Quantitative Pharmacology Research Articles

Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.

Background:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.Methods:A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival.Results:The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression.Conclusions:The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.

Abstracts: ASCPT 2016 Annual Meeting & Quantitative Translational Approaches in Oncology Pre-Conference.

Clinical Pharmacology & TherapeuticsVolume 99, Issue S1 p. S5-S107 Abstracts American Society for Clinical Pharmacology and Therapeutics First published: 24 January 2016 https://doi.org/10.1002/cpt.310Citations: 6 Abstracts appear in presentation number order. PC and OPC denotes abstracts selected for the Quantitative Translational Approaches in Oncology Pre-conference, March 8. PT denotes those abstracts submitted by trainees that were selected to receive Presidential Trainee Awards; these will be on display on Wednesday, March 9, at the Showcase of Top Trainee Abstracts, and during ASCPT poster session hours Thursday and Friday, March 10 and 11. OI, OII, OIII denotes abstracts selected for oral presentation. Oral Sessions are scheduled for Thursday, March 10 and Saturday, March 12. E denotes those abstracts selected for poster presentation at the Encore Poster Session on Wednesday, March 9. PI denotes those abstracts selected for presentation at the Quantitative Pharmacology (QP) Poster Session on Thursday, March 10. PII denotes those abstracts selected for presentation at the Translational and Precision Medicine (TPM) and Development, Regulatory, and Outcomes (DRO) Poster Session on Friday, March 11. PWI, PWII, PWIII, PWIV denote abstracts selected for presentation at Poster Walk Sessions on Wednesday, March 9 (PWI), Thursday, March 10 (PWII, PWIII), and Friday, March 11 (PWIV). Late-breaking abstracts are not published in this Supplement. They will be available in the Final Program and Annual Meeting mobile app. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume99, IssueS1Supplement: Abstracts: ASCPT 2016 Annual Meeting & Quantitative Translational Approaches in Oncology Pre-ConferenceFebruary 2016Pages S5-S107 RelatedInformation

Efficient generation of virtual populations of CKD patients and applications in quantitative systems pharmacology

Efficient generation of virtual populations of CKD patients and applications in quantitative systems pharmacology

The American Society for Clinical Pharmacology and Therapeutics (ASCPT)--A Rich Heritage En Route to an Exciting Future.

The American Society for Clinical Pharmacology and Therapeutics (ASCPT)--A Rich Heritage En Route to an Exciting Future.

Moderate to high throughput in vitro binding kinetics for drug discovery.

This review provides a concise summary for state of the art, moderate to high throughput in vitro technologies being employed to study drug-target binding kinetics. These technologies cover a wide kinetic timescale spanning up to nine orders of magnitude from milliseconds to days. Automated stopped flow measures transient and (pre)steady state kinetics from milliseconds to seconds. For seconds to hours timescale kinetics we discuss surface plasmon resonance-based biosensor, global progress curve analysis for high throughput kinetic profiling of enzyme inhibitors and activators, and filtration plate-based radioligand or fluorescent binding assays for receptor binding kinetics. Jump dilution after pre-incubation is the preferred method for very slow kinetics lasting for days. The basic principles, best practices and simulated data for these technologies are described. Finally, the application of a universal label-free technology, liquid chromatography coupled tandem mass spectrometry (LC/MS/MS), is briefly reviewed. Select literature referencesare highlighted for in-depth understanding. A new reality is dawning wherein binding kinetics is an integral and routine part of mechanism of action elucidation and translational, quantitative pharmacology for drug discovery.

Quantitative pharmacology of the Dopamine DRD1 receptor using baculovirus and controlled expression

Quantitative pharmacology of the Dopamine DRD1 receptor using baculovirus and controlled expression

Modeling and simulation in pediatric drug therapy: Application of pharmacometrics to define the right dose for children

During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum.

Applied Pharmacometrics (AAPS Advances in the Pharmaceutical Sciences Series)

Edited by Stephan Schmidt and Hartmut Derendorf aapspress/Springer, 2014 565 pp, hardcover $239.00 ISBN 9781493913039 eBook $189.- ISBN 9781493913046 In this highly dynamic environment of an evolving discipline, Schmidt and Derendorf have edited a textbook devoted to the application of pharmacometrics in drug development and applied pharmacotherapy. As a multicontributor textbook, this collection of texts captures a current snapshot of state-of-the-art pharmacometric analyses and applications by utilizing the collective expertise of experienced scientists, investigators, and thought leaders in the field. After introductory chapters on quantitative pharmacology, physiologically based pharmacokinetic modeling, and the role of pharmacometrics in precision medicine, the textbook provides a cross-section of applications in different subpopulations, drug development sections, and therapeutic areas. For the patient subgroups, this includes pediatric patients, renal impairment patients, and obese patients. This is supplemented by a chapter on pharmacometrics in toxicology, with a focus on cardiovascular safety. The final two-thirds of the textbook are focused on applications of pharmacometric principles in therapeutic areas such as pulmonary diseases, psychiatric diseases, metabolic diseases, and dermatology. In addition, infectious diseases have received specific emphasis, with separate chapters on pharmacometric applications in bacterial, viral, and fungal infections as well as tuberculosis. Overall, Applied Pharmacometrics is a well-crafted collection of up-to-date applications in modeling and simulation that exemplifies the vast applicability of pharmacometric analyses in drug development and applied pharmacotherapy. It continues in the tradition of high scientific quality of the AAPS Advances in the Pharmaceutical Sciences book series and is highly recommended reading for individuals who are interested in learning and exploring the scope of pharmacometric applications in contemporary drug development and therapeutics in the 21st century.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection.

Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors.

Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors.

Patient adherence: clinical pharmacology's embarrassing relative.

Patient adherence: clinical pharmacology's embarrassing relative.

Pharmacologic considerations in use and development of antituberculosis drugs.

Rational development and deployment of antituberculosis drugs depend on a comprehensive understanding of the pharmacokinetics and pharmacodynamics that underlie their clinical behavior. Successful implementation of a pharmacokinetic-pharmacodynamic approach faces difficulties that, although not unique to tuberculosis as a therapeutic area, in combination pose a significant scientific challenge. In recent years, a multidisciplinary response combining new technological and analytical approaches has begun to directly address many of these issues, shedding light on some previously poorly understood aspects of drug distribution and response. These advances have important implications for optimization of existing and development of novel drug regimens, putting quantitative pharmacology at the heart of preclinical and early drug development.

Highlights of This Issue

Effective preventive drugs are declined by most women at high risk for breast cancer because of systemic toxicity, which may be decreased by the delivery of drugs through the breast skin. Lee and colleagues randomized women awaiting DCIS resection to 6-10 weeks of oral tamoxifen or 4-hyroxytamoxifen gel applied to the breast skin. The authors observed equivalent breast concentrations of 4-hydroxytamoxifen in both groups and similar reductions in the Ki67 labelling of DCIS cells, but far lower plasma concentrations in the transdermal group. Thus transdermal delivery appears to be a viable and potentially safer approach to breast cancer prevention, requiring further study.PARP inhibitors can potentiate the efficacy of temozolomide (TMZ) in multiple tumors; however, in previous animal studies, treatment of TMZ-resistant GBM xenograft models with veliparib and TMZ was ineffective in comparison with TMZ-sensitive models. By comparing isogenic TMZ-sensitive and –resistant GBM models, Gupta and colleagues report that resistant models in vitro are sensitized only by supratherapeutic concentrations of veliparib and TMZ. Using clinically relevant schedules in vivo, veliparib promotes TMZ-induced DNA damage signaling and survival benefit only in TMZ-sensitive models. These results highlight the importance of using clinically achievable drug levels in preclinical studies of PARP inhibitor combinations.Selective inhibition of CDK4/6 represents an area of considerable interest for anti-cancer therapy. To explore the in vivo quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, an integrated pharmacokinetic/pharmacodynamic (PK/PD) model was developed by Tate and colleagues, relating plasma concentration to target engagement, cell cycle arrest, and growth inhibition of colo-205 and A375 xenograft tumors. Model simulations indicate that trough plasma concentrations of 200 ng/mL are associated with robust cell cycle arrest and that continuous dosing is required to achieve sustainable in vivo efficacy. These findings support and reinforce the continuous dosing strategy currently adopted in LY2835219 clinical studies.Tumor-infiltrating lymphocyte (TIL) prevalence predicts improved survival in breast and ovarian cancer. To explore the role of B-cell TILs by genomic subtype, Iglesia and colleagues assessed lymphocyte gene expression in breast and ovarian cancer mRNA-seq data. Furthermore, they developed a method to assess clonal diversity of B-cell populations from mRNA-seq. This work highlights the basal-like and HER2-enriched subtypes of breast cancer, and the immunoreactive subtype of ovarian cancer, as containing B-cell TILs that predict improved survival outcomes and are clonally restricted compared with TILs in other tumor subtypes.

Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts.

Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.

Go west, FDA

The FDA's first two centers for regulatory sciences were focused on modernizing methods and building bridges to academia. The agency now is at earlier drug development and has partnered with Stanford and UCSF to create a center focused on quantitative pharmacology that will give the FDA a foothold on the West Coast.

Impact of Quantitative Pharmacology on Drug Development

Thesuccess of drug development rests over two well defined pillars, a goodunderstanding of the drug’s clinical pharmacology and the appropriate targetpopulation for whom the clinical use is intended. The label for human prescription drugsrequires a good understanding of the pharmacological effects (pharmacodynamicsor PD) and the mechanism of action of the drug as well as detailed informationof the drug’s Pharmacokinetics (PK): Absorption, distribution, metabolism andexcretion. Theunderstanding of the PK characteristics and PD effects (desired or adverse)will provide educated recommendations about the effective dose, dosing regimen,potential drug-drug interactions and hence contraindications and warnings. Further, the influence of demographic factorson the PK and PD attributes (e.g., age, sex, race, hepatic or renal impairment)need to be well understood to provide the appropriate guidance to patients andcaregivers for patients in specific populations (pediatric, geriatric, organimpairment, pregnancy, etc). In summary, a very extensive portion of the labelcovers clinical pharmacology topics, the following label sections are mainlysupported by clinical pharmacology knowledge collected throughout the course ofdrug development:

Parameter Estimation of Population Pharmacokinetic Models with Stochastic Differential Equations: Implementation of an Estimation Algorithm

Population pharmacokinetic (PPK) models play a pivotal role in quantitative pharmacology study, which are classically analyzed by nonlinear mixed-effects models based on ordinary differential equations. This paper describes the implementation of SDEs in population pharmacokinetic models, where parameters are estimated by a novel approximation of likelihood function. This approximation is constructed by combining the MCMC method used in nonlinear mixed-effects modeling with the extended Kalman filter used in SDE models. The analysis and simulation results show that the performance of the approximation of likelihood function for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for the analysis of population pharmacokinetic data.

Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.

Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor

4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R.

Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family

BackgroundIn vitro pharmacology of ligands is typically assessed using a variety of molecular assays based on predetermined molecular events in living cells. Many ligands including opioid ligands pose the ability to bind more than one receptor, and can also provide distinct operational bias to activate a specific receptor. Generating an integrative overview of the binding and functional selectivity of ligands for a receptor family is a critical but difficult step in drug discovery and development. Here we applied a newly developed label-free integrative pharmacology on-target (iPOT) approach to systematically survey the selectivity of a library of fifty-five opioid ligands against the opioid receptor family. All ligands were interrogated using dynamic mass redistribution (DMR) assays in both recombinant and native cell lines that express specific opioid receptor(s). The cells were modified with a set of probe molecules to manifest the binding and functional selectivity of ligands. DMR profiles were collected and translated to numerical coordinates that was subject to similarity analysis. A specific set of opioid ligands were then selected for quantitative pharmacology determination.ResultsResults showed that among fifty-five opioid ligands examined most ligands displayed agonist activity in at least one opioid receptor expressing cell line under different conditions. Further, many ligands exhibited pathway biased agonism.ConclusionWe demonstrate that the iPOT effectively sorts the ligands into distinct clusters based on their binding and functional selectivity at the opioid receptor family.