The Population Pharmacokinetics of Rifampicin in Japanese Pulmonary Tuberculosis Patients

Abstract

In Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration–time data were obtained from 138 patients receiving rifampicin (300–450 mg) and isoniazid (300–400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from −31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

Population pharmacokinetics analyses of rifampicin in adult and children populations: A systematic review

“…A combination of additive and proportional models for residual variability was described in 11 studies, 19,31,32,34,36,38,39,41,42,45,46 whereas an additive residual error model was reported in three studies 43,44,48 and a proportional model was recorded in four others 30,37,40,47 . Lastly, an exponential error model was implemented to quantify the interindividual variability in seven studies 31,35–37,39,43,49 …”

“…30,37,40,47 Lastly, an exponential error model was implemented to quantify the interindividual variability in seven studies. 31,[35][36][37]39,43,49 The finalised models were further evaluated via a basic internal validation approach (eg, goodness of fit), advanced internal validation (eg, bootstrapping, visual predictive check [VPC]) and external validation. In seven studies, a combination of VPC and bootstrapping was employed for model evaluation, 31,32,35,38,41,44,48 while a combination of goodness of fit and VPC was implemented in four studies.…”

“…31,[35][36][37]39,43,49 The finalised models were further evaluated via a basic internal validation approach (eg, goodness of fit), advanced internal validation (eg, bootstrapping, visual predictive check [VPC]) and external validation. In seven studies, a combination of VPC and bootstrapping was employed for model evaluation, 31,32,35,38,41,44,48 while a combination of goodness of fit and VPC was implemented in four studies. 19,30,39,40 Finally, external validation was conducted in two studies with 77 37 and 61 36 subjects, respectively.…”

“…A total of 19 studies, of which 16 involved adults, 19,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] two involved children 50,51 and one involved both adults and children, were included in the review. 47 Six studies were conducted in South Africa, 31,32,52,53,54,55 two in China, 36,43 Mexico, 37,56 South Korea 30,39 and Uganda, 19,49 and one each in Japan, 35 Ghana, 46 Malawi, 47 Singapore 40 and Tanzania. 38 Overall, the number of subjects who participated in the included studies ranged from 25 to 261, while the total number of blood samples ranged between 95 and 2913.…”

“…Seven studies used high-performance liquid chromatography (HPLC) to determine the rifampicin concentration in plasma, 19,31,35,37,43,47,48 while five other studies applied liquid chromatography-mass spectroscopy (LC-MS/MS) with two detectors. 36,[38][39][40]42 In comparison, three studies used liquid chromatography-mass spectroscopy (LC-MS) 30,32,41,49 and one study used ultra-performance liquid chromatography (UPLC).…”