Pharmacokinetics of Doripenem in Healthy Koreans and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients With Normal and Enhanced Renal Function.

BACKGROUND: Dose adjustment is often required in patients with normal or enhanced renal function. The aim of this study is to investigate the pharmacokinetic (PK) properties of doripenem and explore optimal dosing regimens in patients with normal or enhanced renal function according to various minimum inhibitory concentrations (MICs). METHODS: The authors conducted a clinical trial and analyzed PK samples in 11 healthy Korean subjects applying noncompartmental analysis and a population approach. The population PK parameter estimates were used in Monte Carlo simulations to explore optimal dosing regimens for a probability of target attainment of 90% at 40% fTMIC (free drug concentrations above MIC). RESULTS: The time course of doripenem concentrations was well described by a 2-compartment model. The population typical values of clearance and steady-state volume were 22.9 L/h and 19.1 L, respectively, and were consistent with our noncompartmental analysis results. When the MIC was greater than 1 mcg/mL, at least increasing the dose or prolonging the infusion time was essential in patients with normal or enhanced renal function. CONCLUSIONS: These results suggest that dosage adjustment such as increasing the dose or lengthening the infusion time should be considered in patients with normal or enhanced renal function.

Assessment of the influence of severe renal impairment on the pharmacokinetics of mirodenafil in Korean male volunteers.

OBJECTIVE: To evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers. METHODS AND MATERIALS: This open-label, single-dose, parallel group clinical study enrolled a total 12 volunteers (6 healthy volunteers and 6 volunteer patients with severe renal impairment). Each volunteer was orally administered 50 mg mirodenafil and serial blood samples were obtained after drug administration to determine the plasma concentration of mirodenafil using LC-MS/MS. The measured individual plasma concentrations were used to calculate the pharmacokinetic parameters using noncompartmental methods. Tolerability was also assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: All of the volunteers completed the study with no serious adverse events (AEs). A total of 4 AEs were reported, but all were of mild or moderate intensity and not considered to be related to the study drug. The geometric mean (95% CI) of the terminal half-life (t1/2ß) and the apparent clearance (CL/F) values of mirodenafil were 2.2 (1.4 - 3.4) h and 127.2 (95.1 - 170.2) l/h in the volunteer patients, and 3.0 (2.1 - 4.4) h and 136.1 (74.4 - 249.2) l/h in the healthy volunteers, respectively. The geometric mean of the AUC0-t of the volunteer patients was 8% higher and the geometric mean for clearance was 7% lower compared with the healthy volunteers. However, the geometric mean of the Cmax of the volunteer patients was 38% higher than that of the healthy volunteers. CONCLUSIONS: A single oral 50-mg dose of mirodenafil was well tolerated. Exposure (AUC0-t) to mirodenafil was similar in both healthy volunteers and volunteer patients with severe renal impairment and healthy volunteers.