The dose of posaconazole needs to be adjusted higher when patients are heavier, researchers in the Netherlands report. Posaconazole is a broad-spectrum antifungal drug used for prophylaxis and treatment of invasive mold infections. For prophylaxis, steady-state average concentrations should exceed 0.5 mg/L, but remain below 3.75 mg/L. Guidelines for treatment of Aspergillus disease recommend target trough concentrations of 1.0 mg/L. Patients weighing more than 90 kg have been shown to have significantly lower trough concentrations of posaconazole, compared with patients weighing more. Dr. Roeland E. Wasmann of Radboud University Medical Center, in Nijmegen, and colleagues investigated the pharmacokinetics of posaconazole in 16 morbidly obese and eight normal-weight subjects after intravenous doses of 300 or 400 mg and used population pharmacokinetic modeling to assess the effect of body size on posaconazole pharmacokinetics. Total body weight best predicted pharmacokinetic variability, outperforming lean body weight, body surface area, and ideal body weight, the researchers report in the Journal of Antimicrobial Chemotherapy. Model-based simulations of pharmacokinetic curves found significantly lower exposure and peak and trough plasma concentrations of posaconazole with increasing body weight. Probability of target concentration attainment (PTA) based on these models found that the 300 mg dose administered as an IV formulation is sufficient up to 140 kg in a treatment setting; a 400 mg dose will result in >90% PTA above that weight, but a further increase to 500 mg should be considered in patients weighing more than 190 kg. For prophylaxis, the standard 300 mg IV dose results in >90% PTA in patients weighing up to 190 kg while keeping the average concentration below the 3.75 mg/L toxicity threshold. These recommendations can act as a starting point for patients using posaconazole, but they do not eliminate the need for therapeutic drug monitoring, according to the authors. Dr. Wasmann did not respond to a request for comments. Merck Sharp and Dohme Corporation, which sells posaconazole as Noxafil, sponsored the study. Two of the authors report financial ties to the company. —Reuters Staff Source
