Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized.

On the genes, genealogies, and geographies of Quebec.

Population genetic models only provide coarse representations of real-world ancestry. We used a pedigree compiled from 4 million parish records and genotype data from 2276 French and 20,451 French Canadian individuals to finely model and trace French Canadian ancestry through space and time. The loss of ancestral French population structure and the appearance of spatial and regional structure highlights a wide range of population expansion models.

Deciphering the genetic structure of the Quebec founder population using genealogies.

Using genealogy to study the demographic history of a population makes it possible to overcome the models and assumptions often used in population genetics. The Quebec founder population is one of the few populations in the world having access to the complete genealogy of the last 400 years. The goal of this study is to follow the evolution of the Quebec population structure over time from the beginning of European colonization until the present day.

GENLIB: new function to simulate haplotype transmission in large complex genealogies.

Summary: Founder populations with deep genealogical data are well suited for investigating genetic variants contributing to diseases. Here, we present a major update of the genealogical analysis R package GENLIB, centered around a new function which can simulate the transmission of haplotypes from founders to probands along very large and complex user-specified genealogies.

Availability And Implementation: The latest update of the GENLIB package (v1.

The effective family size of immigrant founders predicts their long-term demographic outcome: From Québec settlers to their 20th-century descendants.

Population history reconstruction, using extant genetic diversity data, routinely relies on simple demographic models to project the past through ascending genealogical-tree branches. Because genealogy and genetics are intimately related, we traced descending genealogies of the Québec founders to pursue their fate and to assess their contribution to the present-day population. Focusing on the female and male founder lines, we observed important sex-biased immigration in the early colony years and documented a remarkable impact of these early immigrants on the genetic make-up of 20th-century Québec.

Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma.

Purpose: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM.

Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody-drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors.

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC) ± nivolumab, in patients with selected tumors.

Patients And Methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.

Model-Based Determination of Elotuzumab Pharmacokinetics in Japanese Patients With Multiple Myeloma Incorporating Time-Varying M Protein.

A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time-varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2-compartment model with parallel linear (nonspecific) and Michaelis-Menten elimination from the central compartment and target-mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target-mediated elimination rate (V ) were statistically significant but not considered clinically relevant (magnitude < 20%).

Historical human remains identification through maternal and paternal genetic signatures in a founder population with extensive genealogical record.

Objectives: We describe a method to identify human remains excavated from unmarked graves in historical Québec cemeteries by combining parental-lineage genetic markers with the whole-population genealogy of Québec contained in the BALSAC database.

Materials And Methods: The remains of six men were exhumed from four historical cemeteries in the province of Québec, Canada. DNA was extracted from the remains and genotyped to reveal their mitochondrial and Y-chromosome haplotypes, which were compared to a collection of haplotypes of genealogically-anchored modern volunteers.

Population Pharmacokinetics of Ipilimumab in Combination With Nivolumab in Patients With Advanced Solid Tumors.

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and for the treatment of melanoma, renal cell carcinoma, and colorectal cancer in combination with nivolumab. Ipilimumab time-varying clearance (CL) was assessed by a population pharmacokinetics (PPK) model developed using statistically significant covariates identified in a previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.

Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies.

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies.

Relaxed Selection During a Recent Human Expansion.

Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement.

Antibody-Drug Conjugates as Cancer Therapeutics: Past, Present, and Future.

Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development.

QSP Toolbox: Computational Implementation of Integrated Workflow Components for Deploying Multi-Scale Mechanistic Models.

Quantitative systems pharmacology (QSP) modeling has become increasingly important in pharmaceutical research and development, and is a powerful tool to gain mechanistic insights into the complex dynamics of biological systems in response to drug treatment. However, even once a suitable mathematical framework to describe the pathophysiology and mechanisms of interest is established, final model calibration and the exploration of variability can be challenging and time consuming. QSP models are often formulated as multi-scale, multi-compartment nonlinear systems of ordinary differential equations.

Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology.

Socio-economic status and fertility decline: Insights from historical transitions in Europe and North America.

The timings of historical fertility transitions in different regions are well understood by demographers, but much less is known regarding their specific features and causes. In the study reported in this paper, we used longitudinal micro-level data for five local populations in Europe and North America to analyse the relationship between socio-economic status and fertility during the fertility transition. Using comparable analytical models and class schemes for each population, we examined the changing socio-economic differences in marital fertility and related these to common theories on fertility behaviour.

Antibody-drug conjugate bioanalysis using LB-LC-MS/MS hybrid assays: strategies, methodology and correlation to ligand-binding assays.

Background: Antibody-drug conjugates (ADCs) are complex drug constructs with multiple species in the heterogeneous mixture that contribute to their efficacy and toxicity. The bioanalysis of ADCs involves multiple assays and analytical platforms.

Methods: A series of ligand binding and LC-MS/MS (LB-LC-MS/MS) hybrid assays, through different combinations of anti-idiotype (anti-Id), anti-payload, or generic capture reagents, and cathepsin-B or trypsin enzyme digestion, were developed and evaluated for the analysis of conjugated-payload as well as for species traditionally measured by ligand-binding assays, total-antibody and conjugated-antibody.

An integrated multiplatform bioanalytical strategy for antibody-drug conjugates: a novel case study.

Background: The bioanalytical strategy for antibody-drug conjugates (ADC) includes numerous measurements integrally designed to provide comprehensive characterization of PK, PD and immunogenicity. This manuscript describes the utilization of reagents specifically tailored to an ADC with a microtubule polymerization inhibitor payload and cathepsin B cleavable linker.

Methods: The PK strategy includes the evaluation of physiological levels of total antibody, active ADC, total ADC, antibody-conjugated payload and unconjugated payload.

GENLIB: an R package for the analysis of genealogical data.

Background: Founder populations have an important role in the study of genetic diseases. Access to detailed genealogical records is often one of their advantages. These genealogical data provide unique information for researchers in evolutionary and population genetics, demography and genetic epidemiology.

Adjuvant therapies for HIV-associated neurocognitive disorders.

Objective: HIV-associated neurocognitive disorder (HAND) is a frequent and heterogeneous complication of HIV, affecting nearly 50% of infected individuals in the combined antiretroviral therapy (cART) era. This is a particularly devastating statistic because the diagnosis of HAND confers an increased risk of HIV-associated morbidity and mortality in affected patients. While cART is helpful in the treatment of the more severe forms of HAND, there is a therapeutic gap in the milder forms of HAND, where cART is less effective.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Objectives: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability.

Design: Prospective observational cohort study.

Setting: Level 3 neonatal ICU.

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients.

Aim: Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability.

Method: Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection.