Population Pharmacokinetics with Monte Carlo Simulations of Gentamicin in a Population of Severely Ill Adult Patients from Sub-Saharan Africa

Abstract

In sub-Saharan Africa (SSA), gentamicin is commonly used for severe infections in non-intensive-care-unit (ICU) settings, but pharmacokinetic and pharmacodynamic data for this specific population are lacking. We performed a population pharmacokinetic study in an adult Mozambican non-ICU hospital population treated with gentamicin (n = 48) and developed a pharmacokinetic model using nonlinear mixed-effects modeling. Simulations showed that non-ICU patient populations in SSA may be at substantial risk for underexposure to gentamicin during routine once-daily dosing.

Keywords: aminoglycosides; gentamicin; pharmacodynamics; population pharmacokinetics; severe illness; sub-Saharan Africa.

FIG 1

Observed gentamicin concentration-time data and visual predictive check (VPC) of the final model. Open circles are observed concentrations. Solid line is observed median and dashed lines are 5th and 95th percentiles of the observed data. Red shaded area is the 95% confidence interval (CI) of the model-predicted median; blue shaded areas are the 95% CI of the model-predicted 5th and 95th percentiles. In preparing the plot, the observed and simulated concentrations below the LLQ were set to 0.14 mg/liter (0.5 × LLQ) to promote visual inspection of the figure. Solid and dashed lines run within their respective shaded areas, thereby demonstrating adequate fit of the model.

FIG 2

Simulations of gentamicin peak concentrations (A) and trough concentrations (B) for 1,000 virtual patients with all median characteristics of the population but five different dosing schedules (white, 1.5 mg q8h; gray, 4 mg q24h; red, 5 mg q24h; blue, 6 mg q24h; green, 7 mg q24h) and three CL_CR levels (10th percentile, 31 ml/min; median, 74 ml/min; and 90th percentile, 119 ml/min).