Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.

BACKGROUND AND OBJECTIVES: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models. METHODS: Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response. RESULTS: Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients. CONCLUSIONS: These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. TRIAL REGISTRY: ClinicalTrials.gov NCT00854152 and NCT00854126.

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor).

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size-time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.

Cryo-EM reveals an unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors.

The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available NaV channel-blocking drugs are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9. Moreover, the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the NaV1.7 channel, we pursued high-resolution ligand-bound NaV1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the NaV1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. This work also underscores an important role of the membrane bilayer in the optimization of selective NaV channel modulators targeting VSD4.

Income Pooling in Midlife: A Comparison of Remarried and Cohabiting Relationships.

OBJECTIVES: The share of adults cohabiting at later ages has risen in the past few decades, though little is known about income pooling among midlife cohabitors. Cohabitation could be an attractive option because partners may be able to preserve their economic autonomy and maintain assets for the next generation. Conversely, cohabitation may operate as an alternative to marriage, allowing midlife adults to combine their resources to achieve economies of scale without the legal obligations of marriage. This study compared income pooling among middle-aged remarried and cohabiting adults in the United States. METHODS: Data were from the nationally representative 2013 Families and Relationships Survey. The analytic sample included adults aged 50-65 who were cohabiting or remarried (N = 888). Logistic regression models were used to predict the likelihood of income pooling among cohabiting and remarried midlife adults, net of relationship, demographic, and economic characteristics. RESULTS: Aligning with the hypothesis that cohabitation and remarriage are distinct in middle age, the odds of income pooling were lower for cohabitors than remarrieds. However, the gap between cohabitors and remarrieds narrowed by later ages. DISCUSSION: This study provides insight into the economic organization of midlife cohabiting relationships, which may have implications for individual well-being and relationship decision-making among middle-aged couples.

A Cohort Comparison of Midlife Marital Quality: A Quarter Century of Change.

Marital quality has been declining among recent cohorts, but whether this pattern characterizes middle-aged and older married adults is largely unknown. The doubling of the divorce rate among persons over the age of 50 years foretells poorer quality marriages for today's midlife adults than a generation ago. Combining data on married individuals aged 50-65 years from the 1987-88 National Survey of Families and Households (NSFH) and the 2013 Families and Relationships Study, we conduct a cohort comparison of five dimensions of midlife marital quality. Today's older adults report more marital disagreement and instability as well as less fairness and interaction with their spouses than their counterparts did a generation ago. The two cohorts report comparable levels of marital happiness. Consistent with the upward trend in divorce during the second half of life, the quality of midlife marriages appears to have declined over the past quarter century.

Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib.

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (area under the concentration-time curve from time 0 to infinity and Cmax) following oral administration were within twofold of observed values for dogs and monkeys, and close to twofold for rats, providing validation to the model structure. Adaptation of this oral PBPK model to humans, using human physiologic parameters coupled with predicted human PK, resulted in underpredictions of vismodegib exposure following both single and multiple doses. When observed human PK was used to drive the oral PBPK model, oral PK profiles in humans were well predicted, with fold errors in predicted versus observed drug exposures being close to 1. Importantly, the oral PBPK model captured the unique nonlinear, nondose-dependent PK of vismodegib at a steady state. The mechanism responsible for nonlinearity was consistent with oral absorption being influenced by nonsink permeation conditions. We introduce a new parameter, the permeation gradient factor, to characterize the effect of nonsink conditions on permeation. Using vismodegib as an example, we demonstrate the value of using oral PBPK models in drug discovery to predict the oral PK of compounds with nonlinear absorption characteristics in human. SIGNIFICANCE STATEMENT: A physiologically based pharmacokinetic (PBPK) model was built to demonstrate the value of these models early in the drug discovery stage for the prediction of human pharmacokinetics for compounds with unusual oral pharmacokinetics. In this study, our PBPK model could successfully capture the unique steady-state oral pharmacokinetics of our model compound, vismodegib. The mechanism for nonlinearity can be attributed to nonsink permeation conditions in vivo. We introduce the permeation gradient factor as a parameter to assess this effect.

Opportunities and Considerations in the Application of Artificial Intelligence to Pharmacokinetic Prediction.

The improvement in the ability of the pharmaceutical industry to predict human pharmacokinetic behavior are attributable to major technological shifts from 1990 to the present day. The opportunity for the application of AI/ML based approaches in the pharmaceutical industry is driven by the abundance of data sets that exist within individual pharmaceutical and biotech companies and the availability, within these environments, of abundant computing power. This chapter seeks to describe opportunities for artificial intelligence to contribute to the assessment and evaluation of the dug metabolism and pharmacokinetic (DMPK) properties of novel compounds across the drug discovery and development continuum. Many initiatives are already underway with respect to the application of AI/ML in predicting pharmacokinetic profiles so the question is not whether AI will influence pharmacokinetic prediction but rather how to best utilize and incorporate this and how to evaluate the value added from these applications. Since our understanding of the underlying biology of the in vitro and in vivo systems with respect to ADME, one of the key challenges to AI-based methods will be the ability to adapt to data sets that change in quality over time.

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs.

Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also common but not easily assessed. Intestinal excretion (IE) and enteroenteric recirculation (EER) have not been recognized as common disposition mechanisms for metabolically stable and permeable drugs. IE and intestinal reabsorption (IR:EHR/EER), as well as RTR, are governed by dug concentration gradients, passive diffusion, active transport, and metabolism, and together they markedly impact disposition and pharmacokinetics (PK) of small molecule drugs. Disruption of IE, IR, or RTR through applications of active charcoal (AC), transporter knockout (KO), and transporter inhibitors can lead to changes in PK parameters. The impacts of intestinal and renal reabsorption on PK are under-appreciated. Although IE and EER/RTR can be an intrinsic drug property, there is no apparent strategy to optimize compounds based on this property. This review seeks to improve understanding and applications of IE, IR, and RTR mechanisms.

Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib: Understanding Complex Drug-Drug Interactions.

Fenebrutinib is a CYP3A substrate and time-dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically-based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug-drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic-absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole-fenebrutinib DDI (maximum plasma concentration (Cmax ) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model-informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies.

The Roles of Marital Dissolution and Subsequent Repartnering on Loneliness in Later Life.

OBJECTIVES: Loneliness in later life is associated with poorer health and higher risk of mortality. Our study assesses whether gray divorced adults report higher levels of loneliness than the widowed and whether social support or repartnership offset loneliness. METHOD: Using data from the 2010 and 2012 Health and Retirement Study, we estimated ordinary least squares regression models for women (n = 2,362) and men (n = 1,127) to examine differences in loneliness by dissolution pathway (i.e., divorce versus widowhood), accounting for social support and repartnership. RESULTS: Divorced men were lonelier than their widowed counterparts. Although social support reduced loneliness among men, the difference between the divorced and widowed persisted. Repartnership assuaged men's loneliness and reduced the variation between divorced and widowed men. Among women, the results did not reveal differences in loneliness for the divorced and widowed although social support and repartnership linked to less loneliness. DISCUSSION: Later-life marital dissolutions increasingly occur through divorce rather than spousal death. Some older adults go on to form new partnerships. Our findings demonstrate the importance of gerontological research widening the lens beyond widowhood to consider the ramifications of later-life divorce and repartnership for well-being.

Relationship Quality Among Older Cohabitors: A Comparison to Remarrieds.

OBJECTIVES: Later life marital patterns have undergone shifts over the past few decades, including a rapid growth of cohabiting unions. Despite the increase in older adult cohabitation, research on this population has been slow to keep up. Intimate relationships are linked to well-being and relationship quality is especially important because high-quality relationships offer a number of benefits for well-being, whereas poor-quality relationships often are detrimental. This study compares cohabiting and remarried individuals on two measures of relationship quality. METHOD: Using data from the 2010 and 2012 Health and Retirement Study, I investigate the positive and negative relationship quality of cohabitors relative to their remarried counterparts and whether the association of union type and relationship quality varies by race. RESULTS: Across both positive and negative relationship quality, I found few differences between cohabiting and remarried individuals. Black cohabitors report higher positive relationship quality than remarrieds, whereas White cohabitors and remarrieds do not differ. DISCUSSION: These findings suggest that cohabiting unions and remarriages are comparable among White older adults, but that Black cohabitors may gain more in terms of positive relationship quality than their remarried counterparts.

Divorce Attitudes among Older Adults: Two Decades of Change.

The authors used data from the 1994, 2002, and 2012 General Social Survey (N = 1,450) to examine whether support for divorce has increased among adults aged 50 and older. Consistent with the rise in the gray divorce rate, today's older adults were more accepting of divorce than their predecessors were two decades ago. Attitudinal change was modest between 1994 and 2002 but accelerated after 2002. The acceleration was primarily due to period rather than cohort change, signaling the role of broader shifts in the meaning of marriage as it has become deinstitutionalized. Older birth cohorts and individuals who were either divorced or remarried were especially likely to hold supportive attitudes toward divorce.

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule-Related Therapeutic Modalities.

The well accepted "free drug hypothesis" for small-molecule drugs assumes that only the free (unbound) drug concentration at the therapeutic target can elicit a pharmacologic effect. Unbound (free) drug concentrations in plasma are readily measurable and are often used as surrogates for the drug concentrations at the site of pharmacologic action in pharmacokinetic-pharmacodynamic analysis and clinical dose projection in drug discovery. Furthermore, for permeable compounds at pharmacokinetic steady state, the free drug concentration in tissue is likely a close approximation of that in plasma; however, several factors can create and maintain disequilibrium between the free drug concentration in plasma and tissue, leading to free drug concentration asymmetry. These factors include drug uptake and extrusion mechanisms involving the uptake and efflux drug transporters, intracellular biotransformation of prodrugs, membrane receptor-mediated uptake of antibody-drug conjugates, pH gradients, unique distribution properties (covalent binders, nanoparticles), and local drug delivery (e.g., inhalation). The impact of these factors on the free drug concentrations in tissues can be represented by K p,uu, the ratio of free drug concentration between tissue and plasma at steady state. This review focuses on situations in which free drug concentrations in tissues may differ from those in plasma (e.g., K p,uu > or <1) and discusses the limitations of the surrogate approach of using plasma-free drug concentration to predict free drug concentrations in tissue. This is an important consideration for novel therapeutic modalities since systemic exposure as a driver of pharmacologic effects may provide limited value in guiding compound optimization, selection, and advancement. Ultimately, a deeper understanding of the relationship between free drug concentrations in plasma and tissues is needed.

Depressive Symptoms Following Later-life Marital Dissolution and Subsequent Repartnering.

The doubling of the divorce rate among individuals over age 50 during the past 20 years underscores the urgency of studying the consequences of gray divorce and subsequent repartnering for adult well-being. We filled this gap by using the 1998-to-2014 Health and Retirement Study to evaluate how the levels of depressive symptoms changed following gray divorce versus widowhood. Individuals who divorced or became widowed already had experienced higher levels of depressive symptoms before dissolution relative to those who remained married. Compared with those who became widowed, those who transitioned to divorce experienced a lower elevation and a shorter time to recovery in depressive symptoms. When repartnering, both groups experienced similar magnitudes of initial reduction and subsequent rates of increase. Both the negative consequences of marital dissolution and the beneficial effects of repartnership for mental health persisted for several years, although ultimately they reverted to their predissolution levels of depressive symptoms.

Exposure-Effect Relationships in Established Rat Adjuvant-Induced and Collagen-Induced Arthritis: A Translational Pharmacokinetic-Pharmacodynamic Analysis.

The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis. A range of doses of indomethacin (a nonsteroidal anti-inflammatory drug), and three disease-modifying antirheumatic drugs (DMARDs), methotrexate, etanercept, and tofacitinib, were evaluated in AIA and CIA rats. Dexamethasone was included in this study as a positive control. The area under the ankle diameter-time profile (AUCankle) and ankle histopathology summed scores (AHSS) were used as efficacy endpoints for activity against disease symptoms (joint inflammation) and disease progression (joint damage), respectively. Translational PK-PD analysis was performed to rank order preclinical efficacy endpoints at clinically relevant concentrations. For each drug tested, inhibition of AUCankle and AHSS scores was generally comparable in both magnitude and rank order. Overall, based on both AUCankle and the AHSS inhibition, the rank ordering of preclinical activity for the DMARDs evaluated was tofacitinib > etanercept ≥ methotrexate. This ranking of preclinical efficacy was consistent with reported clinical efficacy. Of interest, indomethacin showed equal or often better efficacy than the three DMARDs evaluated on inhibiting AHSS despite having limited ability to prevent joint damage clinically in patients. The translational value of performing PK-PD analysis of arthritis models in rats is discussed.

Evaluation of the predictive performance of physiologically based pharmacokinetic models for intramuscular injections of therapeutic proteins.

Several physiologically-based pharmacokinetic (PBPK) models have been reported for intravenous (IV) and subcutaneous (SC) injections, but there has been a paucity of work for intramuscular (IM) injections. The primary objective of this work was a wide-scale evaluation of the predictive performance of IM PBPK models of therapeutic proteins. PBPK models for all administration routes available in the literature have regarded muscle as the total muscle (TM) in the body; however, anatomically, the body is composed of discrete muscle groups. Clinically, IM is administered to a specific muscle (SM). We explored the predictive performance of IM PBPK models with an SM or TM dosing site. The plasma concentration-time profiles of seven therapeutic proteins after an IM dose in humans served as the clinically observed data for model evaluation - this was a diverse group ranging from 30 to 149 kDa from six protein classes. Pharmacokinetic parameters Cmax, tmax, AUC0-∞, and ka were estimated. SM and TM IM PBPK approaches were compared using Average Fold Error (AFE) and Pearson Chi-Square LineShape analyses. This work represents the first wide-scale validation of IM PBPK models and suggests that these models predict IM PBPK reasonably well. The SM and TM approach provided comparable performance.

Repartnering Following Gray Divorce: The Roles of Resources and Constraints for Women and Men.

The doubling of the gray divorce rate (i.e., divorce at age 50 or older) over the past few decades portends growth in later-life repartnering, yet little is known about the mechanisms undergirding decisions to repartner after gray divorce. Using data from the 1998-2014 Health and Retirement Study, we examined women's and men's likelihoods of forming a remarriage or cohabiting union following gray divorce by estimating competing risk multinomial logistic regression models using discrete-time event history data. About 22 % of women and 37 % of men repartnered within 10 years after gray divorce. Repartnering more often occurred through cohabitation than remarriage, particularly for men. Resources such as economic factors, health, and social ties were linked to repartnering, but constraints captured by the contours of the marital biography were also salient, underscoring the distinctive features of union formation in later life.

Antecedents of Gray Divorce: A Life Course Perspective.

Objectives: Increasingly, older adults are experiencing divorce, yet little is known about the risk factors associated with divorce after age 50 (termed "gray divorce"). Guided by a life course perspective, our study examined whether key later life turning points are related to gray divorce. Method: We used data from the 1998-2012 Health and Retirement Study to conduct a prospective, couple-level discrete-time event history analysis of the antecedents of gray divorce. Our models incorporated key turning points (empty nest, retirement, and poor health) as well as demographic characteristics and economic resources. Results: Contrary to our expectations, the onset of an empty nest, the wife's or husband's retirement, and the wife's or husband's chronic conditions were unrelated to the likelihood of gray divorce. Rather, factors traditionally associated with divorce among younger adults were also salient for older adults. Marital duration, marital quality, home ownership, and wealth were negatively related to the risk of gray divorce. Discussion: Gray divorce is especially likely to occur among couples who are socially and economically disadvantaged, raising new questions about the consequences of gray divorce for individual health and well-being.

Later Life Marital Dissolution and Repartnership Status: A National Portrait.

Objectives: Our study compares two types of later life marital dissolution that occur after age 50-divorce and widowhood-and their associations with repartnership status (i.e., remarried, cohabiting, or unpartnered). Method: We used data from the Health and Retirement Study to provide a portrait of later life divorce and widowhood for women and men. Next, we tested whether marital dissolution type is related to women's and men's repartnered status, distinguishing among remarrieds, cohabitors, and unpartnereds, net of key sociodemographic indicators. Results: Divorcees are more often repartnered through either remarriage or cohabitation than are widoweds. This gap persists among women net of an array of sociodemographic factors. For men, the differential is reduced to nonsignificance with the inclusion of these factors. Discussion: Later life marital dissolution increasingly occurs through divorce rather than widowhood, and divorce is more often followed by repartnership. The results from this study suggest that gerontological research should not solely focus on widowhood but also should pay attention to divorce and repartnering during later life.