Population Pharmacokinetics of Rifampin in Pulmonary Tuberculosis Patients, Including a Semimechanistic Model To Describe Variable Absorption

Abstract

This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to 600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 liters ⅐ h ؊1 , while the volume of distribution was estimated to be 53.2 liters. Interindividual variability was estimated to be 52.8% for clearance and 43.4% for volume of distribution. Interoccasional variability was estimated for CL/F (22.5%) and mean transit time during absorption (67.9%). The use of single-drug formulations was found to increase both the mean transit time (by 104%) and clearance (by 23.6%) relative to fixed-dose-combination use. A strong correlation between clearance and volume of distribution suggested substantial variability in bioavailability, which could have clinical implications, given the dependence of treatment effectiveness on exposure. The final model successfully described rifampin pharmacokinetics in the population studied and is suitable for simulation in this context.

Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

“…Other PK studies found similar results (2,36). However, as the overall published data show no agreement, further studies with patients with HIV infection are needed to clarify the possible relationships between the PK of RIF and HIV infection.…”

“…This model had no covariates. The model structure is consistent with those of previous models describing plasma RIF concentrations; those models were linear one-compartment models and included few or no covariates (24,36).…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…The pharmacokinetic parameters for standard first-line drugs and for drugs used in both MDR and XDR tuberculosis are shown in table 9, mainly based on publications from South Africa, India, and the USA. [404][405][406][407][408][409][410][411][412][413][414][415][416] Predicting what concentration a patient will achieve is difficult, given the multiple determinants of pharmacokinetic variability. 191 Therefore, to identify the specific concentration-time profile, the drug concentrations should be measured in the patient directly.…”

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

“…For the purposes of parameter estimation, rifampin oral clearance (CL sys /F) was assumed to be 19.2 l/h based on a nonlinear mixed-effects population pharmacokinetic model fitted to data from 261 pulmonary tuberculosis patients (95% confidence interval, 18.4 -20.0 l/h) (Wilkins et al, 2008). This value is comparable to the estimate obtained by a noncompartmental analysis of rifampin pharmacokinetics in 28 healthy women (18.9 Ϯ 5.6 l/h) (LeBel et al, 1998).…”