A quantitative systems pharmacology model of colonic motility with applications in drug development.

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.

Asia-Inclusive Clinical Research and Development Enabled by Translational Science and Quantitative Clinical Pharmacology: Toward a Culture That Challenges the Status Quo.

Access lag to innovative therapies in Asian populations continues to present a challenge to global health. Recent progressive changes in the global regulatory landscape, including newer guidelines, are enabling simultaneous global drug development and near-simultaneous global drug registration. The International Conference on Harmonization (ICH) E17 guideline outlines general principles for the design and analysis of multiregional clinical trials (MRCTs). We posit that translational research and quantitative clinical pharmacology tools are core enablers for Asia-inclusive global drug development aligned with ICH E17 principles. Assessment of ethnic sensitivity should be initiated early in the development lifecycle to inform the need for, and extent of, Asian phase I ethno-bridging data. Relevant ethno-bridging data may be generated as standalone Asian phase I trials, as part of Western First-In-Human trials, or under accelerated development settings as a lead-in phase in an MRCT. Quantitative understanding of human clearance mechanisms and pharmacogenetic factors is vital to forecasting ethnic sensitivity in drug exposure using physiologically-based pharmacokinetic models. Stratification factors to control heterogeneity in MRCTs can be identified by reverse translational research incorporating pharmacometric disease models and model-based meta-analyses. Because epidemiological variations can extend to the molecular level, quantitative systems pharmacology models may be useful in forecasting how molecular variation in therapeutic targets or pathway proteins across populations might impact treatment outcomes. Through prospective evaluation of conservation in drug- and disease-related intrinsic and extrinsic factors, a pooled East Asian region can be implemented in Asia-inclusive MRCTs to maximize efficiency in substantiating evidence of benefit-risk for the region at-large with a Totality of Evidence approach.

Applications of Quantitative System Pharmacology Modeling to Model-Informed Drug Development.

Significant advances in analytical technologies have dramatically improved our ability to deconvolute disease biology at molecular, cellular, and tissue levels. Quantitative system pharmacology (QSP) modeling is a computational framework to systematically integrate pharmaceutical properties of a drug candidate with scientific understanding of that deeper disease etiology, target expression, genetic variability, and human physiological processes, thus enabling more insightful drug development decisions related to efficacy and safety. In this chapter, we discuss the key attributes of QSP models in comparison to traditional models. We discuss a recommended four-step process to construct a QSP model to support drug development decisions. A number of illustrative QSP examples related to high-value drug development questions and decisions impacting target identification, lead generation and optimization, first in human studies, and clinical dose and schedule optimization are covered in the chapter. The future perspectives of QSP in the context of potential regulatory acceptance are also discussed.

FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges/gaps, and future perspective.

The pharmaceutical industry is actively applying quantitative systems pharmacology (QSP) to make internal decisions and guide drug development. To facilitate the eventual development of a common framework for assessing the credibility of QSP models for clinical drug development, scientists from US Food and Drug Administration and the pharmaceutical industry organized a full-day virtual Scientific Exchange on July 1, 2020. An assessment form was used to ensure consistency in the evaluation process. Among the cases presented, QSP was applied to various therapeutic areas. Applications mostly focused on phase 2 dose selection. Model transparency, including details on expert knowledge and data used for model development, was identified as a major factor for robust model assessment. The case studies demonstrated some commonalities in the workflow of QSP model development, calibration, and validation but differ in the size, scope, and complexity of QSP models, in the acceptance criteria for model calibration and validation, and in the algorithms/approaches used for creating virtual patient populations. Though efforts are being made to build the credibility of QSP models and the confidence is increasing in applying QSP for internal decisions at the clinical stages of drug development, there are still many challenges facing QSP application to late stage drug development. The QSP community needs a strategic plan that includes the ability and flexibility to Adapt, to establish Common expectations for model Credibility needed to inform drug Labeling and patient care, and to AIM to achieve the goal (ACCLAIM).

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

Protein therapeutics: new applications for pharmacogenetics.

Pharmacogenetic studies have traditionally focused on genes involved in processes that affect the pharmacokinetics of small-molecule drugs, such as drug metabolism. However, attention is shifting to the effects of genetic variations in drug targets and associated pathway components on drug responses. We describe how these variations are important for understanding differences in responses to the growing number of protein therapeutics that are entering clinical practice. Pharmacogenetic studies of these drugs are surveyed, and issues important to the success of such endeavours are discussed. As novel protein therapeutics are introduced, we anticipate that the use of pharmacogenetics will assume a key role in their development and clinical application.

Targeting RNA: A Transformative Therapeutic Strategy.

The therapeutic pathways that modulate transcription mechanisms currently include gene knockdown and splicing modulation. However, additional mechanisms may come into play as more understanding of molecular biology and disease etiology emerge. Building on advances in chemistry and delivery technology, oligonucleotide therapeutics is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. These targets include over 10,000 proteins in the human genome that have hitherto been considered undruggable by small molecules and protein therapeutics. The approval of five oligonucleotides within the last 2 years elicited unprecedented excitement in the field. However, there are remaining challenges to overcome and significant room for future innovation to fully realize the potential of oligonucleotide therapeutics. In this review, we focus on the translational strategies encompassing preclinical evaluation and clinical development in the context of approved oligonucleotide therapeutics. Translational approaches with respect to pharmacology, pharmacokinetics, cardiac safety evaluation, and dose selection that are specific to this class of drugs are reviewed with examples. The mechanism of action, chemical evolution, and intracellular delivery of oligonucleotide therapies are only briefly reviewed to provide a general background for this class of drugs.

A Semi-Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.

A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3-7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11 mL, respectively. Global sensitivity analysis demonstrated that the CSF-to-plasma drug distribution rate (0.09 hour-1 ) is a major determinant of the maximum nusinersen concentration in central nervous system (CNS) tissues. Physiological age-based and body weight-based allometric scaling was implemented with exponent values of -0.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric phase I PK profiles. The developed model can be used to guide the design of clinical trials with ASOs.

Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.

Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.

Population pharmacokinetics of recombinant factor VIII Fc fusion protein.

Population pharmacokinetics (PK) of FVIII activity-time profiles following recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor VIII (rFVIII) dosing were evaluated in previously treated patients with severe hemophilia A (from two clinical trials). Potential covariates that may be determinants of variability in FVIII activity were identified. A 2-compartment model adequately described the PK of both compounds. von Willebrand Factor (VWF) concentration was the major covariate for rFVIIIFc clearance, reflecting its protective role in FVIII activity clearance. The effect of body weight and hematocrit on the central volume of distribution of rFVIIIFc was minor. The results of these analyses confirmed that rFVIIIFc clearance (1.65 dL/h) is much lower than that of rFVIII (2.53 dL/h), while the steady state volumes of distribution were similar. The strong positive correlations between the PK parameters of rFVIIIFc and rFVIII suggest that individuals who have high time-related PK characteristics with rFVIII are likely to have comparable characteristics with rFVIIIFc. Steady-state activity-time profiles for selected rFVIIIFc dosing regimens were simulated accounting for uncertainty in model parameters. These population PK analyses and simulations provide a comprehensive characterization of the PK of rFVIIIFc and rFVIII and may be useful for designing dosing regimens.

Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis.

OBJECTIVE: Our objective was to develop a population pharmacokinetic and pharmacodynamic model of etanercept in patients with rheumatoid arthritis, with the American College of Rheumatology response criterion of 20% improvement (ACR20) used as a binary clinical outcome variable. METHODS: Concentration-time profiles from 25 subjects, administered 25 mg subcutaneous etanercept twice weekly for 24 weeks, were pooled with data from 77 subjects, enrolled in a 24-week, randomized, double-blind study comparing 25 mg and 50 mg subcutaneous etanercept twice weekly. The cumulative area under the concentration-time curve (AUC) was used as the exposure variable, and ACR20 was the binomial clinical outcome. ACR20 data from another 80 placebo-treated patients enrolled in a randomized, double-blind phase III study were used to describe the placebo time course of ACR20. A logistic regression analysis with NONMEM was applied to describe the exposure-response relationship, and the 95% confidence intervals (95% CIs) were constructed by bootstrapping 1000 times. RESULTS: The population mean apparent clearance was 0.117 L/h (95% CI, 0.108-0.130 L/h) for white female patients and 0.138 L/h (95% CI, 0.118-0.163 L/h) for white male patients. Interindividual variability and interoccasion variability were 41.1% and 27.6%, respectively. The mean absorption half-life was 20.9 hours, and the elimination half-life was 95.4 hours. An improved response profile in male patients was shown, but the multiplicative factor between slope on cumulative AUC between male and female patients was not statistically significant (1.69; 95% CI, 0.37-9.99). The model-predicted percentage of patients achieving ACR20 at 6 months after dosing of 25 mg subcutaneously twice weekly was 54.9%, comparable to the observed 52.9%. CONCLUSION: The population pharmacokinetic analysis confirmed that etanercept is slowly absorbed and eliminated after subcutaneous administration. The logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in patients with rheumatoid arthritis receiving etanercept.

Safety and systemic absorption of pulmonary delivered human IFN-beta1a in the nonhuman primate: comparison with subcutaneous dosing.

Safety and bioavailability of pulmonary delivered interferon-beta 1a (IFN-beta1a, AVONEX, Biogen, Inc., Cambridge, MA) was evaluated in the nonhuman primate. Pulmonary bioavailability following intratracheal (i.t.) instillation of 50 microg/kg IFN-beta1a to rhesus macaques was approximately 10%. To evaluate pulmonary safety, IFN-beta1a was administered intrabronchially to rhesus and cynomolgus macaques at a dose of 60 microg/dose one, three, or seven times per week for 4 weeks. At scheduled termination, lungs were evaluated for gross and histomorphologic changes. IFN-beta1a or vehicle (human serum albumin [HSA] in phosphate-buffered saline [PBS]) treatment resulted in minimal to mild subchronic alveolitis, located primarily near the instillation sites. These responses were considered nonspecific and consistent with either instillation of a foreign protein or minor injury associated with the instillation procedure. In one rhesus macaque treated every day for 4 weeks, IFN-beta1a induced mild to moderate eosinophilic alveolitis, considered possibly an isolated type I hypersensitivity response to HSA or IFN-beta1a. Partial resolution of pulmonary lesions was seen in all recovery animals killed 2 weeks after cessation of treatment. In conclusion, this study shows that pulmonary administration of human IFN-beta1a is safe and that the pulmonary route of administration is a possible alternate route for the systemic delivery of IFN-beta1a.

Interferon beta assessment in non-Chinese and Chinese subjects: pharmacokinetics and pharmacodynamic activity of an endogenous cytokine are not race dependent.

Interferon beta-1a (IFNß-1a) is a first-line therapy for relapsing multiple sclerosis when administered as 30 mcg intramuscularly (IM) once weekly. This endogenous cytokine displays pharmacokinetic (PK) attributes consistent with a glycoprotein of 20-kDa molecular weight that is administered IM. In this study, 24 healthy Chinese subjects (11 male, 13 female) each received 4 once-weekly 60-mcg IM doses of IFNß-1a. Serial blood samples were drawn for PK and pharmacodynamic (PD) assessments following the first and last dose of drug. Results were compared with historical data from a recent PK/PD assessment conducted in non-Chinese subjects. Noncompartmental analysis revealed that no meaningful differences in either IFNß-1a exposure or response were apparent between the Chinese and non-Chinese populations. Thus, it was concluded that no adjustment in dose regimen is warranted for future assessments of safety and efficacy in multiple sclerosis patients of Chinese origin.

Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function.

This phase I, open-label, single-dose study evaluated the pharmacokinetics, safety, and tolerability of renally excreted drug dexpramipexole in subjects with normal and impaired renal function, i.e. mild, moderate, severe renal impairment, or end-stage renal disease (ESRD) requiring hemodialysis when matched by age and sex. Dexpramipexole area under the curves (AUCs), but not Cmax , were significantly increased with the severity of renal impairment after a single dose administration. The geometric mean ratio of dose-normalized AUC(0-72) was 1.4, 1.7, 2.7, and 4.5, respectively, in mild, moderate, severe renal impairment, and ESRD subjects when compared to healthy subjects. There was a strong association between renal function (eGFR) and dexpramipexole CLr. The slope (90% confidence interval(CI)) of eGFR and renal clearance (CLr) in the regression model was 3.1 (2.4, 3.7). Dexpramipexole elimination in ESRD subjects during both dialysis and non-dialysis (i.e., interval between dialysis) was insignificant. Single 75 mg and 150 mg doses of dexpramipexole were well tolerated, and the safety profile was comparable across renal function groups. Extensive drug accumulation may occur with repeated dosing in patients with significant renal impairment. It is recommended that dexpramipexole not to be given to patients with severe renal impairment or in those with ESRD.

Nonclinical development of a biosimilar: the current landscape.

Preclinical studies have always been a critical component in the development program of a biopharmaceutical. With the advent of biosimilars the traditional preclinical program has changed to a new paradigm that integrates the concept of comparability with existing knowledge of the biopharmaceutical reference drug. Recently, the recommended preclinical program espoused by the European Medicines Agency has been modified to an abbreviated one that now emphasizes in vitro studies in lieu of in vivo for monoclonal antibody biosimilars. Likewise, the US FDA guidance on biosimilars suggests a flexible approach rather than the 28-day comparative toxicology studies that have historically been conducted for worldwide marketing. For now, structure and function studies will continue to be the foundation of the overall analytical assessment of biosimilarity. Traditional, comparative animal safety assessments will have limited value in determination of biosimilarity and in an abbreviated design they may have most value in providing assurance of safety in first-in-human trials when structural attributes are not indistinguishable. Unless this value can be proven, particularly as analytical technology improves in sensitivity, accuracy and precision, the need for these animal safety studies will diminish. Thus, the future lies in the ever evolving and sophisticated analytical studies that will replace the current in vivo studies for biosimilar products.