Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Abstract

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TBcoinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4. Rifampin is a key drug in the treatment of tuberculosis (TB), and the World Health Organization (WHO) currently recommends weight-adjusted doses of 8 to 12 mg/kg daily. Despite its being used in the treatment of TB for nearly 50 years, there is evidence that current rifampin exposures may be suboptimal. Rifampin's efficacy is exposure dependent (1-3); therefore, the efficacy and toxicity of higher doses are under investigation. Recent reports show that larger doses of rifampin are well tolerated by humans (4) and may improve treatment outcomes, as well as reduce the treatment duration from the current 6 months (5, 6).Rifampin is mainly hepatically cleared, and it undergoes extensive first-pass metabolism (7), whose saturation with higher doses has been reported since early pharmacokinetic (PK) studies (8). Thus, when the rifampin dose is increased above a certain level, a more-than-proportional increase in the plasma rifampin concentration results. Rifampin also induces its own metabolism via the pregnane X receptor (9), a phenomenon known as clearance autoinduction, resulting in less exposure at steady state than after a single dose.Previous studies have proposed rifampin PK models (10), but those trying to characterize clearance autoinduction have done so mostly by relying on only two PK sampling occasions (11), which limited their ability to characterize the process. Nonlinearity in a dose-exposure relationship suggesting saturation of rifampin clearance has been reported (8). However, a population PK model has not jointly described the autoinduction and hepatic extraction (E H ) of rifampin. In this study, we analyzed rich data from an intensive sampling scheme to develop a rifampin PK model for TB patients that accounts for both clearance autoinduction and saturation of E H . This model was then employed to explore changes in rifampin exposure when doses are incr...

A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses

“…The maximum predicted typical CL/F at the preinduced state was 14.9 L/h/70 kg (i.e., at 0 mg/L, Figure b ), 3.44 times higher than the typical CL/F for a concentration of, e.g., 85.8 mg/L (highest observed rifampicin concentration in the dataset). A previous model‐based estimate of k m is 3.35 mg/L, which is markedly lower than our estimate of 35.3 mg/L. The discrepancy between these estimates may exist because in contrast to the model presented here, Chirehwa et al .…”

“…A previous model‐based estimate of k m is 3.35 mg/L, which is markedly lower than our estimate of 35.3 mg/L. The discrepancy between these estimates may exist because in contrast to the model presented here, Chirehwa et al . assumed a well‐stirred liver model and do not include doses above 10 mg/kg.…”

“…The model predicted 1.73, 1.89, 1.91, 1.94, 1.97, and 1.99‐fold increases in CL/F for the 10, 20, 25, 30, 35, and 40 mg/kg dose groups, respectively, at steady state compared to a single dose. Previous models predicted increases of 1.85 and 1.89 for the 10 mg/kg dose. The predicted half‐life for the autoinduction was 4.79 days, which agrees well with the estimate from Chirehwa et al .…”

“…Previous models predicted increases of 1.85 and 1.89 for the 10 mg/kg dose. The predicted half‐life for the autoinduction was 4.79 days, which agrees well with the estimate from Chirehwa et al . of 4.5 days but is shorter than the estimate reported by Smythe et al .…”

“…The nonlinear increase in exposure of rifampicin with dose has been known since the early 1970s and was described in the first clinical trial that evaluated the concept of high‐dose rifampicin more recently . Reported reasons for the nonlinear increase in exposure include saturable biliary excretion as well as an exposure‐dependent bioavailability (F) . The decrease in rifampicin exposure with time is due to increased elimination by induction of enzymes and/or transporters caused by the antibiotic itself, referred to as autoinduction .…”