title: 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-TB-coinfected 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 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Maxwell T
authors.initials: MT
authors.lastname: Chirehwa
authors.affiliation: Strategic Health Innovation Partnerships (SHIP), South African Medical Research Council, Cape Town, South Africa.
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.affiliation: TB Research Unit: Clinical and Biomedical, South African Medical Research Council, Durban, South Africa.
authors.forename: Thuli
authors.initials: T
authors.lastname: Mthiyane
authors.affiliation: Intercountry Support Team for East and Southern Africa, World Health Organization Regional Office for Africa, Harare, Zimbabwe.
authors.forename: Philip
authors.initials: P
authors.lastname: Onyebujoh
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa paolo.denti@uct.ac.za.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D001835:Body Weight; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D060085:Coinfection; D003198:Computer Simulation; D004977:Ethambutol / Q000008:administration & dosage; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000821:virology; D006207:Half-Life; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin