Steven W. Martin

Model-based drug development: a rational approach to efficiently accelerate drug development.

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In todays development paradigm, late‐stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model‐based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.

AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development

Background and aims Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. Methods In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03–10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α4β7+ lymphocytes was measured to demonstrate drug activity. Results No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α4β7+ lymphocytes in patients receiving PF-00547,659. Conclusions The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.

Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis.

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs).

A mathematical model of the human menstrual cycle for the administration of GnRH analogues

Endometriosis is a gynecological condition resulting from proliferation of endometrial‐like tissue outside the endometrial cavity. Estrogen suppression therapies, mediated through gonadotropin‐releasing hormone (GnRH) modulation, decrease endometriotic implants and diminish associated pain albeit at the expense of bone mineral density (BMD) loss. Our goal was to provide model‐based guidance for GnRH‐modulating clinical programs intended for endometriosis management. This included developing an estrogen suppression target expected to provide symptomatic relief with minimal BMD loss and to evaluate end points and study durations supportive of efficient development decisions. An existing multiscale model of calcium and bone was adapted to include systematic estrogen pharmacologic effects to describe estrogen concentration‐related effects on BMD. A logistic regression fit to patient‐level data from three clinical GnRH agonist (nafarelin) studies described the relationship of estrogen with endometrial‐related pain. Targeting estradiol between 20 and 40 pg/ml was predicted to provide efficacious endometrial pain response while minimizing BMD effects.

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

The paper presents a differential equation model for the feedback mechanisms between gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), development of follicles and corpus luteum, and the production of estradiol (E2), progesterone (P4), inhibin A (IhA), and inhibin B (IhB) during the female menstrual cycle. Compared to earlier human cycle models, there are three important differences: The model presented here (a) does not involve any delay equations, (b) is based on a deterministic modeling of the GnRH pulse pattern, and (c) contains less differential equations and less parameters. These differences allow for a faster simulation and parameter identification. The focus is on modeling GnRH-receptor binding, in particular, by inclusion of a pharmacokinetic/pharmacodynamic (PK/PD) model for a GnRH agonist, Nafarelin, and a GnRH antagonist, Cetrorelix, into the menstrual cycle model. The final mathematical model describes the hormone profiles (LH, FSH, P4, E2) throughout the menstrual cycle of 12 healthy women. It correctly predicts hormonal changes following single and multiple dose administration of Nafarelin or Cetrorelix at different stages in the cycle.

A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients.

Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R0), body-weight (BW) normalized central elimination rate (Kel/BW−0.25) and central volume (Vc/BW1.0). AAFE of less than three-fold was estimated for the binding affinity constant (KD). The other four parameters, i.e., complex turnover rate (Kint), target turnover rate (Kdeg), central to peripheral distribution rate constant (Kpt) and peripheral to central rate constant (Ktp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.

Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers

AIMS Anrukinzumab is an anti-IL13 monoclonal antibody. The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates. METHODS A population pharmacokinetic (PK) model was developed in NONMEM, using data from five clinical studies including healthy volunteers, asthma and ulcerative colitis (UC) patients. Different dosing regimens including different routes of administration were also included in the data. RESULTS The PK of anrukinzumab were described by a two compartment model with first order absorption and elimination. The population estimates (relative standard error) of the volumes of distribution in the central (Vc ) and peripheral (Vp ) compartments were 3.8 (4.6%) and 2.2 l (8.7%), respectively. In non-UC patients, the population estimate of the systemic clearance (CL) and inter-compartmental CL was 0.00732 l h(-1) (4.9%) and 0.0224 l h(-1) (15.4%). For subcutaneous administration, the absorption rate constant was 0.012 h(-1) (6.6%) and bioavailability was nearly 100% in healthy and mild to moderate asthma patients. Both V and CL increased with body weight. CL (but not V) decreased with increasing baseline albumin concentrations. UC patients had an increased CL of 72.3% (10.5%), after correction for differences in body weight and albumin. Moderate to severe asthma patients had decreased bioavailability compared with other populations. CONCLUSIONS Anrukinzumabs PK behave like a typical antibody. UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients. This finding suggests a higher dose level may be required for this population.

A model‐based longitudinal meta‐analysis of FEV1 in randomized COPD trials

A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases. We used a systems model to better understand the effect of modulating various components on blood coagulation. A computational model of the coagulation network was built to match in‐house in vitro thrombin generation and activated Partial Thromboplastin Time (aPTT) data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII‐deficient plasma. Sensitivity analysis applied to the model revealed that lag time, peak thrombin concentration, area under the curve (AUC) of the thrombin generation profile, and aPTT show different sensitivity to changes in coagulation factors’ concentrations and type of plasma used (normal or factor VIII‐deficient). We also used the model to explore how variability in concentrations of the proteins in coagulation network can impact the response to FVIIa treatment.

Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease

A model‐based, longitudinal meta‐analysis of the efficacy on morning trough forced expiratory volume in 1 second (FEV1) in chronic obstructive pulmonary disease (COPD) is presented. Literature data from 142 randomized maintenance trials were included, comprising 106,422 patients who received 19 compounds. 1982 morning trough FEV1 observations were available, each representing the mean FEV1 for a study arm at a specific timepoint. The final model for absolute FEV1 included baseline, disease progression, placebo effect, and drug effect estimates for all compounds, with interstudy variability on all model components and additional interarm variability on baseline. A dose–response relationship was identifiable for 10 of the 19 compounds. Drug–drug interactions among direct bronchodilators and the effect of concomitant background COPD treatment were included. Covariates were identified on baseline. Disease progression was proportional to the baseline FEV1, and a mean baseline of <1.2 L resulted in a lower efficacy, in particular for antiinflammatory treatments.