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


Smythe, W; Khandelwal, A; Merle, C; Rustomjee, R; Gninafon, M; lo, MB; Sow, OB; Olliaro, PL; Lienhardt, C; Horton, J; Smith, P; McIlleron, H; Simonsson, USH; (2012) A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients. Antimicrobial agents and chemotherapy, 56 (4). pp. 2091-2098. ISSN 0066-4804 DOI: https://doi.org/10.1128/AAC.05792-11

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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.

Item Type: Article
Keywords: pulmonary tuberculosis, dose rifampin, metabolism, induction, nonmem, size, absorption, clearance, standard, humans
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Research Centre: TB Centre
PubMed ID: 22252827
Web of Science ID: 301898500054
URI: http://researchonline.lshtm.ac.uk/id/eprint/30295

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