Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).
2021 02 17
Journal Article
Authors:
Lodise, T.P.;
Van Wart, S.;
Sund, Z.M.;
Bressler, A.M.;
Khan, A.;
Makley, A.T.;
Hamad, Y.;
Salata, R.A.;
Silveira, F.P.;
Sims, M.D.;
Kabchi, B.A.;
Saad, M.A.;
Brown, C.;
Oler, R.E.;
Fowler, V.;
Wunderink, R.G.
Secondary:
Antimicrob Agents Chemother
Volume:
65
Issue:
3
PMID:
33168615
Keywords:
Acinetobacter baumannii; Adult; Animals; Anti-Bacterial Agents; Critical Illness; Humans; Microbial Sensitivity Tests; Minocycline
Abstract:
Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) 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 [AUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of 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) 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). 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 infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.
