III-40 Glauco Nardotto

Population pharmacokinetics of rifampicin and 25-O-desacetyl-rifampicin in Brazilian patients with pulmonary tuberculosis living or not with HIV.

Glauco Nardotto (1), Valdes Bollela (2), Oscar Della Pasqua (3), Elin Svensson (4), Vera Lanchote (1)

(1) School of Pharmaceutical Sciences of Ribeirão Preto – USP, Brazil; (2) School of Medicine of Ribeirão Preto – USP, Brazil; (3) School of Pharmacy – UCL, UK; (4) Department of Pharmacy of Uppsala University.

Introduction:

Rifampicin (RIF) is possibly the most important drug among the four first-line anti-tuberculosis drugs (FLATDs). Currently, the World Health Organization recommends treating TB with fixed-dose combined tablets (FDC) of these antibiotics according to the patient body weight (1,2). Despite its extensive use, the knowledge of RIF dosing to ensure optimal drug exposure remains limited(3–5). Then, this study presents the population pharmacokinetics of RIF and 25-O-desacetil-rifampicin (desRIF) in Brazilian patients with pulmonary tuberculosis diagnosed negative for HIV (TB-HIV−) or living with HIV (TB-HIV+).

Objective:

Evaluate by modeling whether HIV, body size descriptors, SLCO1B1 genotype and other covariates affect RIF pharmacokinetics, and the dosing implications of these influences.

Methods

We included TB-HIV− (n=15) and TB-HIV+ (n=18) patients after they had started the second month of treatment with fixed-dose combined tablets (FDC) containing rifampicin (150 mg), isoniazid (75 mg), pyrazinamide (400 mg), and ethambutol (250 mg). All patients received, according to their body weight, 2 FDC (20-35 Kg), 3 (36 to 50 Kg), or 4 (> 50 kg), under fasting. The population PK analysis of RIF linked to desRIF was evaluated by nonlinear mixed-effects modeling conducted in NONMEN version 7.5.

Results

RIF and desRIF pharmacokinetic were characterized by a mono-compartmental structural model with first-order elimination. RIF absorption was better described by transit with 1 compartment (Nn = 1) model in which Ka = Ktr = (Nn+1)/MTT, being: MTT: mean transit time, Ka: first-order absorption constant, Ktr: transit compartment constant. The desRIF formation was parameterized as a fraction of rifampicin apparent clearance (CL/F) converted into desRIF [(CL/F)*Fmet)], being: CL/F = [(CL/F)*Fmet)] + [(CL/F)*(1-Fmet)]. The typical values of CL/F and Fmet were 34.7 L/h and 0.109.

There are few clinical studies analysing the formation of the rifampicin metabolite (6–8), and only one evaluates the population PK of RIF and desRIF in healthy Asian adults that arbitrarily fixed the Fmet to 1 (8). Therefore, possibly this is the first RIF PK model to allow estimation of Fmet.

HIV and SLCO1B1 gene polymorphism (rs4149056 and rs11045819) did not affect the pharmacokinetics of RIF and desRIF, while the free fat mass (FFM) affected CL/F by a power function.

However, Population simulated patients weighting < 50 Kg, ≤ 35 Kg or ≥ 50 Kg taking 450 mg (2 FDC), 300 mg (3 FDC) or 600 mg (4 FDC) of RIF presented AUC0-24, Cmax and Css medians of 13, 8 or 19 mg·h/mL, 4.2, 3 or 5 mg/mL and 0.5, 0.38 or 0.7 mg·h/mL. Therefore, individuals weighing less than 50 Kg presented lower RIF exposure suggesting that these patients should receive higher doses than 450 mg RIF to reach the same plasma exposure as those weighing ≥ 50 kg receiving 600 mg RIF.

Furthermore, population simulated individuals with bodyweight ≥ 50 Kg (receiving 600 mg RIF) presented a median Css of 0.71 µg/mL. Simulated population patients with FFM between 24-28 and 29-33 kg should receive a median (interquartile interval) maintenance dose of 554.16 (670.30-456.65) and 579.98 (701.05-479.21) mg of RIF to achieve a Css ≈ 0.71 µg/mL. Therefore, although FFM affects the CL/F of RIF by power model, FFM did not implicate clinically considerable changes in the values of RIF dose among the individuals. Apparently, there is no need to change the RIF dose according to the bodyweight or FFM, and the patients in this study could receive 600 mg of RIF regardless the body size. Similarly, previous reports in other patient populations also demonstrated that the currently recommended dose regimen of FLATDs provides lower RIF exposure in patients with body weight lower than 50 Kg (9,10). Possibly, this is also the case for Brazilian pulmonary TB patients that should receive the same RIF dose regardless the body size.

Conclusions

Apparently, there is no need to change the RIF dose according to HIV and body size among patients with pulmonary tuberculosis from Brazil. The polymorphic loci of the SLCO1B1 gene: g.521T>C (rs4149056) and g.463C>A (rs11045819) polymorphism did not influence the pharmacokinetics.

  1. Ministério da Saúde. Manual de recomendações para o controle da tuberculose no brasil [Internet]. Brasília, Brasil: Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica; 2019 [cited 2020 May 19] p. 1–288. Report No.: 2. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/manual_recomendacoes_controle_tuberculose_brasil_2_ed.pdf
  2. TB CARE I. International standards for Tuberculosis Care [Internet]. San Francisco, United States: University of California; 2014 [cited 2017 May 19] p. 1–92. (International standards for Tuberculosis Care). Report No.: 3. Available from: http://www.tbcare1.org/publications/
  3. Egelund E, Alsultan A, Peloquin C. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharmacol Ther. 2015 Oct 1;98(4):387–93.
  4. Clewe O, Karlsson MO, Simonsson USH. Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution. J Pharmacokinet Pharmacodyn. 2015 Dec 1;42(6):699–708.
  5. McCune JS, Reynolds KS. Developing and using therapeutics for emerging infections. Clin Pharmacol Ther. 2015 Oct;98(4):346–51.
  6. Acocella G. Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet. 1978 Apr 1;3(2):108–27.
  7. Loos U, Musch E, Jensen JC, Mikus G, Schwabe HK, Eichelbaum M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin Wochenschr. 1985 Dec 1;63(23):1205–11.
  8. Seng K-Y, Hee K-H, Soon G-H, Chew N, Khoo SH, Lee LS-U. Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults. J Antimicrob Chemother. 2015 Dec 1;70(12):3298–306.
  9. Susanto BO, Svensson RJ, Svensson EM, Aarnoutse R, Boeree MJ, Simonsson USH. Rifampicin Can Be Given as Flat-Dosing Instead of Weight-Band Dosing. Clinical Infectious Diseases. 2020 Dec 15;71(12):3055–60.
  10. Muliaditan M, Della Pasqua O. How long will treatment guidelines for TB continue to overlook variability in drug exposure? J Antimicrob Chemother. 2019 Nov 1;74(11):3274–80.

Reference: PAGE 30 (2022) Abstr 10164 [www.page-meeting.org/?abstract=10164]

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