores a novel application of memantine, an FDA already approved medication, in the treatment of ALI, which is currently lacking effective therapy.

Exposure-Response Modeling to Support Dosing Selection for Phase IIb Development of Kukoamine B in Sepsis Patients.

Aim: Kukoamine B, a small molecule compound, is being developed for the treatment of sepsis in a Phase II clinical trial. The objective of this study was to optimize dosing selection for a Phase IIb clinical trial using an exposure-response model. Methods: Data of 34 sepsis patients from a Phase IIa clinical trial were used in the model: 10 sepsis patients from the placebo group and a total of 24 sepsis patients from the 0.06 mg/kg, 0.12 mg/kg, and 0.24 mg/kg drug groups. Exposure-response relationship was constructed to model the impact of the standard care therapy and area under curve (AUC) of kukoamine B to the disease biomarker (SOFA score). The model was evaluated by goodness of fit and visual predictive check. The simulation was performed 1,000 times based on the built model. Results: The data of the placebo and the drug groups were pooled and modeled by a nonlinear mixed-effect modeling approach in sepsis. A latent-variable approach in conjunction with an inhibitory indirect response model was used to link the standard care therapy effect and drug exposure to SOFA score. The maximum fraction of the standard care therapy was estimated to 0.792. The eliminate rate constant of the SOFA score was 0.263/day for the standard care therapy. The production rate of SOFA score (Kin) was estimated at 0.0569/day and the AUC at half the maximal drug effect (EAUC50) was estimated at 1,320 h*ng/mL. Model evaluation showed that the built model could well describe the observed SOFA score. Model-based simulations showed that the SOFA score on day 7 decreased to a plateau when AUC increased to 1,500 h*ng/mL. Conclusion: We built an exposure-response model characterizing the pharmacological effect of kukoamine B from the standard care therapy in sepsis patients. A dose regimen of 0.24 mg/kg was finally recommended for the Phase IIb clinical trial of kukoamine B based on modeling and simulation results.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Priming of indirect defence responses in maize is shown to be genotype-specific

Priming is an induced defence mechanism in which plants that have been exposed to elicitors, such as herbivore-induced plant volatiles (HIPVs), go into an alert state with faster and stronger responses against a future biotic challenge. This study evaluated whether HIPVs emitted by maize genotypes after herbivory by fall armyworm (Spodoptera frugiperda) larvae could prime neighbouring maize plants for an enhanced indirect defence response, and if priming was consistent across different genotypes. Two genotypes were selected based on their differences in HIPV emission: Sintetico Spodoptera (SS), a relatively high emitter of HIPVs, and L3, a relatively low emitter of HIPVs. SS plants that were previously exposed to SS HIPVs initiated earlier and enhanced volatile production upon larval challenge, compared to SS plants that were previously exposed to SS undamaged plant volatiles. In addition, SS plants exposed to SS HIPVs and then to larval challenge attracted an egg parasitoid, Telenomus remus, at an earlier stage than SS plants that were only subjected to larval challenge, indicating a priming effect. There was no evidence of a priming response by L3 plants that were previously exposed to L3 or SS HIPVs. When comparing the gene expression of HIPV-exposed and undamaged plant volatile (UDV)-exposed plants, jasmonate-induced protein GRMZM2G05154 and UDP-glucosyltransferase bx8 genes related to the biosynthesis of DIBOA-Glu were upregulated. These data indicate that priming by HIPVs enhances indirect defence in maize plants as reported by other studies, and provide new information showing that the priming effect can be genotype-specific.

Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total.

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.

Pharmacokinetic-pharmacodynamic modeling for hepatic delivery and efficacy of antisense oligonucleotides with lipophilic ligands in mice.

Conjugation with lipophilic ligands such as cholesterol and α-tocopherol dramatically improves the delivery and efficacy of antisense oligonucleotides (ASOs) in the liver. To estimate the hepatic ASO concentration and the efficacy of ASOs conjugated with lipophilic ligands in mice, we constructed a pharmacokinetic-pharmacodynamic (PK-PD) model that consisted of a two-linear compartment model for the plasma and the hepatic ASO concentration, and two indirect response models for the hepatic apolipoprotein B (Apo-B) mRNA and plasma total cholesterol. The model provided a good fit of the hepatic ASO concentration although it showed an overprediction of Apo-B mRNA and an underprediction of the plasma total cholesterol within 2-fold at a later time after single intravenous administration of ASOs conjugated with lipophilic ligands. In addition, the model simulations indicated that the efficacy at a dose regimen of ASOs conjugated with lipophilic ligands (0.2mg/kg, once a week) in mice was comparable to that at an effective dose of unchanged ASO (2.5mg/kg, once a week). Although further studies are required to refine the parameters of the PK-PD model, this approach could be used to guide dose-ranging pharmacological studies for ASOs conjugated with lipophilic ligands in mice.