Clinical Pharmacokinetics. The posaconazole oral tablet - not the marketed delayed-release tablet, but a premarketing formulation used before the oral suspension - showed dose-linearity in exposure up to a single dose of 800 mg, with saturation of absorption occurring above 800 mg in healthy volunteers [24]. Using simulation-based approaches it has been proposed that the non-linear absorption might be attributable to the extensive precipitation of posaconazole in the small intestine due to the incomplete gastric dissolution in the pH shift from stomach to the intestine, caused by its high lipophilicity and weakly basic property [25, 26]. Hence, development of this oral tablet was not pursued and an oral suspension was brought to the market. Unfortunately, this suspension also demonstrated high inter-individual variability as typically patients that received the suspension did demonstrate dose-limited absorption above a daily dose of 800 mg with a highly variable and erratic absorption [27]. A gastric-resistant tablet formulation was subsequently designed for releasing posaconazole in the small intestine, in order to avoid the erratic absorption caused by the gastric conditions and to improve the systemic absorption. The systemic exposure after administration of this delayed-release tablet showed dose-linearity between 200 mg to 400 mg, while higher doses were not explored [28]. Finally, an intravenous formulation was designed for patients who do not tolerate oral medication. Dose-linearity was observed between doses of 200 mg and 300 mg whereas non-linearities were observed below 200 mg [29, 30]. Intravenous doses above 300 mg were not investigated. The exposure of these two new formulations still shows substantial interpatient variability [31-34]. The published population pharmacokinetic findings on posaconazole are discussed below and are summarized in Table 1. Model-independent findings on the clinical pharmacokinetics of posaconazole in healthy volunteers and patients are also discussed and are summarized in Table 2 and Table 3, respectively. Posaconazole PKPD Table 1 Summary of population pharmacokinetic parameter values for posaconazole. Authors XxxXxxxx et al [38]. Xxxx et al.[35] Xxxxxxxxxx et al.[36] Xxxxxxxxxxx et al.[37] Dolton et al.[39] Xxxxxxxxxxx et al.[40] Iersel et al.[41] Xxxxxxxxxxx et al.[52] Xxxx et al.[30] Year 2010 2010 2012 2012 2014 2017 2018 2019 NA Formulations Sus Sus Sus Sus Sus DR-taba DR-xxxx Sus and DR-taba Inj Populations AML/MDS allogeneic HSCT SICU...
