Paolo Denti (1), Yanhui Lu (2), Erin Bliven-Sizemore (3), Kelly E. Dooley (2)
(1) University of Cape Town, Cape Town, South Africa, (2) The Johns Hopkins University School of Medicine Baltimore, MD, United States, (3) Centers for Disease Control and Prevention, Atlanta, GA, United States
Objectives: Rifamycins are antibiotics largely used in the treatment of tuberculosis and are potent inducers of a wide range of drug-metabolising enzymes, including most notably the cytochrome P450 (CYP) family. Consequently, this gives rise to a number of drug-drug interactions. The objective of this analysis is to quantify the level of CYP3A induction caused by escalating doses of rifapentine (RPT). To do this, midazolam (MDZ) has been used as a probe drug for CYP3A and rifampicin (RIF) as a comparison inducer. MDZ is first hydroxylated to α-OH-MDZ by CYP3A which is then glucuronidated by UDP-glucuronosyltransferases.
Methods: On day 1 of the study [1], 29 healthy volunteers received a single oral dose of MDZ (15 mg). Thereafter, either RIF or RPT was administered daily, and on day 15 participants received a second single dose of MDZ. Intense PK sampling was performed on both occasions, and the plasma was assayed for MDZ and its main metabolite, α-OH-MDZ. The participants were randomised into 5 cohorts; subjects received 10 mg/kg of RIF or 5, 10, 15 or 20 mg/kg of RPT. The data were interpreted with a nonlinear mixed-effects model implemented in NONMEM VII. A well-stirred liver model [2] was assumed to capture with a single hepatic parameter (CLint) both CL and first-pass metabolism. Allometric scaling [3] adjusted for body size, the M3 method [4] was used to handle BLQ values, and BSVs and BOVs were included using a lognormal distribution. The effect of the rifamycins on MDZ PK was investigated.
Results: Including in the model only the effect of rifamycins on hepatic CLint, prolonged exposure to RIF increased CLint of MDZ approximately 8 fold, while the effect of RPT was even stronger, about 20 fold. Also the levels of α-OH-MDZ were found decreased after rifamycin exposure, but to a lower extent than MDZ: this was captured in the model with an increase in CLint of α-OH-MDZ by more than 3 and 5 fold for RIF and RPT, respectively. No significant increase in the induction effect was detected with escalating doses of RPT.
Conclusions: The well-stirred liver model can be used to describe the PK of MDZ and captures well the induction effect of rifamycins. With the current data it is not possible to separate pre-hepatic CYP3A metabolism, although some may be expected (i.e. in the enterocytes). Inclusion of IV midazolam data in the model may help address this. Another improvement could result from the use of RIF exposure, rather than dose, since large variability was detected in RIF induction.
References:
[1] K. E. Dooley, E. E. Bliven-Sizemore, M. Weiner, Y. Lu, E. L. Nuermberger, W. C. Hubbard, E. J. Fuchs, M. T. Melia, W. J. Burman, and S. E. Dorman, "Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.," Clinical pharmacology and therapeutics, vol. 91, no. 5, pp. 881-8, May 2012.
[2] T. Gordi, R. Xie, N. V Huong, D. X. Huong, M. O. Karlsson, and M. Ashton, "A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction.," British journal of clinical pharmacology, vol. 59, no. 2, pp. 189-98, Feb. 2005.
[3] B. J. Anderson and N. H. G. Holford, "Mechanism-based concepts of size and maturity in pharmacokinetics.," Annual review of pharmacology and toxicology, vol. 48, pp. 303-32, Jan. 2008.
[4] J. E. Ahn, M. O. Karlsson, A. Dunne, and T. M. Ludden, "Likelihood based approaches to handling data below the quantification limit using NONMEM VI.," Journal of pharmacokinetics and pharmacodynamics, vol. 35, no. 4, pp. 401-21, Aug. 2008.
Reference: PAGE 22 () Abstr 2956 [www.page-meeting.org/?abstract=2956]
Poster: Other Drug/Disease Modelling