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.     

Post-thrombolytic coagulopathy and complications in patients with pulmonary embolism treated with fixed-dose systemic alteplase

Journal of Thrombosis and Thrombolysis - Alteplase treatment can cause a systemic coagulopathy although the incidence and contributory factors are unknown in pulmonary embolism (PE). Fixed-dosing...     

How can hospitals change practice to better implement smoking cessation interventions? A systematic review

Smoking cessation reduces the risk of death, improves recovery, and reduces the risk of hospital readmission. Evidence and policy support hospital admission as an ideal time to deliver smoking-cessation interventions. However, this is not well implemented in practice. In this systematic review, the authors summarize the literature on smoking-cessation implementation strategies and evaluate their success to guide the implementation of best-practice smoking interventions into hospital settings. The CINAHL Complete, Embase, MEDLINE Complete, and PsycInfo databases were searched using terms associated with the following topics: smoking cessation, hospitals, and implementation. In total, 14,287 original records were identified and screened, resulting in 63 eligible articles from 56 studies. Data were extracted on the study characteristics, implementation strategies, and implementation outcomes. Implementation outcomes were guided by Proctor and colleagues' framework and included acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, and sustainability. The findings demonstrate that studies predominantly focused on the training of staff to achieve implementation. Brief implementation approaches using a small number of implementation strategies were less successful and poorly sustained compared with well resourced and multicomponent approaches. Although brief implementation approaches may be viewed as advantageous because they are less resource-intensive, their capacity to change practice in a sustained way lacks evidence. Attempts to change clinician behavior or introduce new models of care are challenging in a short time frame, and implementation efforts should be designed for long-term success. There is a need to embrace strategic, well planned implementation approaches to embed smoking-cessation interventions into hospitals and to reap and sustain the benefits for people who smoke.     

Initial assessment of α-synuclein structure in platelets

Journal of Thrombosis and Thrombolysis - Over the last few years data from our group have indicated that α-synuclein is important in development of immune cells as well as potentially...     

Rupture Resolution Rating System (3RS): Development and validation

Objective: Our aim was to examine the reliability and validity of the Rupture Resolution Rating System (3RS), an observer-based measure of alliance ruptures and resolution processes. Method: We used the 3RS to rate early sessions from 42 cases of cognitive behavior therapy. We compared the 3RS to a simplified version of the Structural Analysis of Social Behavior (SASB), as well as patient and therapist self-reports of ruptures and the alliance. Results: Coders achieved high rates of interrater reliability on the frequency of confrontation and withdrawal ruptures and resolution strategies (ICCs?=?.85 to .98), as well as ratings of the therapist’s contribution to ruptures and the extent to which ruptures were resolved (ICC?=?.92). Predictive validity analyses found that confrontation markers (d?=?.74), successful resolution (d?=?.67), and ratings of the therapist’s contribution to ruptures (d?=?.61) predicted dropout from therapy. Analyses of convergent validity with the SASB failed to meet predictions; however, we observed theoretically coherent relations between 3RS and SASB variables. Confrontation rupture markers were significantly associated with patient self-report of rupture (d?=?1.54) and therapist self-reported alliance (r?=??.50, p?=?.002). Conclusions: This study provides evidence that the 3RS is a reliable and useful tool for examining psychotherapy process and predicting dropout.

Clinical or methodological significance of this article: This study provides evidence of the reliability and validity of the 3RS, an observer-based measure of alliance ruptures and resolution processes. The 3RS can be used to identify problems in the therapeutic relationship that are associated with premature dropout from therapy.