Guide Dose Selection Research Articles

Postoperative stereotactic radiosurgery for patients with resected brain metastases: a volumetric analysis.

Postoperative stereotactic radiosurgery (SRS) is increasingly utilized following resection of brain metastases (BM); however, there are no volumetric data guiding dose selection. We performed a volumetric analysis to guide cavity SRS dosing for resected BM. 83 consecutive patients with gross total resection who underwent postoperative SRS to 90 cavities were identified. The 12Gy isodose lines (V12total) along with the volume of brain parenchyma receiving 12Gy excluding cavity fluid, ventricular fluid, and calvarium (V12parenchyma) were contoured. Local recurrence (LR) and radionecrosis (RN) were calculated using cumulative incidence rates. Multivariate analysis (MVA) and cutpoint analysis were conducted. Median follow-up was 12.3months; median dose was 16Gy. 1- and 2-year cumulative incidence rates of LR were 7.9% and 11.0%. Radiation dose [hazard ratio (HR) 2.04, p = 0.002] was significantly associated with time to LR on MVA. 1- and 2-year cumulative incidence rates of RN were 2.6% and 5.5% respectively. MVA demonstrated increased risk of RN with a larger V12parenchyma (HR 1.46, p = 0.0496). Cavities ≤ 10cc showed a low 2-year RN risk (4.3%), but had a modest LR risk (13.9%). A radiation dose ≥ 18Gy significantly improved LC (HR 4.79, p = 0.01). V12parenchyma should be examined in postoperative SRS to assess RN risk. Cavities > 10cc treated with 16Gy achieved excellent LC and minimal RN at 2years. Cavities ≤ 10cc may be better treated with a dose ≥ 18Gy to significantly improve LC given the low RN rate observed with 16Gy.

Drug dosing in obese adults.

Drug doses often warrant adjustment in obese patients. Clinicians should consider the patient’s body composition when calculating doses. Drug clearance is greater in obesity and correlates with lean body weight. Body size metrics help guide dose selection, but there are advantages and disadvantages to all of them. Chronic dosing using total body weight can lead to drug toxicity. Studies evaluating weight-based dosing strategies are required for many drugs.

A dose response study of the effect of prostaglandin E2 on thermal nociceptive sensitivity

Inhibition of prostaglandin (PG) biosynthesis has been used to relieve pain for thousands of years. Today non-steroidal anti-inflammatory drugs (which largely inhibit PG synthesis) are widely used to treat pain. Four main types of PGs (PGD2, PGE2, PGF2 and PGI2) are synthesized from arachidonic acid during inflammation and have been demonstrated to impact nociception. PGE2 has been the most studied and utilized for its pain producing properties and has been demonstrated to increase hypersensitivity in rodent nociceptive behavioral models when applied centrally and/or peripherally. Surprisingly, there are no published reports that use withdrawal from radiant light beam (Hargreaves apparatus) to examine the dose response effect of peripherally applied PGE2 on thermal nociceptive hypersensitivity. To address this gap in the literature, we performed a dose response study examining the effect of PGE2 on thermal hypersensitivity (assessed using a Hargreaves apparatus) where rats were injected with 0.003–30μg of PGE2, intradermally into the hindpaw. Thermal hypersensitivity was assessed by measuring withdraw latency from a radiant light beam (Hargreaves test) and our primary objective was to determine the dose of PGE2 causing the most pronounced increase in thermal hypersensitivity (i.e. lowest withdraw latency). A secondary objective was to determine the minimum dose of PGE2 required to cause statistically significant decreases in thermal withdrawal latency as compared to rats injected with vehicle. We found that rats injected with the 30μg dose of PGE2 exhibited the most pronounced thermal nociceptive hypersensitivity though secondary analysis showed that rats injected with PGE2 doses of 0.03–30μg had lower withdrawal latencies as compared to rats injected with vehicle. This work fills an evidence gap and provides context to guide dose selection in future rodent pain behavior studies.

PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) EFFECTS OF PF-06648671, A NOVEL GAMMA SECRETASE MODULATOR (GSM), FOLLOWING SINGLE AND MULTIPLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS

Unlike gamma secretase inhibitors, GSMs shift the cleavage of amyloid-β (Aβ) peptides in favor of shorter forms without inhibiting overall Aβ precursor protein processing, thus preferentially lower the production of longer, amyloidogenic forms. This study aimed to characterize PF-06648671 plasma exposure and cerebrospinal fluid (CSF) Aβ (Aβx-42, Aβx-40, Aβx-38 and Aβx-37) response relationship in healthy subjects. Clinical data were obtained from three Phase 1 studies: first-in-human single ascending dose (PK), single dose CSF biomarker (PK/PD; 150, 300 mg, and placebo), and multiple dose (PK/PD; 40, 100, 200, 360 mg and placebo) studies. Drifts in baseline (a rising tendency) were observed in placebo subjects after serial CSF sampling over 36 hours, which was taken into account in the model. Indirect response model was applied in a way that PF-06648671 plasma concentrations change the production rate of CSF Aβ peptides (decreased Aβ42 and Aβ40; increased Aβ37 and Aβ38). Population PK/PD modeling was performed using NONMEM 7.3. The inhibitory effect on CSF Aβ42 was greater than on Aβ40, whereas the stimulatory effect on Aβ37 was greater than on Aβ38. Preliminary results suggested CSF Aβ42 reductions after 100 and 350 mg q.d. administrations at steady state are approximately 50% and 66% on average, and about 200% and 400% increase in Aβ37, respectively. Indirect response model was developed to characterize exposure-dependent and differential effects of PF-06648671 on CSF Aβ's in healthy subjects. PK/PD relationship of PF-06648671 in human demonstrated a good translatability from preclinical model. The clinical PK/PD model has been used to predict the drug effect on individual Aβ peptides as well as the ratio of these Aβ peptides in CSF across a range of PF-06648671 doses. These results will guide dose selection in future Phase 2/3 trials.

Micropatterned Co‐Cultures of Human Hepatocytes and Stromal Cells for the Assessment of Drug Clearance and Drug‐Drug Interactions

Drug clearance rates from the body can determine drug exposure that can affect efficacy or toxicity. Thus, accurate prediction of drug clearance during preclinical development can help guide dose selection in humans, but animal testing is not always predictive of human outcomes. Because hepatic drug metabolism is a rate-limiting step in the overall clearance of many drugs, primary human hepatocytes (PHHs) in suspension cultures or monolayers are used for drug clearance predictions. Yet, the precipitous decline in drug metabolism capacity can lead to significant underestimation of clearance rates, particularly for low turnover compounds that have desirable one-pill-a-day dosing regimens. In contrast, micropatterned co-cultures (MPCCs) of PHHs and fibroblasts display phenotypic stability for several weeks and can help mitigate the limitations of conventional cultures. Here, we describe protocols to create and use MPCCs for drug clearance predictions, and for modeling clinically-relevant drug-drug interactions that can affect drug clearance. © 2017 by John Wiley & Sons, Inc.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

A multivariable model to predict survival for patients with hepatic carcinoma or liver metastasis receiving radiotherapy.

New parameters that correlate with overall survival were identified in patients with liver lesions treated with radiation therapy. Pretreatment information and parameters of radiation treatment plans for 129 metastatic and 66 hepatocellular carcinoma liver cancer patients were analyzed. Study end points included overall survival collected from patient charts and electronic records. Two practical nomograms were constructed for primary hepatocellular carcinoma and liver metastasis patients. For patients with a Child-Pugh A, radiation dose escalation provided a significant survival benefit. However, for those with Child-Pugh B or C, increasing dose does not impact on survival. The developed models can potentially guide dose selection and provide prognostic information but still require external validation.

Pharmacodynamics of anti-HIV gene therapy using viral vectors and targeted endonucleases.

A promising curative approach for HIV is to use designer endonucleases that bind and cleave specific target sequences within latent genomes, resulting in mutations that render the virus replication incompetent. We developed a mathematical model to describe the expression and activity of endonucleases delivered to HIV-infected cells using engineered viral vectors in order to guide dose selection and predict therapeutic outcomes. We developed a mechanistic model that predicts the number of transgene copies expressed at a given dose in individual target cells from fluorescence of a reporter gene. We fitted the model to flow cytometry datasets to determine the optimal vector serotype, promoter and dose required to achieve maximum expression. We showed that our model provides a more accurate measure of transduction efficiency compared with gating-based methods, which underestimate the percentage of cells expressing reporter genes. We identified that gene expression follows a sigmoid dose-response relationship and that the level of gene expression saturation depends on vector serotype and promoter. We also demonstrated that significant bottlenecks exist at the level of viral uptake and gene expression: only ∼1 in 220 added vectors enter a cell and, of these, depending on the dose and promoter used, between 1 in 15 and 1 in 1500 express transgene. Our model provides a quantitative method of dose selection and optimization that can be readily applied to a wide range of other gene therapy applications. Reducing bottlenecks in delivery will be key to reducing the number of doses required for a functional cure.

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

ABSTRACTPrompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16–21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38–59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

Studies of human pancreatic elastase treatment of rabbit and human vein rings to predict human therapeutic doses.

Vascular tissue contains abundant elastic fibers that contribute to vessel elasticity. Vonapanitase (formerly PRT‐201) is a recombinant human chymotrypsin‐like elastase family member 1 (CELA1) shown to cleave the elastin component of elastic fibers, resulting in increased vessel diameter. The purpose of these current studies was to determine vein diameter, wall thickness, elastin content, and vonapanitase potency in veins used in a model of arteriovenous fistula (AVF) and in patients undergoing AVF creation for hemodialysis access to guide dose selection for human trials. Rabbit linguofacial, maxillary, and external jugular veins, and human basilic and upper and lower arm cephalic veins were dissected postmortem and sectioned into 2 mm length rings. Rings were incubated in vonapanitase at 37°C at varying concentrations and times. Elastin content was estimated histologically and by quantifying desmosine, a protein cross‐link unique to elastin. Rabbit veins were substantially thinner and contained less elastin than human veins. In human veins, elastin content was greatest in basilic and least in lower arm cephalic. Vonapanitase removed elastin in a time‐ and concentration‐dependent manner in all vein types. A lower concentration of vonapanitase was required to remove elastin from rabbit relative to human veins. In summary, vonapanitase reduced the elastin content of rabbit and human veins but did so at a lower concentration in the rabbit veins. Rabbit models may overestimate the potency of vonapanitase in humans. These results indicate that human dose selection should be guided by human vein ring experiments.

Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Potency of a Human Monoclonal Antibody to Diphtheria Toxin Relative to Equine Diphtheria Anti-toxin in an Animal Model

Background. Morbidity and mortality from toxigenic Corynebacterium diphtheriae is greatly reduced by prompt administration of anti-toxin. Current treatment relies upon equine-derived antibodies to diphtheria toxin (Diphtheria Anti-Toxin [DAT]) that carry the risk of a severe allergic reaction. The global supply of DAT is extremely limited as most manufacturers have ceased production. MassBiologics of the University of Massachusetts Medical School has developed a human monoclonal antibody (S315) that neutralizes diphtheria toxin in vitro and protects toxin-exposed animals. A human monoclonal has the potential to provide a safer alternative to equine DAT and address critical supply issues for global use. Methods. To guide dose selection for investigational new drug-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the National Institutes of Health (NIH) Minimum Requirements (1946) potency assay for DAT preparations. Guinea pigs (5 per cohort) were dosed with a single subcutaneous injection of DAT (1.25–2.5 IU) or S315 (8–100 µg) premixed with a fixed dose of toxin. Animals were monitored daily for 30 days and assigned a score for presence of symptoms (lethargy, dehydration, weak limbs) or death. A logistic analysis was performed using Fieller's theorem to calculate the 95% confidence intervals (CIs) around the ED50 for each group. Results. All animals receiving ≥27.5 µg of S315 or ≥1.75 IU of DAT survived toxin exposure whereas all animals receiving ≤22.5 µg of S315 or ≤1.25 IU of DAT died, yielding a potency estimate of 17 µg S315 /IU DAT (95% CI, 16–21) for an endpoint of survival. Because some of the surviving animals exhibited transient limb weakness, possibly a manifestation of peripheral neuropathy due to diphtheria toxin, the ED50 required to prevent any signs of diphtheria intoxication were also calculated for DAT and S315, yielding a relative potency of 48 µg/IU (95% CI, 38–59). Conclusion. To support the advancement of S315 into clinical trials, these potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model in which antibody will be administered after exposure to diphtheria toxin, more closely modeling the timing of anti-toxin administration in humans. Disclosures. H. Smith, MassBiologics of the University of Massachusetts Medical School: Employee, Salary; P. Cheslock, MassBiologics of the University of Massachusetts Medical School: Employee, Salary; M. Leney, MassBiologics of the University of Massachusetts Medical School: Employee, Salary; B. Barton, MassBiologics of the University of Massachusetts Medical School: Collaborator, Salary; D. Molrine, MassBiologics of the University of Massachusetts Medical School: Employee, Salary

Population Pharmacokinetics and Pharmacodynamics of AG-348 in Healthy Human Volunteers Guide Dose Selection for the Treatment of Pyruvate Kinase Deficiency

▪ INTRODUCTIONPyruvate kinase (PK) deficiency is a glycolytic enzymopathy that results in non-spherocytic hemolytic anemia with a variable clinical presentation, ranging from mild or fully compensated forms to life-threatening neonatal anemia and life-long chronic hemolytic anemia associated with severe, debilitating co-morbidities. PK deficiency is caused by mutations in the PKLR gene, which in the red blood cell (RBC) results in defective pyruvate kinase isoform R (PK-R). PK-R catalyzes the final, irreversible step in glycolysis, the process on which mature RBCs rely almost exclusively to generate the energy carrier molecule adenosine triphosphate (ATP). PK-deficient RBCs and their progenitors are characterized by changes in metabolism associated with defective glycolysis, including a build-up of phosphoenolpyruvate (PEP) and 2,3-diphosphoglycerate (2,3-DPG), and lowered ATP levels. AG-348 is an orally available, allosteric activator of PK-R. It is hypothesized that intervention with AG-348 restores glycolytic pathway activity and normalizes RBC metabolism in vivo (Kung C et al. Blood, 2013). Biochemical experiments demonstrate that AG-348 is a potent pan-activator of many PK-R alleles associated with PK deficiency. Treatment of PK-deficient patient RBCs ex vivo with AG-348 results in increased ATP levels, and reductions in PEP and 2,3-DPG, consistent with pharmacological activation of the PK-R enzyme. This analysis integrates the pharmacokinetic and pharmacodynamic (PK/PD) properties of AG-348 in healthy human volunteers using population PK/PD modeling and simulation. METHODSPK/PD modeling using a non-linear mixed effects approach was performed to understand the pharmacokinetics of AG-348 and PK/PD relationship of AG-348 to 2,3-DPG and ATP in humans. The PK/PD model integrated data from two phase 1, single-center, randomized, double-blind, placebo-controlled, dose escalation studies (one single and one 14-day multiple ascending dose) that enrolled a total of 96 healthy volunteers (Yang H et al. EHA Learning Center, 2015). AG-348 dose level ranged from 15-2500 mg given once (QD) or twice (BID) daily. Blood was collected from all patients to assess AG-348 pharmacokinetics, and for determination of levels of ATP and 2,3-DPG. Population simulations using the final model were performed to examine the dose-exposure-biomarkers relationship at various dose levels and duration of dosing. RESULTSAG-348 showed rapid absorption following oral administration. Plasma exposure of AG-348 increased in a dose-proportional manner following a single dose. A three-compartmental model with a non-linear absorption compartment and a saturable induced enzyme compartment best described the pharmacokinetics of AG-348. Time-varying clearance was added to describe the observed decrease in exposure over time with multiple dosing; this is consistent with pre-clinical data that AG-348 is a moderate inducer of CYP3A4, the major oxidation pathway of AG-348. The multiple-dose data were well described by a semi-mechanistic autoinduction model with an indirect model and a saturable induction compartment. The PK/PD relationship between plasma AG-348 to ATP and 2,3-DPG showed best fit with a turnover model where the drug effect was described by an Emax model. Model simulations predicted maximum enzyme induction and PD response 3 weeks after the first dose following BID dosing. Population PK/PD simulations further supported the choice of 50 mg and 300 mg BID doses for the phase 2 study (Fig 1 and 2). The proposed current model incorporating PK/PD data over a wide range of AG-348 exposures and time-varying changes in clearance provides a useful tool for prediction of AG-348 pharmacokinetics that can be used to optimize AG-348 dosing for PK deficiency treatment. Furthermore, the population PK/PD model of AG-348 to ATP and 2,3-DPG biomarkers in healthy volunteers provides a good foundation to facilitate the analysis and understanding of patient data in the ongoing phase 2 study. CONCLUSIONThis study represents the first comprehensive longitudinal analysis of AG-348 and its PD activity in humans. This integrated PK/PD model, incorporating time-varying PK/PD properties, forms the basis for understanding the exposure-response relationship in the ongoing phase 2 and future clinical studies of AG-348, as well as providing guidance on dosing selection to optimize the treatment of PK deficiency. [Display omitted] [Display omitted] DisclosuresLe:Agios Pharmceuticals: Employment, Equity Ownership. Cohen:Agios: Consultancy. Chen:Agios: Employment. Kim:Agios: Employment. Silver:Agios: Consultancy. Agresta:Agios: Employment, Equity Ownership. Merica:Agios Pharmaceuticals: Employment, Equity Ownership. Kung:Agios: Employment, Equity Ownership. Kosinski:Agios: Employment, Equity Ownership; General Electric: Equity Ownership; SDIX: Equity Ownership. Silverman:Agios: Employment, Equity Ownership. Biller:Agios Pharmaceuticals: Employment, Equity Ownership; Arbutus BioPharma (formerly Tekmira): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Arvinas: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Denali: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Yang:Agios Pharmaceuticals: Employment, Equity Ownership.

Special populations and pharmacogenetic issues in tuberculosis drug development and clinical research.

Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug-drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials.

Pediatric Dose Determinations for the Phase I Study of the DOT1L Inhibitor, EPZ-5676, in MLL-r Acute Leukemia: Leveraging Early Clinical Data in Adults through Physiologically-Based Pharmacokinetic Modeling

Introduction: Relapsed/refractory (R/R) MLL-r acute leukemia in children has a poor prognosis, with a reported 5 year overall survival for children less than one year of age with recurrent MLL-r leukemia being 4-20%. The MLL gene, on chromosome 11q23, codes for a histone methyltransferase (HMT) that is responsible for methylation of H3K4, a modification associated with active transcription. Translocations of MLL result in the loss of the SET or catalytic domain of the protein with the most common translocation partners, AF4, AF9, and ENL, recruiting another HMT, DOT1L. The aberrant recruitment of DOT1L to MLL fusion target genes results in ectopic H3K79 methylation and increased expression of genes including HOXA9 and MEIS1, which are involved in leukemogenesis of MLL-rearranged leukemias. EPZ-5676 is a small molecule inhibitor of DOT1L with sub-nanomolar affinity and >37,000 fold selectively against other HMTs. Preclinically, EPZ-5676 selectively inhibits intracellular histone H3K79 methylation, downstream target gene expression and demonstrated complete tumor regressions in an MLL rearranged leukemia xenograft model. The first in human phase I open label study in adult patients with R/R leukemia is ongoing (CT.gov: NCT01684150). Due to the unmet need of MLL-r leukemia in children, we leveraged early clinical data in adult patients to successfully guide dose selection and trial design for a companion pediatric study.Methods: Pediatric starting dose selection was informed using a physiologically-based PK (PBPK) modeling and simulation approach (Simcyp, UK), such that the maturation and developmental aspects of various physiological and biochemical processes important in drug disposition were accounted for e.g. tissue blood flows, organ size, and drug metabolizing enzyme expression. In addition to pharmacokinetic data from adult patients across the dose range of 12 – 90 mg/m2/day administered as a continuous IV infusion (CIV), various in vitro data including physicochemical properties, plasma protein binding, blood partitioning, in vitro metabolic stability and P450 phenotyping were incorporated into the model.Results: Dose proportional pharmacokinetics was observed in adult patients, with rapid attainment of steady-state plasma concentrations on Day 1 of CIV (ASH abstract, 2014). A successful model fit of the adult clinical exposures (n = 16) was achieved that adequately described the time-concentration profiles and PK parameters in terms of population mean and variability. The median clearance observed in adults was 6.00 L/h, and was well predicted using a permeability-limited liver model. System variables related to the pediatric population (organ size, blood flows, enzyme expression) were appropriately adjusted and simulations were performed at a fixed dose across various age groups from 0-18 years. The median clearance predicted in pediatric patients was 0.54, 0.80, 1.09, 1.90 and 4.21 L/h in 1-3 months, 3-6 months, 6 months-2 years, 2-6 years and 6-18 years, respectively. Based on simulations of the predicted steady-state systemic exposure of EPZ-5676 using these pediatric models, dose adjustments of 55%, 65%, 73%, 83% and 100% of the adult dose would be needed to achieve equivalent exposures in the respective age bands. For practical and safety purposes, this was further simplified in a conservative manner to derive a pediatric starting dose of 80% and 50% of the highest adult dose (90 mg/m2/day) in > 12 month olds and < 12 month olds respectively.Conclusions: This study demonstrates that prospective application of modeling and simulation tools, such as PBPK, can support clinical trial design in rare populations early in clinical development, as recently highlighted in FDA’s “Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases.” These modeling results provided dosing recommendations for the ongoing trial of EPZ-5676 in pediatric MLL-r R/R leukemia which is currently open and enrolling children aged 3 months to 18 years. (CT.gov: NCT02141828). DisclosuresWaters:Epizyme, Inc: Employment, Equity Ownership. Thomson:Epizyme, Inc: Employment. Gardner:Simcyp: Employment. Johnson:Simcyp: Employment. Olhava:Epizyme: Employment. Pollock:Epizyme: Employment, Equity Ownership. Legler:Epizyme, Inc: Employment. Copeland:Epizyme, Inc: Employment, Equity Ownership; Mersana: Membership on an entity’s Board of Directors or advisory committees; New Enterprise Associates: Ad hoc consultant, Ad hoc consultant Other. Hedrick:Epizyme, Inc: Employment; Pharmacyclics, Inc: Equity Ownership.

AQW051, a novel and selective nicotinic acetylcholine receptor α7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys.

Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15mg/kg) administered 1h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30min at the highest AQW051 dose (15mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15mg/kg). To understand the exposure-effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.

PET Measurement of Receptor Occupancy as a Tool to Guide Dose Selection in Neuropharmacology

Receptor occupancy studies are becoming commonplace for verifying drug mechanism of action and selecting early development candidates. Positron emission tomography (PET) has been applied to pharmacodynamic (PD) studies in several therapeutic areas including neurology, cardiology, and oncology. Prospective use of PET to define dosing requirements has been proposed particularly for central nervous system (CNS)-targeted drugs; however, correlations with clinical outcomes have been mostly anecdotal and not causally established.

Prediction of H3 Receptor Occupancy Diurnal Fluctuations Using Population Modeling and Simulation with Focus on Guiding Dose Selection in a Phase IIa Study

4-[(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzamide (“AZ1”) is a histamine 3 (H3) autoreceptor in vivo antagonist. Sleep disturbance is a well-known class-effect for H3 antagonists and associated with high H3 receptor occupancy (RO) at night. The objective of the present work was to investigate if it was possible to obtain large diurnal fluctuations in RO for AZ1 and to suggest suitable doses for a Phase IIa study. Four Phase I studies were pooled and used to build a population pharmacokinetic model in NONMEM. Based on simulations of the PK model and the reported Ki-value for H3 RO from a human PET-study, RO vs. time profiles were simulated. The model well described the AZ1 pharmacokinetics. Simulations predicting plasma concentration and RO vs. time profiles for several doses were explored and doses with a wide range of fluctuation in RO over the dosing interval could be identified. By using population modeling and simulations of PK data and the Ki-value from a human PET study, predictions of RO vs. time for unstudied doses of AZ1 was made. Using this methodology it was possible to suggest doses with expected large diurnal fluctuations in RO.

THERAPY OF ENDOCRINE DISEASE: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe

BackgroundConventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring.Objectivesi) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations.MethodsThe review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment.ResultsOptimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs.ConclusionsThis review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.

The economics of personalised medicine and pharmacogenetic testing

Health economic evaluations are central to decisions on the availability of new treatments and other health care interventions in several jurisdictions across Europe. Health technologies are not approved for use in the United Kingdom if they are considered to represent poor value for money; that is, if their cost-effectiveness exceeds around £30,000 (€40,000) per quality-adjusted life-year. Personalized medicine, in which treatments are prescribed according to patients’ characteristics, holds promise for more favorable health outcomes. However, as pharmaceutical market shares are potentially reduced as a consequence, there is uncertainty as to whether the compensatory price adjustments result in cost-effective treatment strategies. It is necessary, therefore, to conduct stratified cost-effectiveness analyses of treatments based on prognostic factors that reveal populations in which treatments are most likely to be effective or less likely to be harmful. The cost-effectiveness of pre-prescription genotyping is illustrated using a series of case studies: (1) HLA-B*5701 testing, which has dramatically reduced the incidence of hypersensitivity reactions to abacavir in patients with HIV; (2) VKORC1 and CYP2C9 genotyping to guide dose selection with warfarin; (3) HLA-A*3101 testing for the reduction in the incidence of carbamazepine-induced cutaneous adverse drug reactions; (4) testing for genetic polymorphisms in UGT1A1 and irinotecan-induced neutropenia and diarrhea; and (5) CYP2C19 testing before clopidogrel treatment in patients with acute coronary syndrome. With the exception of abacavir, a specific limitation of these analyses, which introduces considerable uncertainty to the estimation of cost-effectiveness, relates to the evidential standards for demonstration of the clinical effectiveness of tests. None declared.