Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (ϳ8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (ϳ9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

Flanagan

Minassian

Morris

et al. 2014

“…As part of these real-world evaluations, attention should be given to studying the hematologic toxicity profile of tedizolid in patients with chronic kidney disease (CKD) because of the increased risk for linezolid-induced thrombocytopenia in this patient popula- tion (27)(28)(29)(30). For linezolid, this risk for thrombocytopenia might arise from its increased exposure in patients with renal insufficiency (28,29) The accumulation of the two primary metabolites of linezolid also increases with the severity of renal dysfunction, resulting in metabolite levels 7-to 8-fold higher than those in patients with normal kidney function; however, their involvement in thrombocytopenia remains unclear (31). Because patients with CKD were excluded from tedizolid phase 3 trials, as is frequently the case when evaluating an antibacterial drug for a new indication, little is known about how tedizolid might affect platelet levels in this specific patient population.…”

Section: Discussionmentioning

confidence: 99%

Platelet Profile in Patients with Acute Bacterial Skin and Skin Structure Infections Receiving Tedizolid or Linezolid: Findings from the Phase 3 ESTABLISH Clinical Trials

Lodise

Fang

Minassian

et al. 2014

c Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan-specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm 3 ) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm 3 (؊5.9%), <112,500 cells/mm 3 (؊2.4%), and <100,000 cells/mm 3 (؊1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.)

“…Linezolid treatment is associated with reversible thrombocytopenia, particularly when used for Ն14 days (2,(5)(6)(7). Patients with baseline platelet counts of 241 ϫ 10 9 /liter or less (8) and renal insufficiency (9) are at particular risk for linezolid-induced thrombocytopenia. In this context, implementing systematic monitoring programs (10) and predicting and minimizing the extent of platelet decline in high-risk patients is important.…”

mentioning

confidence: 99%

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Boak

Rayner

Grayson

et al. 2014

103

h Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10-to 28-day therapy for platelet nadirs of <100 ؋10 9 / liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.