Rifampicin Alters Metformin Plasma Exposure but Not Blood Glucose Levels in Diabetic Tuberculosis Patients

Lindsey H M Te Brake, Vycke Yunivita, Resvi Livia, Nanny Soetedjo, Eleonora van Ewijk-Beneken Kolmer, Jan B Koenderink, David M Burger, Prayudi Santoso, Reinout van Crevel, Bachti Alisjahbana, Rob E Aarnoutse, Rovina Ruslami, TANDEM Consortium, Lindsey H M Te Brake, Vycke Yunivita, Resvi Livia, Nanny Soetedjo, Eleonora van Ewijk-Beneken Kolmer, Jan B Koenderink, David M Burger, Prayudi Santoso, Reinout van Crevel, Bachti Alisjahbana, Rob E Aarnoutse, Rovina Ruslami, TANDEM Consortium

Abstract

The pharmacokinetic (PK) and clinical implications of combining metformin with rifampicin are relevant to increasing numbers of patients with diabetic tuberculosis (TB) across the world and are yet unclear. We assessed the impact of rifampicin on metformin PKs and its glucose-lowering effect in patients with diabetic TB by measuring plasma metformin and blood glucose during and after TB treatment. Rifampicin increased metformin exposure: plasma area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-τ ) and peak plasma concentration (Cmax ) geometric mean ratio (GMR; during vs. after TB treatment) were 1.28 (90% confidence interval (CI) 1.13-1.44) and 1.19 (90% CI 1.02-1.38; n = 22). The metformin glucose-lowering efficacy did not change (Δglucose - Cmax ; P = 0.890; n = 18). Thus, we conclude that additional glucose monitoring in this population is not warranted. Finally, 57% of patients on metformin and rifampicin, and 38% of patients on metformin alone experienced gastrointestinal adverse effects. Considering this observation, we advise patients to take metformin and rifampicin with food and preferably separated in time. Clinicians could consider metoclopramide if gastrointestinal adverse effects occur.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Schematic overview of the most important transporters involved in the absorption, hepatic uptake, and excretion of metformin.14, 38, 39, 40, 41, 42 The physiological significance of the transporters depicted in gray is unclear.14 MATE, multidrug and toxin extrusion; OCT, organic cation transporter; PMAT, plasma membrane monoamine transporter.
Figure 2
Figure 2
Individual changes in steady‐state metformin pharmacokinetic parameters, AUC 0–τ (a), Cmax (b) and tubular secretion (c), with and without co‐administration of rifampicin. Metformin plasma concentrations were extrapolated from 8 until 12–24 hours to calculate AUC 0–τ for patients taking metformin once or twice daily. Tubular secretion was based on observed urine collections up to 8 hours after metformin intake. Data were assessed with paired‐samples t test on the log‐transformed parameters. AUC0–τ, area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval; Cmax, maximum plasma concentration. ETH, ethambutol; IC, informed consent; INH, isoniazid; MTF, metformin; PK‐GC, pharmacokinetic‐glucose curve sampling session; PZA, pyrazinamide; RIF, rifampicin.
Figure 3
Figure 3
Individual changes in G‐AUC (a) and Gmax (b), after a 75‐g glucose challenge, with and without co‐administration of rifampicin. Data were assessed with paired‐samples t test on log‐transformed blood glucose parameters (n = 18). AUC, area under the blood concentration‐time curve from; Gmax, maximum blood glucose concentration.
Figure 4
Figure 4
Schematic overview of the study design in weeks from the start of tuberculosis (TB) treatment (wk 0). The TB treatment period (week 0–24) is colored dark gray. Patients were enrolled if they were continuation phase of TB treatment. Daily intake of TB drugs (for > 7days) is indicated by dashed lines. In between sessions, there was at least a 1‐month washout period, after which any induction caused by rifampicin was expected to have dissipated.9 AUC, area under the plasma concentration‐time curve; Cmax, maximum plasma concentration.

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