Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically III Adults in a Phase IV Open-Label Multicenter Study (ACUMIN)

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii. Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC) of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f(ub)) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f(ub)). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK PD profiling studies of this nature, these findings need clinical confirmation.

Automated summary

This multicenter study investigated the pharmacokinetics and pharmacokinetic-pharmacodynamic profile of intravenous minocycline in critically ill patients with MDR Acinetobacter baumannii infections. The study found that the dosing regimen of minocycline 200 mg i.v. every 12 hours may not be optimal for patients with MIC values of >1 mg/liter, requiring further clinical confirmation.