Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to "full" simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more efficient and informative and the awareness that many industries make extensive use of simulation in product development have advanced considerably the use of simulation of clinical trials in pharmaceutical product development over the past decade. The structural and stochastic components of trial simulation models are explained as a prelude to a listing of representative simulation projects, reflecting investigative applications of statistical methods, trial design comparisons, and full simulation of new drugs being developed. Lessons learned from these projects are reviewed in the context of their current impact and potential for influencing the future of drug development.

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region. Another case from a different region is described. The cases were identified from the Hunter Area Toxicology Service Database and regional psychiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurred in the absence of prior exposure. No reversible electrocardiographic changes or biochemical abnormalities were demonstrated. Anticholinergic effects were minimal. All seven cases made full recovery. A high-pressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approximate retention times were norclozapine, 3.8 minutes; clozapine, 5 minutes; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite. Using the HPLC assay, serial clozapine and norclozapine plasma concentrations were measured in three of these cases of clozapine self-poisoning. Toxicokinetic modeling was conducted by simultaneous analysis of clozapine and norclozapine observations. A two-compartment model with a metabolite compartment attached to the central compartment was used. Clozapine metabolism to norclozapine was best described by linear elimination of norclozapine and nonlinear norclozapine formation. The Km (1918 +/- 2093 micrograms/l) relative to observed concentration (3396 +/- 962 micrograms/l) suggests that norclozapine formation was saturated at the time of the first observation.

Introduction Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen. Methods Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 μg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 μg/mL, the concentration above which C5 is completely inhibited. Results Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 μg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 μg/mL and free C5 concentrations remained < 0.5 μg/mL. Conclusion High levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study. Trial Registration ClinicalTrials.gov identifier, NCT04369469

Problem:We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals. Method ofStudy: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19. Participants enrolled at our center from August 2020 to February 2021. Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement. Eculizumab was administered on day 1 (1200 mg IV) with additional doses if still hospitalized (1200 mg IV on Days 4 and 8; 900 mg IV on Days 15 and 22; optional doses on Days 12 and 18). The primary outcome was survival at Day 15. Secondary outcomes included survival at Day 29, need for mechanical ventilation, and duration of hospital stay. We evaluated pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes. Results: Eight participants were enrolled at the Cedars-Sinai Medical Center, six during pregnancy (mean 30 ± 4.0 weeks) and two in the postpartum period. Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask. The median number of doses of eculizumab was 2 (range 1-3); the median This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.