Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi

Abstract

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations.

Population pharmacokinetic modeling of plasma Δ9‐tetrahydrocannabinol and an active and inactive metabolite following controlled smoked cannabis administration

“…ability to safely operate a vehicle). Such modeling tools are in common use by the Food and Drug Administration, European Medicines Agency, the pharmaceutical industry, and by clinicians when studying therapeutic drugs …”

“…Such modeling tools are in common use by the Food and Drug Administration, European Medicines Agency, the pharmaceutical industry, and by clinicians when studying therapeutic drugs. 13 While the current analysis only involved 6 subjects, it provides a potentially useful model of THC and 2 of its major metabolites as well as the expected range of parameter estimates that might occur in a group of healthy male cannabis users. Further studies that would expand on the types of subjects, THC doses, steadystate (i.e.…”

“…Also, the first metabolite, 11‐hydroxy‐THC, is equipotent to THC and should be included in any analysis. As with proprietary drug development, population pharmacokinetic modeling of dense Phase I data is the first step . Such a structural population pharmacokinetic model of THC and its metabolites would not only describe the relationships among their variable concentration histories, it would establish the basis for exploring interindividual variability in THC pharmacokinetics and pharmacodynamics, testing for pharmacokinetic variability between low‐ and high‐potency cannabis products, and for interpreting sparse data from phase 3‐like observational cannabis studies .…”

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

“…In human medicine and during development of a new chemical entity, phase III PK studies typically involve a large number of subjects and oftentimes (Rubino, Bhavnani, Moeck, Bellibas, & Ambrose, 2015), but not always (Desai et al, 2016), contain patient data derived from a sparse sampling schedule. In veterinary medicine, similarly large studies are uncommon often due to economic and practical constraints.…”

Isavuconazole for the treatment of invasive aspergillosis and mucormycosis: current evidence, safety, efficacy, and clinical recommendations

“…Evaluation of PK parameters from phase I and phase III studies from SECURE trial concluded that adequate ISZ levels were achieved in serum and the long elimination half-life of ISZ (terminal phase half-life of 25–31 h) supported once- or twice-daily dosing for clinical trials 66. Dose adjustments are, therefore, not required when switching between oral and intravenous formulations, and absorption is not dependent on food or drugs that increase the gastric pH 67,68. Concentration-dependent efficacy was tested in a rabbit model of IPA.…”