Oliver Sander

Community screening and treatment of asymptomatic carriers of Plasmodium falciparum with artemether-lumefantrine to reduce malaria disease burden: a modelling and simulation analysis

BackgroundAsymptomatic carriers of Plasmodium falciparum serve as a reservoir of parasites for malaria transmission. Identification and treatment of asymptomatic carriers within a region may reduce the parasite reservoir and influence malaria transmission in that area.MethodsUsing computer simulation, this analysis explored the impact of community screening campaigns (CSC) followed by systematic treatment of P. falciparum asymptomatic carriers (AC) with artemether-lumefantrine (AL) on disease transmission. The model created by Okell et al (originally designed to explore the impact of the introduction of treatment with artemisinin-based combination therapy on malaria endemicity) was modified to represent CSC and treatment of AC with AL, with the addition of malaria vector seasonality. The age grouping, relative distribution of age in a region, and degree of heterogeneity in disease transmission were maintained. The number and frequency of CSC and their relative timing were explored in terms of their effect on malaria incidence. A sensitivity analysis was conducted to determine the factors with the greatest impact on the model predictions.ResultsThe simulation showed that the intervention that had the largest effect was performed in an area with high endemicity (entomological inoculation rate, EIR > 200); however, the rate of infection returned to its normal level in the subsequent year, unless the intervention was repeated. In areas with low disease burden (EIR < 10), the reduction was sustained for over three years after a single intervention. Three CSC scheduled in close succession (monthly intervals) at the start of the dry season had the greatest impact on the success of the intervention.ConclusionsCommunity screening and treatment of asymptomatic carriers with AL may reduce malaria transmission significantly. The initial level of disease intensity has the greatest impact on the potential magnitude and duration of malaria reduction. When combined with other interventions (e.g. long-lasting insecticide-treated nets, rapid diagnostic tests, prompt diagnosis and treatment, and, where appropriate, indoor residual spraying) the effect of this intervention can be sustained for many years, and it could become a tool to accelerate the reduction in transmission intensity to pre-elimination levels. Repeated interventions at least every other year may help to prolong the effect. The use of an effective diagnostic tool and a highly effective ACT, such as AL, is also vital. The modelling supports the evaluation of this approach in a prospective clinical trial to reduce the pool of infective vectors for malaria transmission in an area with marked seasonality.

Randomized, Prospective, Three-Arm Study to Confirm the Auditory Safety and Efficacy of Artemether-Lumefantrine in Colombian Patients with Uncomplicated Plasmodium falciparum Malaria

The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone-proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis

Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)‐17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2‐compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150‐kDa human IgG1 antibody interacting with a soluble target.

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use

Quantitative pharmacology (QP) applications in translational medicine, drug‐development, and therapeutic use were crowd‐sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial‐burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model‐informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy.

Innovation in the Design of Clinical Trials: Necessary for Innovation in Medicine

Pondering the great advances that have occurred in the 20 and 21 centuries in medical research, each person reading this will think of a plethora of advances. Each individual will have their own list, and although there will not be unanimity, there are certain to be many advances that would be agreed upon by most. We will argue that two of those advances that should be on most lists were, if not invented, used and promoted in 1925 by an individual who did not initially apply these to medical research, but instead was applying them to the study of agriculture. R.A. Fisher’s Statistical Methods for Research Workers used both the notion of randomization of experiments and the P-value and explained and demonstrated how these concepts allowed for clearer interpretation of scientific principles when one was trying to draw conclusions from data. The P-value, although recently often criticized (see ASA statement on P-values and the plethora of reactions), allows the researcher to calibrate their raw findings to the variability inherent in all data and to the amount of information collected and then attaches it to probability as a means to make judgments. Before the P-value was widely used, scientists were often misled when they drew conclusions if too little data were collected. Further, the P-value along with the concept of power could be used so that a scientist could reasonably understand how much data should be collected in order to be able to have a reasonable chance that the data clearly shows an effect when this effect truly exists. It is clear that without this ability much of the scientific progress since 1900 could not have taken place, or at least would have been greatly slowed. The P-value has rightly been criticized, but much of the criticism is not due to the tool, instead it is due to how the tool has been used. The near universal ritualistic agreement that a P-value < 0.05 was always the cutoff of when an effect was real and when it was not, without any consideration of the conditions behind its generation, is one such problem. Even if the conditions were well understood and seemed favorable for the generation of 1 out of 20 still might not be the right amount of evidence for the situation (it could be more or less). However, for scientists not to make these mistakes the P-value must be understood. The difficulty is, of course, that many of us who use the P-value as the means of drawing conclusions do not understand it well enough to understand its pitfalls. Some have suggested that this problem would be solved if the adoption of Bayesian inference were more widespread. Although it is true that in some ways Bayesian inference is more intuitive, it still involves the use of probabilistic