Variability in the pharmacokinetics of rifapentine in South African tuberculosis patients : a classical and population approach
Doctoral Thesis
2004
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University of Cape Town
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Abstract
Tuberculosis is recognised as one of the leading public health problems in sub-Saharan Africa. The treatment and control of the disease depends largely on a limited number of chemotherapeutic agents, most of which have been used for the past 30 years. Discovery and development of new antimycobacterial agents has been relatively stagnant. New impetus from the Global Alliance for Tuberculosis Drug Development aims to register a new faster-acting and affordable drug by 2010. Until such an agent is freely available, though, it is necessary to use the available means at our disposal. Treatment regimens based on rifapentine, with its less demanding schedule, lack of autoinduction and increased absorption following food intake could make it an excellent candidate to anchor an intermittent chemotherapy regimen. The studies thus far on patients receiving proven bioavailable preparations of rifapentine do not comment on the respective plasma levels but have concentrated on specific outcomes. As a result little is known as to the magnitude of variability in plasma levels amongst patients receiving rifapentine. This degree of variability may prove to be important as rifapentine continues to be investigated as an alternative to rifampicin. This thesis describes the pharmacokinetics of rifapentine in a South African tuberculosis patient population with special reference to variability in serum drug levels between patients and between occasions. Forty-five patients received rifapentine doses of 600, 750 and 900 mg based on body weight. Doses were administered on study days one and five. All patients had already received not less than four weeks and no more than six weeks of standard antimycobacterial therapy (isoniazid, rifampicin, pyrazinamide and ethambutol). In total, twenty blood samples were collected per patient from 0 - 168 hours. Rifapentine and 25desacetyl rifapentine concentrations were determined using validated high pressure liquid chromatography methods. Median peak plasma concentrations, time to reach this peak, plasma elimination half-lives and area under the concentration-time curve were calculated for both parent drug and metabolite on both occasions using non-compartmental methods. The pharmacokinetics of the parent drug was best described using a one-compartment model, with a lag time and first-order absorption and elimination. Estimated population parameters were absorption rate constant, lag time on absorption, clearance/bioavailability, and volume of distribution/bioavailability. Between subject and between occasion variability was below 25% for all parameters except KA which showed a between subject variability of 52%. The pharmacokinetics of the metabolite in this study were best described by a one-compartment model with no first-pass metabolism and a clearance value that declined in a non-linear fashion over time. Parameters estimated were, volume of distribution, induced metabolite clearance, baseline metabolite clearance, and slope of decline in clearance over time. In South African tuberculosis patients the 15 mg/kg dose of rifapentine was well absorbed and well tolerated. The variability observed between individuals and between occasions was small and similar to that seen in data from previous studies in healthy volunteers.
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Includes bibliographical references (leaves 101-115).
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Reference:
Langdon, G. 2004. Variability in the pharmacokinetics of rifapentine in South African tuberculosis patients : a classical and population approach. University of Cape Town.