PK-PD Model Research Articles

PASSIVITY BASED FRACTIONAL ORDER ADAPTIVE CONTROL OF DEPTH OF ANESTHESIA

In this paper, a passivity based model reference adaptive controller with fractional-order adaptation mechanism is utilized for control of depth of anesthesia. The propofol infusion rate is adjusted to reach an appropriate Bispectral Index (BIS). The Pharmacokinetic-Pharmacodynamic (PK-PD) model is employed to model the distribution of propofol in patient body. Since, the PK-PD model parameters depend on physical specifications of patient, employing an adaptive controller to control this system is inevi-table. The utilized controller is a pole placement con-troller in which its polynomial coefficients are ad-justed according to a fractional-order adaptation mechanism. Simulation results on several patients demonstrate the efficiency of the proposed method in the presence of disturbance, noise, and model uncertainties.

PKPD Assessment of the Anti-CD20 Antibody Obinutuzumab in Cynomolgus Monkey is Feasible Despite Marked Anti-Drug Antibody Response in This Species

The pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (PKPD) relationship for B-cell depletion was characterized. The PKPD model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration. Marked immunogenicity against obinutuzumab was observed approximately 10 days after single dose, leading to an up to ∼30-fold increase in obinutuzumab clearance in the affected monkeys. Despite this accelerated clearance, the PK could be characterized, either by disregarding the clearance in noncompartmental PK analysis or by capturing it explicitly as an additional time-dependent clearance process in compartmental modeling. This latter step was crucial to model the PKPD of B-cells as an indirect response to obinutuzumab exposure, showing that—without immune response—the limiting factor is obinutuzumab elimination with concentrations below 0.02 μg/mL required for initiation of B-cell recovery.Overall, the results demonstrate that despite a marked anti-drug antibody response in the nonclinical animal species, the PK and PKPD of obinutuzumab could be characterized successfully by appropriately addressing the immune-modulated clearance pathway in data analysis and modeling.

Abstract 3884: Advancing Glioblastoma drug regimen development to support combination therapy through integrated PKPD modeling and simulation-based predictions

Abstract Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma remains fatal; the median survival rate is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Development of tumor resistance, particularly to temozolomide (TMZ), creates a substantial clinical challenge. The primary focus of our work is to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, our aim is to combine TMZ with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. To accomplish this objective, an integrated PKPD modeling approach is used. The approach is largely based on the work of Cardilin, et al, 2018. A PK model for each drug is first defined. This is subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models are tumor static concentration (TSC) curves of dual or triple combination drug regimens that identify combination drug exposures predicted to arrest tumor growth. This approach has been applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib efficacy in combination with TMZ in a glioblastoma xenograft model (Raub, et al, 2015). A PKPD model was developed to predict tumor growth kinetics for TMZ and abemaciclib monotherapy, as well as combination therapy. Population PK models in immune deficient NSG mice for temozolomide and abemaciclib were developed based on data obtained from original and published studies. Subsequently, the PK model was linked to tumor volume data obtained from U87-MG GBM subcutaneous xenografts, again using both original data as well as data from the Raub, et al, 2015 study. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 30%). The developed PKPD model was used to calculate plasma concentrations of TMZ and abemaciclib that would arrest tumor growth, as well as combinations of concentrations of the two drugs that would accomplish the same endpoint. This so-called TSC curve for the TMZ and abemaciclib combination pair evidenced an additive effect of the two agents when administered together. These results will be presented. In addition, results from on-going PKPD studies of TMZ in combination with two other small molecule inhibitors, RG7388, an MDM2 inhibitor, and GDC0068, an AKT inhibitor, will also be presented. Citation Format: Saugat Adhikari, Harlan E. Shannon, Karen E. Pollok, Robert E. Stratford. Advancing Glioblastoma drug regimen development to support combination therapy through integrated PKPD modeling and simulation-based predictions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3884.

Abstract 3881: Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor

Abstract Introduction: Deoxycytidine kinase (dCK) is essential for DNA synthesis through salvage pathways and DI-87 is a novel dCK inhibitor in preclinical development. This study used PET imaging to measure dCK inhibition and pharmacokinetic-pharmacodynamic (PK-PD) modeling to relate tumor drug levels to tissue with dCK activity and tumor shrinkage. Methods: Oral DI-87 was administered to NSG mice with plasma and tumor PK assessed over 24 hrs by mass spectrometry. NSG mice with CEM tumors were administered varying doses of DI-87 followed by the [18F]CFA PET probe and PET imaging. NSG mice with CEM tumors were administered thymidine and DI-87 concurrently and tumor growth monitored. PK-PD modeling was conducted with NONMEM (v. 7.3). Results: DI-87 plasma concentrations peaked at 3 hr; tumor peak concentrations occurred later. Tumor concentrations were less than one third of plasma concentrations. Full dCK inhibition by PET imaging occurred between 10 and 25 mg/kg and decreasing doses led to faster recovery of activity. Full recovery of enzyme activity occurred by 36 hrs with full inhibition being maintained at the 12 hr time point at the 25 mg/kg dose. Maximal growth inhibition occurred with full dCK inhibition over the dosing range (25 mg/kg BID) when DI-87 was given in combination therapy with thymidine; thus increased doses led to more persistent dCK inhibition with predictable increased growth inhibition. Conclusions: Combining PET probes with PK-PD modeling led to an optimized dosing schedule for combination therapy with DI-87. Citation Format: Soumya Poddar, Mina Nikanjam, Edmund Capparelli, Thuc Le, Liu Wei, Caius Radu. Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3881.

Abstract 3895: A phase I-II pharmacokinetic drug-drug interaction evaluation of oral palbociclib in combination with vemurafenib in patients suffering metastatic melanoma with BRAF V600 mutated and CDKN2A loss & expression of Rb

Abstract Background: A novel combination of vemurafenib (VM), a selectif inhibitor of BRAF V600 mutated protein + oral palbociclib (Palbo) a highly selective reversible oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6, could provide a synergistic antitumor activity in patients with metastatic melanoma harbouring BRAF V600 mutation and CDKN2A loss. VM has been shown to be an inductor of CYP3A4 which is also mainly involved in Palbo metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of VM and Palbo. Methods: metastatic melanoma harbouring BRAF V600 mutation and CDKN2A loss patients were treated with a 14 days on followed by 7 days off dosing schedule of Palbo + continuous bid dosing of VM. Dose levels [DL, Palbo (mg/day)/VM (mg/bid)] ranged from 25/720 to 200/960. For PK analysis, 7 time point samples were collected on D1C1, D21C1, and D7C2, for Palbo and VM assays. Plasma concentrations of Palbo and VM, were measured using ultra high performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry validated methods. Population PK (PPK) was modeled using a non linear mixed effect model program (Monolix version 2018r) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). The following parameters were calculated absorption constant (Ka); apparent distribution volume (V/F); apparent clearance (CL/F) Results: A total of 18 patients were treated by the combination of Palbo + VM. VM and palbo plasma concentrations were measured in 236 and 275 blood samples respectively. A one-compartment open model with linear elimination adequately described Palbo concentration-time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters. The PPK parameters obtained for the structural model were: Ka = 0.791 h-1, CL/F=76.0L/h, V1/F=2830 L. Albuminemia had a significant impact on palbo CL. A one-compartment model adequately fitted the VM plasma concentration-time data. The PPK parameters were CL/F=0.133 L/h, V/F=83.6 L and Ka has been fixed at 0.2 h-1. Body weight (BW) was the best size descriptor when VM CL and V terms were normalized to a mean BW of 70 Kg according to an allometric scaling rule. Conclusions: The PPK modeling satisfactorily described the plasma Plabo and VM time-concentration curves in patients. The main covariate effect was related to BW and albuminemia. There is no significant evidence for drug-drug PK interaction between Palbo and VM. PK-PD modeling will be performed. Citation Format: Samuel Huguet, Thierry Lesimple, Arthur Geraud, Mouna Amini-Adle, Caroline Dutriaux, Laetitia Da Meda, Florence Capelle, Zineb Ghrieb, Samia Mourah, Olivier Madar, Didier Bouton, Mathieu Resche-Rigon, Celest Lebbe, Keyvan Rezai. A phase I-II pharmacokinetic drug-drug interaction evaluation of oral palbociclib in combination with vemurafenib in patients suffering metastatic melanoma with BRAF V600 mutated and CDKN2A loss & expression of Rb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3895.

Abstract 1328: Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors

Abstract cKIT belongs a family of transmembrane tyrosine kinase growth factor receptors and gain of function mutations result in constitutive c-KIT activation that provide an important pathogenic role in gastrointestinal stromal tumors (GIST). AZD3229 is a highly potent and selective oral best-in-class KIT inhibitor that is active against a wide spectrum of primary and secondary KIT mutations that are known to confer resistance to standard of care agents. AZD3229 demonstrates rapid, extensive and sustained inhibition of KIT signaling in preclinical xenograft models with KIT primary exon 11 del mutations and primary/secondary ATP-binding pocket mutations (GIST 430/654A and patient-derived xenograft (PDX) model of KIT V654A, HGiXF-106) and A-loop mutations (PDX model of KIT Y823D, HGiXF-105 and Ba/F3 KIT D816H). In these models, AZD3229 results in anti-tumour activity (tumour regressions ranging from -60% to -99 % TGI) when dosed orally up to 20 mg/kg BID. The objective of this PK-PD modeling work was to (1) establish the PK-PD-Efficacy relationship for AZD3229 across the four cell-lines and PDX mouse models tested; (2) to confirm the extent and duration of pKIT inhibition required for optimal efficacy, as defined by tumor regressions. Inhibition of KIT phosphorylation observed with AZD3229 shows a direct relationship to free mouse plasma concentration and an estimated in vivo EC90 was estimated for each model (Ba/F3 D816H = 20 nM; GIST 430/V654A= 43 nM; HGiX-106 = 76 nM; HGiX-105 = 4 nM). No change in the extent of inhibition of KIT phosphorylation was observed on repeat dosing. Optimal efficacy is observed when sustained inhibition of pKIT, >90% is achieved over the dosing interval. Conclusion: Exploring the in vivo activity and PK-PD relationship in multiple cell-line derived xenograft and PDX models harboring different mutations provides a benchmark from which to anchor human dose predictions that partly reflect the spectrum of responses likely to be seen in GIST patients. Citation Format: Venkatesh Pilla Reddy, Aaron Smith, Michael Grondine, Rana Anjum, Rhys D. Jones. Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1328.

Abstract 3906: PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice

Abstract Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses the early stages of T cell activation. In preclinical studies, blockade of CTLA-4 led to an increase in T-cell proliferation. Anti-CTLA-4 monoclonal antibodies (mAbs) have been shown to be an effective approach for tumor immunotherapy. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) characterization of these antibodies is essential for designing first-in human trials. PK prediction is especially challenging for monoclonal antibodies attributed to target-mediated drug disposition (TMDD). We generated a humanized B-hCTLA-4 mouse model, in which exon 2 of the murine CTLA-4 gene was replaced with its human counterpart. In homozygous mice, only human protein expression can be detected, while mouse CTLA-4 was knocked out. Using B-hCTLA-4 mice, we developed a mAb PK/PD model to characterize the anti-tumor effects of hCTLA-4 antibodies. MC38 cancer cells were inoculated into both C57BL/6 wild type and humanized CTLA-4 animals. After administering different antibody concentrations (ranging from 3.0, 1.0, 0.3, 0.1mg/kg), serum samples from each animal were taken at specific time points for PK/PD analysis. An NCA approach was used to determine serum concentrations of mAb in mice. The levels of 13 cytokines (IL-23, IL-1α, IFN-r, TNF-a, IL-6 etc.) were quantified using LEGENDplex bead-based immunoassays. The PK half-life was 50~100h and the cytokine concentration ranged from 0-2000pg/ml depending on the dose used. The Tumor Growth Inhibition (TGI) value was also evaluated as a PD effect in the MC38/B-hCTLA-4 model. The TGI value reached nearly 100% when the dose was above 0.3mg/kg. The PK/PD assays showed that the anti hCTLA-4 mAb tested has a dose-dependent tumor inhibition effect in hCTLA-4 mice. Results from TMDD model data showed that the humanized mice reached QuasiSteady State faster than wild type mice, indicating that the humanized mice are an appropriate TMDD model. In conclusion, humanized B-hCTLA-4 mice are a promising PK/PD model for CTLA-4 mAb preclinical trials. Citation Format: Madeline Lee, Jie Xiang, Tian Gan, Yuelei Shen, Chaoshe Guo. PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3906.

Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice.

Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.

Study on pharmacodynamic material basis of Naomaitong to protect neuronal cells based on PK-PD model

The PK-PD correlation models by using pharmacodynamics and pharmacokinetics were applied to study the material basis of Naomaitong,a clinical empirical prescription for the treatment of cerebral apoplexy,in inhibiting the death of PC12 nerve cells induced by Na_2S_2O_4 and Glu. In this experiment,PC12 cell death models induced by Na_2S_2O_4 and Glu were established respectively.With LDH lateral leakage and NO content as pharmacodynamic indexes,PK-PD model was established by SVM algorithm to evaluate the effective components of Naomaitong in inhibiting neural cell death. The results showed that the positive correlation of emodin methyl ether-8-O-β-D-glucopyranoside,aloe emodin,chrysophanol,rhein,emodin,ginsenoside Rg1,ginsenoside Rc,3'-methoxypuerarin and ligustilide was significant,obviously improving the LDH release and NO content. The results indicated that the contribution of Radix Puerariae Lobatae Radix and Rhei Radix et Rhizoma in Naomaitong could protect the nerve cell death induced by Na_2S_2O_4 and Glu respectively. PK-PD model was used to screen the neuroprotective components in Naomaitong,revealing the possible pharmacodynamic material basis of Naomaitong in the treatment of cerebral ischemia injury.

Pharmacokinetic-pharmacodynamic population modelling in paediatric anaesthesia and its clinical translation.

Pharmacokinetic-pharmacodynamic (PKPD) population modelling has advanced adult anaesthesia. Current literature was reviewed to discern use of this analytic technique for benefit in the perioperative management of children. Variability in drug response, selection of a dose that achieves a desired target concentration and optimizing sampling protocols for further studies are all facets of paediatric anaesthesia that have benefitted from modelling approaches. PKPD models have driven the maintenance dose rate in target-controlled infusion pumps used for total intravenous anaesthesia. Although many of the models used in these pumps were developed in adults, translation for paediatric use has followed, including subgroups, such as neonates and obese children. The use of drug effect measures (e.g. bispectral index) has improved the predictive performance of pharmacodynamic models. Simulation studies have facilitated an increase in safety by quantifying drug variability, and identifying where possible adverse drug events may occur. Modelling and simulation continue to have an important role optimizing drug use during anaesthesia. Models incorporating influential covariates that better describe drug pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify drug role and impact. Their use developing paediatric clinical studies improves trial conduct, often with fewer subjects required for study.

Safety and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.

8012 Background: BION-1301 (BION) is first in class humanized monoclonal antibody directed against a proliferation-inducing ligand (APRIL) for treatment of relapsed/refractory (R/R) multiple myeloma (MM). APRIL secreted by cells in the bone marrow (BM) niche binds to BCMA (B-Cell maturation antigen) and TACI (transmembrane activator and CAML interactor) expressed on human MM cells to drive their proliferation and survival. In patients (pts) with MM, serum APRIL levels are elevated and are correlated with promotion of malignancy, chemo- and immune-resistance. This study evaluated tolerability and clinical activity of BION monotherapy in R/R MM pts. Methods: Adults with MM, progression after ≥3 systemic therapies, and ECOG 0-1 were enrolled in this phase 1/2, open-label study. The phase 1 study is evaluating 6 cohorts with increasing BION doses of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Response was assessed by investigators Q4W. Serum was analyzed for BION, anti-drug antibodies (ADA), and soluble unbound “free APRIL” (fAPRIL) and evaluated by PK-PD modeling. Results: As of 7Dec2018, 15 pts were enrolled in 4 cohorts at doses between 50-1350 mg given Q2W. 5/15 (33%) had ECOG 0 and pts received median of 6 prior systemic therapies (range: 4-17). Related treatment emergent adverse events (TEAE) were reported in 8/15 (36%); most common related TEAE included anemia (n=3), arthralgia (n=2), and dysgeusia (n=2). 1 subject receiving 4th dose of BION experienced grade 3 wheezing considered infusion-related and serious. No dose-limiting toxicities were observed. Of 14/15 evaluable for response, no objective response was observed and 5/14 (36%) had stable disease. Median time on treatment was 2 months (range: 0.9-4.9+) and median of 3 doses of BION (range: 2-11) were administered. BION exposure increased dose proportionally from 50-1350 mg, and half-life (T1/2) and clearance (CL) did not differ significantly (median T1/2 = 9.0 days [range: 3.9-20], median CL = 0.52 L/day [range: 0.32-0.72]). Levels of fAPRIL in serum and BM decreased with increasing BION doses. By 450 mg, 95% target engagement (TG) was achieved around peak exposure levels. Non-neutralizing ADA was detected in 1/15 pts. Conclusions: BION, at doses 50-1350 mg given Q2W, was well-tolerated and dose-dependently reduces serum levels of fAPRIL. To date, objective responses have not been observed. The study is ongoing with pts exposed to higher and/or more frequent doses with the objective of achieving accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.

Mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) modeling and simulation of oxaliplatin for hematological toxicity in rats

Oxaliplatin (L-OHP) is a platinum (Pt)-based anticancer agent and is widely used for treating gastroenterological cancer. However, L-OHP-induced hematological toxicity is a critical undesirable effect that limits the dose of L-OHP. An ideal chemotherapeutic strategy that avoids severe hematological toxicity while maintaining positive chemotherapeutic outcomes has not been established for L-OHP. In this study, a pharmacokinetic–pharmacodynamic (PK–PD) model was developed that can link the associations between L-OHP administration regimens and the risk of hematological toxicity.The plasma concentration of L-OHP and neutrophil, lymphocyte and platelet counts after L-OHP (3, 5, and 8 mg/kg) administration to rats were used to develop the PK–PD model. The mechanism-based PK–PD model comprised a semi-physiological PD model that adequately described and simulated the entire time-course of alterations in blood cell counts.The model-based simulation proposed that a combination of the PK–PD model and monitoring of platelet counts throughout L-OHP-based chemotherapy is a valuable approach to determine an individualized optimal dosing strategy including the washout period.The current results might provide a framework for population PK–PD model analysis using hematological data of patients receiving L-OHP and investigations of chemotherapeutic strategies that are difficult to address in patients.

Semi-mechanistic modelling of neutropenia

Population pharmacokinetics and pharmacodynamics PKPD modelling of chemotherapy-induced neutropenia can help with efficacy optimization and toxicity prevention in cancer patients. These medications focus on the fast-growing cells within the body and destroy them. Most of the fast-growing cells in the body are usually cancer cells, but there is an increased chance that certain healthy cells, such as white blood cells could be killed during chemotherapy. Several approaches have been identified for different drugs. Both empirical and mechanist approaches are discussed in this paper. Further, the author identified the pharmacokinetic-pharmacodynamic profile described by Friberg et al. (2003) as the most commonly used. This model consists of five sectors that represent proliferation, maturation, as well as elimination from the circulation of the neutrophils or leucocytes. This review covers these aspects and promotes a full understanding of dose prediction using semi-mechanistic modelling.

Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C-Reactive Protein in Hospitalized Patients With Gram-Positive Infections.

Teicoplanin is an antibiotic agent used for the treatment of Gram-positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large-scale population, including patients with a wide range of ages, body weights, and renal functions. The PK of teicoplanin was described with a 2-compartment model, and the PD of C-reactive protein (CRP) concentrations was described with a turnover maximum inhibition model. The elimination half-life of teicoplanin calculated from the final estimated parameters was 169hours, and renal function was a significant covariate of teicoplanin clearance. The teicoplanin concentration producing 50% of the maximum inhibition of CRP production was estimated to be 2.66mg/L. The minimum concentration of teicoplanin in patients with higher loading doses (15mg/kg) reached the target range (15-30mg/L) with a probability of >50% in the dosing simulation. We described the influence of body size, body composition, and renal function on the PK of teicoplanin. The population PKPD model of teicoplanin and CRP in this study should provide useful information for development of a dosing strategy including the sequential clinical benefit of teicoplanin.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal-induced triglyceride turnover in healthy subjects.

Non-alcoholic steatohepatitis (NASH) is a liver disease in which fatty infiltration is accompanied by liver inflammation. GSK3008356 is under development as a selective inhibitor of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme involved in the formation of triglyceride (TG). Decreased DGAT1 activity can reduce circulating TG and liver TG, and therefore could potentially prevent or treat NASH. The aim of the current study was to develop a population pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the PK disposition of GSK3008356 and its relation to the changes in blood TG. Drug concentrations were measured in 104 healthy adults receiving various single (SD) and repeat doses (RD) in a first time in human (FiH) study. A 30% fat meal was given at hour 2 postdose, and blood postprandial TG concentrations were measured at various time points. The population PKPD model consists of several parts including a PK model, drug effect model, meal effect model, and a turnover model. The pharmacokinetic data were described using a 3-compartment model. Drug effect was described by an inhibitory sigmoidal Emax model. Since TG levels change with the introduction of a meal, a bi-exponential meal effect model was utilized. The total change in TG was fitted using a turnover model with drug and meal effects on the TG production rate. The current analysis presents a PKPD modeling strategy of time-varying TG data coming from both endogenous and exogenous sources. In general, the presented model could be utilized in the model-based drug development of drugs that influence TG levels in blood.

Pharmacokinetics and Pharmacodynamics Modeling and Simulation Systems to Support the Development and Regulation of Liposomal Drugs.

Liposomal formulations have been developed to improve the therapeutic index of encapsulated drugs by altering the balance of on- and off-targeted distribution. The improved therapeutic efficacy of liposomal drugs is primarily attributed to enhanced distribution at the sites of action. The targeted distribution of liposomal drugs depends not only on the physicochemical properties of the liposomes, but also on multiple components of the biological system. Pharmacokinetic–pharmacodynamic (PK–PD) modeling has recently emerged as a useful tool with which to assess the impact of formulation- and system-specific factors on the targeted disposition and therapeutic efficacy of liposomal drugs. The use of PK–PD modeling to facilitate the development and regulatory reviews of generic versions of liposomal drugs recently drew the attention of the U.S. Food and Drug Administration. The present review summarizes the physiological factors that affect the targeted delivery of liposomal drugs, challenges that influence the development and regulation of liposomal drugs, and the application of PK–PD modeling and simulation systems to address these challenges.

3552 Advancing Glioblastoma (GBM) drug regimen development to support combination therapy through integrated PKPD modeling and simulation-based predictions

OBJECTIVES/SPECIFIC AIMS: Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma remains fatal; the median survival rate is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, metastasis and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ), creates a substantial clinical challenge.The primary focus of our work is to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, our aim is to combine TMZ with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. METHODS/STUDY POPULATION: To accomplish this objective, an integrated PKPD modeling approach is used. The approach is largely based on the work of Cardilin, et al, 2018. A PK model for each drug is first defined. This is subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models are tumor static concentration (TSC) curves of dual or triple combination drug regimens that identify combination drug exposures predicted to arrest tumor growth. This approach has been applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib efficacy in combination with TMZ in a glioblastoma xenograft model (Raub, et al, 2015). RESULTS/ANTICIPATED RESULTS: A PKPD model was developed to predict tumor growth kinetics for TMZ and abemaciclib monotherapy, as well as combination therapy. Population PK models in immune deficient NSG mice for temozolomide and abemaciclib were developed based on data obtained from original and published studies. Subsequently, the PK model was linked to tumor volume data obtained from U87-MG GBM subcutaneous xenografts, again using both original data as well as data from the Raub, et al, 2015 study. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 30%). The developed PKPD model was used to calculate plasma concentrations of TMZ and abemaciclib that would arrest tumor growth, as well as combinations of concentrations of the two drugs that would accomplish the same endpoint. This so-called TSC curve for the TMZ and abemaciclib combination pair evidenced an additive effect of the two agents when administered together. These results will be presented. In addition, results from on-going PKPD studies of TMZ in combination with two other small molecule inhibitors, RG7388, an MDM2 inhibitor, and GDC0068, an AKT inhibitor, will also be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: Our long-term goals are to further elucidate SOC-induced responses in GBM and establish combination treatment regimens that are safe and significantly improve therapeutic efficacy. Collectively, our studies will broadly influence chemotherapy of GBM by establishing a process to rationally design combination approaches that mitigate resistance development. These studies will ultimately provide opportunities to study other targeted agents tailored to individual molecular signatures of GBM, as well as other tumor types.

A Cell-Level Systems PK-PD Model to Characterize In Vivo Efficacy of ADCs.

Here, we have presented the development of a systems pharmacokinetics-pharmacodynamics (PK-PD) model for antibody-drug conjugates (ADCs), which uses intracellular target occupancy to drive in-vivo efficacy. The model is built based on PK and efficacy data generated using Trastuzumab-Valine-Citrulline-Monomethyl Auristatin E (T-vc-MMAE) ADC in N87 (high-HER2) and GFP-MCF7 (low-HER2) tumor bearing mice. It was observed that plasma PK of all ADC analytes was similar between the two tumor models; however, total trastuzumab, unconjugated MMAE, and total MMAE exposures were >10-fold, ~1.6-fold, and ~1.8-fold higher in N87 tumors. In addition, a prolonged retention of MMAE was observed within the tumors of both the mouse models, suggesting intracellular binding of MMAE to tubulin. A systems PK model, developed by integrating single-cell PK model with tumor distribution model, was able to capture all in vivo PK data reasonably well. Intracellular occupancy of tubulin predicted by the PK model was used to drive the efficacy of ADC using a novel PK-PD model. It was found that the same set of PD parameters was able to capture MMAE induced killing of GFP-MCF7 and N87 cells in vivo. These observations highlight the benefit of adopting a systems approach for ADC and provide a robust and predictive framework for successful clinical translation of ADCs.

Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK-PD modeling analysis in pigs.

Florfenicol, a structural analog of thiamphenicol, has broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic-pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E.coli) with PK-PD integrated model in the target infectious tissue. 220 E.coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC50 (8μg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time-killing curves also coincided with the MBC determination. The recommended dosages (30mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC24hr , AUC0-∞ , Tmax , T1/2 , Cmax , CLb, and Ke were 49.83, 52.33μg*h/ml, 1.32, 10.58hr, 9.12μg/ml, 0.50L/hr*kg, 0.24hr-1 and 134.45, 138.71μg*hr/ml, 2.05, 13.01hr, 16.57μg/ml, 0.18L/hr*kg, 0.14hr-1 in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52mg/kg for 50% target and 33.95, 39.79, and 42.55mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16μg/ml. The current data presented provide the optimal regimens (39.79mg/kg) and susceptible breakpoint (16μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.