Influence of eltrombopag on the pharmacokinetics of ceftriaxone in healthy volunteers

Introduction: Ceftriaxone is a third-generation cephalosporin used in pediatric and adult patients for the treatment of a wide range of infections, such as urinary, pulmonary, intra-abdominal and central nervous system (1). Ceftriaxone is 40-67% excreted in 24 h urine (2) and 40-50% in bile as unchanged drug (3). The elimination of ceftriaxone in bile occurs through BCRP protein (Breast Cancer Resistance Transporter) and MRP protein-2 (Multidrug Resistance-Associated Protein-2) (4)expressed in the canalicular membrane of hepatocytes. Eltrombopag, an agonist of the thrombopoietin receptor indicated for the treatment of immune thrombocytopenic purpura, is a substrate and based on in vitro data (IC50 1.19 ug/mL) aninhibitor of the efflux drug transporter BCRP (5).

Aim: This study evaluates the influence of eltrombopag on the pharmacokinetics of total and free (unbound)plasma concentrations of ceftriaxone in healthy volunteers.

Subjects and methods: The study comprised healthy volunteers (n=12) distributed into 3 groups according to eltrombopag administration: healthy volunteers treated with intravenous (iv)1 g ceftriaxone (group 1; n=4);healthy volunteers treated with iv 1 g ceftriaxone and two oral doses of 25 mg eltrombopag, being the first dose administered in the day before ceftriaxone administration and the second dose 4 h before ceftriaxone administration (group 2; n=4) and healthy volunteers treated with iv 1 g ceftriaxone and two oral doses of 50 mg eltrombopag, being the first dose in the day before the ceftriaxone administration and the second dose 4 h before ceftriaxone administration (group 3; n=4). Serial blood samples were collected until 48h after ceftriaxone administration. Ceftriaxone was analyzed in plasma as total and free concentrations using LC-MS/MS. Pharmacokinetic parameters were evaluated using the WinNonlin software and were expressed as geometric means(one way ANOVA, p<0.05). The clinical protocol was approved by the local Ethics Committees.

Results: The following ceftriaxone pharmacokinetics parameters were observed, respectively for groups 1, 2 and 3: Maximum plasma concentration (Cmax) 125.15vs 134.13 vs 131.71ug/mL; area under the plasma concentration vs time (AUC0-∞) 1219.24vs 1274.64vs 1184.73 ug. h/mL; distribution volume (Vd) 7.97vs 7.44vs 7.57 L; total clearance(Cl)0.82vs0.78 vs0.84 L/h and free fraction (fu) 0.15vs0.18vs0.15. The pharmacokinetics of ceftriaxone does not differ among groups.

Conclusion: Oral doses of 25 and 50 mg eltrombopag do not change ceftriaxone pharmacokinetics in healthy volunteers.

(1) Gergs Uet al. (2014). J Pharm Pharmacol 66: 1552–1558.

(2) Patel IH et al (1981). Antimicrob Agents Chemother 20: 634–641.

(3) Brogard JM et al (1987). Schweiz Med Wochenschr 117: 1549–1559.

(4) Kato Y et al (2008). Drug Metab Dispos 36: 1088–1096.

(5) Allred AJ et al (2011). Br J Clin Pharmacol72: 321-329.