Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single‐dose cohorts, as many as necessary to obtain the dose‐response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose‐response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive‐cohort data for OZ439 (mixing the data of the three single‐dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three‐compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug‐induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single‐cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single‐cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Volunteer infection studies are routinely used in antimalarial drug development to generate early pharmacokinetic/pharmacodynamic data for compounds.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Can in silico analyses be used to suggest improvements to volunteer infection study designs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Multiple dose adaptive trial designs can potentially reduce the number of cohorts needed to establish the dose‐response relationship in volunteer infection studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Real time data analyses can be used to recommend doses for adaptive volunteer infection studies.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been recognized as a valuable system for defining the key pharmacokinetic (PK) and pharmacodynamic (PD) relationships for dose selection in antimalarial drug development. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ In such studies, healthy volunteers are inoculated intravenously with a given quantity (with small variability) of Plasmodium‐infected red cells. Parasitemia is then followed by quantitative polymerase chain reaction until a prespecified treatment threshold is reached when the test drug is administered. Parasite and drug concentrations are then measured. These studies are conducted prior to phase II dose‐response (D‐R) trials and can be included in an integrated first‐in‐human study protocol, or after completion of the first‐in‐human PK and safety study. IBSM studies have been typically designed as flexible multiple cohort studies where each volunteer of one cohort receives a single dose of the same amount of drug (“single dose per cohort”). ² , ³ , ⁴ , ⁵ After each cohort, a decision is made to stop or to add a cohort to test a lower or higher dose based on the response observed in the previous cohorts.For the multiple single‐dose‐per‐cohort design, the starting dose is typically selected based on safety and PK information from a phase I single ascending dose (SAD) study and, more recently, on preclinical data from a severe combined immunodeficient mouse model, with the dose selected on the basis of being best able to inform the D‐R relationship, rather than aiming for cure. This approach, where a single dose is tested in all subjects of the initial cohort, risks missing the dose likely to be most informative for defining the PK/PD relationship.An alternative approach is to spread a range of doses across a smaller number of subjects within the initial cohort and use PK/PD models developed based on data from this cohort to support dose selections of subsequent cohorts and studies. Using data from a previous study, ² we undertook an in silico investigation of such an adaptive study design, aiming to reduce the number of subjects exposed to inefficacious doses, and to establish a D‐R relationship. This multiple‐dose‐groups‐per‐cohort design, referred to as the “2‐2‐4” design, is contrasted with the already implemented study design depicted in Figure  1 .Open in a separate windowFigure 1Comparison of standard and adaptive designs of IBSM studies. A/B/C, dose levels to be selected during the progress of the study based on pharmacokinetic/pharmacodynamic results of the initial cohort; CHMI, controlled human malaria infection; D‐R, dose‐response; IBSM, induced blood stage malaria infection; n, number of subjects at each dose.The objectives of this retrospective analysis were to: (i) compare PK/PD parameter estimates from the initial cohort of the 2‐2‐4 study design with the prior results from the data of the full study and (ii) propose a preliminary workflow to establish D‐R early in an IBSM study, and use modeling and simulation (M&S) to support dose selections for subsequent cohorts and later phase clinical trials.     

Real-World Palbociclib Use in HR+/HER2− Advanced Breast Cancer in Canada: The IRIS Study

Background: Palbociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). Palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2− ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study ({"type":"clinical-trial","attrs":{"text":"NCT03159195","term_id":"NCT03159195"}}NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. Methods: This retrospective chart review included women with HR+/HER2− ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan–Meier analysis. Results: Thirty-three physicians examined medical records for 247 patients (P+L, n = 214; P+F, n = 33). Median follow-up was 8.8 months for P+L and 7.0 months for P+F. Most patients were initiated on palbociclib 125 mg/d (P+L, 90.2%; P+F, 84.8%). Doses were reduced in 16.6% of P+L and 14.3% of P+F patients initiating palbociclib at 125 mg/d. The PFR for P+L was 90.3% at 12 months and 78.2% at 18 months; corresponding SRs were 95.6% and 93.0%. For P+F, 6-month PFR was 91.0%; 12-month SR was 100.0%. Conclusions: Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.     

A Review of Machine Learning Techniques for Keratoconus Detection and Refractive Surgery Screening

ABSTRACT

Various machine learning techniques have been developed for keratoconus detection and refractive surgery screening. These techniques utilize inputs from a range of corneal imaging devices and are built with automated decision trees, support vector machines, and various types of neural networks. In general, these techniques demonstrate very good differentiation of normal and keratoconic eyes, as well as good differentiation of normal and form fruste keratoconus. However, it is difficult to directly compare these studies, as keratoconus represents a wide spectrum of disease. More importantly, no public dataset exists for research purposes. Despite these challenges, machine learning in keratoconus detection and refractive surgery screening is a burgeoning field of study, with significant potential for continued advancement as imaging devices and techniques become more sophisticated.     

Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.     

Challenges for Research into Military Investigations

In cases of suspected violations of rules, regulations or the law by armed forces personnel, investigations are invariably mandatory. Military investigations differ from well-researched civilian criminal investigations. Differing from civilian police detectives, most military investigators – as disciplinary supervisors and military police personnel – have a number of tasks to accomplish, which include leading in combat and ensuring military readiness. Military investigations can lead to substantive negative or positive consequences for military readiness, including mental health, unit cohesion and subjective legal certainty. This impact on unit cohesion and mental health is influenced by any prior history of distress or trauma; military investigations are often preceded by contravention of internal disciplinary acts, complaints and traumatic events. This study explores factors in the differing military and legal systems of Germany and the United Kingdom (UK) that might help military personnel to successfully conduct investigations while ensuring deployment readiness and maintaining human rights.     

Sperm fishing: antigen-antibody complexes for the capture and enrichment of spermatozoa in mixed cell substrates

ABSTRACT

In many sexual assault cases, the most common evidence gathered comes in the form of intimate swabs. These swabs contain cells from both the female and male. In these cases the most common cell present is epithelial cells from the female with relatively few spermatozoa from the male. To produce an STR DNA profile suitable for an investigation, separation of the cell types is required to prevent a mixed profile that may complicate interpretation. While there are methods that can achieve this separation, they are labour intensive and have no guarantee of complete separation of the spermatozoa. Immunomagnetic bead separation techniques are being adapted from other scientific fields to be used in forensic biology to separate spermatozoa from mixed substrates. This study tested the binding of a Hyaluronidase PH-20 (SPAM1) antibody to spermatozoa in mixed cell samples that have been dried and stored for a short period of time. Fluorescently tagged antibodies were incubated with cellular mixtures and visualized using fluorescent microscopy. Successful binding of the antibodies to spermatozoa was observed in all samples. The SPAM1 antibody appears to be suitable for selection of spermatozoa and creates opportunities for linking with magnetic beads facilitate cell separation and DNA profiling.