Evaluation of linezolid-induced thrombocytopenia based on hospital pharmacometrics

Aims: Thrombocytopenia and anemia are among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. Two studies based on a myelosuppression model assuming non-immune mediated decreased production of platelets noted that the platelet count reached a nadir at day 15 to 20 post linezolid treatment. In contrast, several case reports propose a mechanism involving increased elimination of platelets by linezolid induced immune-mediated destruction. In light of the uncertainty about the mechanism of linezolid induced thrombocytopenia we have investigated the possibility that either myelosuppression or enhanced platelet destruction may be important in a individual patients using hospital data. Methods: The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. Renal function (RF) was calculated using the Cockcroft & Gault formula with total body weight (TBW) of 70kg and a standard creatinine clearance of 6 L/h/70kg. The decrease of platelets by linezolid exposure was assumed to occur with one of two mechanisms in each patient. These mechanisms are inhibition of formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. We assumed all observed changes in PDI or PDI were related to plasma linezolid concentration. The pharmacodynamic model is composed of a compartment representing proliferating platelet precursor cells in the bone marrow, a compartment of systemic circulating platelets, and a link between them through three transit compartments reflecting platelet maturation. Results: The pharmacokinetic parameters for linezolid CL, VC, VP and Q were: CL (L/h) = (1.86×e(-0.0205×(AGE-69))+1.44×RF)×(TBW/70)^0.75 VC (L) = 22.9×(TBW/70) VP (L) = 24.7×(TBW/70) Q (L/h) = 10.9×(TBW/70)^0.75 About half of linezolid elimination is explained by renal CL with normal RF. Impaired RF is common in patients requiring linezolid so RF is an important determinant of linezolid exposure. There was a small (2%/y) decrease of non-renal CL with age. The population mean estimated plasma protein binding of linezolid was 18% and independent of observed concentrations. The estimated mixture model fraction of patients with platelet count decreased due to PDI was 0.97 thus the fraction due to PDS was 0.03. RF had no significant influence on linezolid effect on PDI. Simulations of predicted platelet count of PDI and PDS models were performed with typical linezolid current dosage. When PDI is assumed then the predicted nadir of platelet count is at 14 days after linezolid administration. On the other hand, when PDS is assumed then the platelet count drops sharply to reach the predicted nadir after 2 days. Conclusion: We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model has identified that the most common mechanism of thrombocytopenia associated with linezolid is inhibition of platelet formation. Target concentration intervention to reduce linezolid exposure is expected to reduce the risk of thrombocytopenia associated with impaired renal function.