A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients

Abstract

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h ؊1 at the first dose, increased 1.82-and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction. Rifampin is an indispensable constituent of first-line therapy used to treat drug-susceptible Mycobacterium tuberculosis. During the 2-month intensive phase of standard short-course antituberculosis treatment, patients receive rifampin together with isoniazid, pyrazinamide, and ethambutol. Rifampin and isoniazid are given for a further 4-month continuation phase, completing the 6-month treatment regimen. Isoniazid is responsible for killing the majority of organisms within the first 2 days of treatment. From the third to the seventh day of treatment, rifampin and pyrazinamide continue the bactericidal function (30), while ethambutol protects against the development of rifampin resistance in the event of preexisting isoniazid resistance (8). The ability of rifampin to eradicate persisting organisms has allowed the shortening of treatment from 12 to 6 months (43).Rifampin is a potent activator of the nuclear pregnane X receptor (PXR), which regulates the transcription of multiple drugmetabolizing enzymes and drug transporters (9, 13). Although the exact mechanism is not known, following chronic intravenous or oral dosing, rifampin induces its own metabolism by increasing its systemic and presystemic clearances (27,31). This effect might, in part, be attributed to the PXR-mediated induction of P-glycoprotein (P-gp), a trans-mem...

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

“…This suggests that doses intended to achieve the same dose in milligrams per kilogram of body weight across weight bands are not appropriate and lower-weight patients should be prescribed larger doses. This finding is driven by saturation of first-pass metabolism, which was more evident for patients in the highestweight band, the relatively increased clearance per unit of body size described by allometric scaling theory, and FFM being the most appropriate body size descriptor for scaling of clearance, which is consistent with previous evidence (11,33). Geiseler et al showed that daily dosing of a number of anti-TB drugs, including rifampin, should be based on the ideal body weight rather than the TBW (34).…”

“…The model suggests that, on average, clearance of rifampin almost doubles from the first day of treatment to steady state, and the induction process takes around 2 weeks to reach 90% of the fully induced state. The duration of the process differs from that reported in other studies, possibly because of the richness of data and the dosing strategies used (daily versus intermittent dosing) (11,28). Though the induction half-life estimated by our model is shorter than that reported by Smythe et al, the extent of the autoinduction effect on clearance is roughly the same.…”

“…To characterize rifampin absorption, a first-order model with and without lag time and a chain of transit compartments were assessed (19). Different approaches were used to describe autoinduction of rifampin: estimating a different clearance value at each PK sampling occasion, using an enzyme induction model (11), or using an exponential maturation model with clearance increasing with time on treatment (20).…”

“…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).…”

Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

“…Drug exposure may be influenced by a number of variables, such as concomitant food intake, comorbidities, and intraindividual differences in pharmacokinetics (8)(9)(10)(11)(12). Therefore, it seems rational to monitor drug exposure in patients with suspected malabsorption, gastrointestinal disorders, drug-drug interactions, diabetes mellitus, or HIV coinfection (13).…”