Journal of Antimicrobial Chemotherapy (2007) 60, 1398–1401 doi:10.1093/jac/dkm393 Advance Access publication 20 October 2007 Elevated gatifloxacin and reduced rifampicin concentrations in a single-dose interaction study amongst healthy volunteers Helen McIlleron1*, Jennifer Norman1, Thomas P. Kanyok2, P. Bernard Fourie3, John Horton4 and Peter J. Smith1 Downloaded from https://academic.oup.com/jac/article/60/6/1398/824439 by guest on 27 September 2021 1Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, South Africa; 2Tropical Diseases, Special Programme for Research and Training, World Health Organization, Geneva, Switzerland; 3Medicine in Need, Cambridge, MA, USA; 4Tropical Projects, Hitchin, UK Received 8 August 2007; returned 7 September 2007; revised 21 September 2007; accepted 22 September 2007 Objectives: Pharmacokinetic drug–drug interactions were investigated between the fluoroquinolone gatifloxacin and a fixed dose combination (FDC) of rifampicin, isoniazid and pyrazinamide. Patients and methods: The single-dose pharmacokinetics of the four drugs was evaluated in an open- label three-way cross-over study amongst 22 healthy volunteers following administration of gatifloxa- cin, the FDC or the two products together. Results: Modest but potentially important drug–drug interactions affecting gatifloxacin and rifampicin concentrations were detected. The elimination rate of gatifloxacin was reduced such that the AUC from 0 h to infinity was increased with a geometric mean ratio (GMR) [90% confidence interval (CI)] of 1.14 (1.10, 1.18). Conversely, the AUC from 0 h to infinity for rifampicin was reduced (GMR: 0.81, 90% CI: 0.81, 0.96) when rifampicin, isoniazid and pyrazinamide were given together with gatifloxacin. Conclusions: Studies in patients including pharmacokinetic evaluation at steady state, efficacy and toxicity are required to determine the importance of the interactions for use of the combination of gatifloxacin, rifampicin, isoniazid and pyrazinamide in the treatment of tuberculosis. Keywords: pharmacokinetics, pyrazinamide, isoniazid, Mycobacterium tuberculosis Introduction Materials and methods More effective antitubercular regimens that will allow reduced The study was approved by the University of Cape Town Research treatment durations are urgently needed. Promising activities have Ethics Committee (REC REF: 005/2004) and the Secretariat been demonstrated for moxifloxacin and gatifloxacin in vitro in Committee on Research Involving Human Subjects of the World murine models and in extended bactericidal studies.1–3 Four Health Organization (RPC 077). Twenty-four volunteers were month regimens including gatifloxacin or moxifloxacin in combi- enrolled after giving their written informed consent to participate. nation with rifampicin, pyrazinamide and isoniazid or ethambutol They had normal findings upon medical history, physical examin- are currently being evaluated in patients. Pharmacokinetic inter- ation and laboratory testing (full blood count, serum chemistry; actions within these treatment regimens have the potential to hepatitis B surface antigen; urinary pH, protein, glucose, blood compromise their efficacy or safety. Identification of a pharmaco- and screen for drugs of abuse). They had not taken prescribed medication in the 2 weeks before the study, or over-the-counter kinetic basis for altered drug activity may facilitate the rational preparations (except paracetamol) in the week before the study, development of drug combinations and doses. We investigated the or smoked or donated blood in the 2 months before the study, single-dose pharmacokinetic interactions between gatifloxacin and or consumed .6 U alcohol/day. The women were using con- a fixed dose combination (FDC) comprising rifampicin, isoniazid traception measures. Pregnant or breast-feeding women were not and pyrazinamide in healthy volunteers. enrolled. ..................................................................................................................................................................................................................................................................................................................................................................................................................................... *Corresponding author. Tel: þ27-21-406-6292; Fax: þ27-21-448-1989; E-mail: [email protected] ..................................................................................................................................................................................................................................................................................................................................................................................................................................... 1398 # The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] Gatifloxacin interaction with TB drugs Single doses of each of three treatments (gatifloxacin 400 mg in maximum observed drug concentration (Cmax), time to Cmax (Tmax), w one Gatispan 400 tablet; rifampicin 600 mg, isoniazid 300 mg and plasma half-life (t1/2) associated with the terminal slope of the semi- pyrazinamide 1600 mg as four FDC tablets of AkuriT-Zw; and logarithmic concentration–time curve and AUC extrapolated to w Gatispan together with the FDC in the same doses; both products infinity (AUC0–1). manufactured and supplied by Lupin Ltd, India) were given with Stata version 8.2 (Stata Corp., College Station, TX, USA) was 240 mL of water under fasting conditions. The treatments were used for statistical tests and to summarize results. Wilcoxon separated by 2 weeks. The sequence of treatments was randomized. matched pairs sign-rank test was used to detect significant differ- Venous samples collected in heparinized tubes before and at 0.5, 1, ences between untransformed pharmacokinetic measures. Geometric 1.5, 2, 2.5, 3.5, 5, 8, 12, 24, 36 and 48 h after dosing were placed in mean ratios [90% confidence intervals (CIs)] were calculated to crushed ice before separation of the plasma by centrifugation (750 g compare Cmax and AUC0–1 for the combined treatments with those for 10 min). Within 1 h of sampling, plasma was stored at 2808C for the gatifloxacin tablet and the FDC when given alone. until analysis. Plasma drug concentrations were quantified by tandem HPLC mass spectrometry (Applied Biosystems API 2000). A 20Â2.1 mm Downloaded from https://academic.oup.com/jac/article/60/6/1398/824439 by guest on 27 September 2021 Hypersil Gold C18 column (Thermo, MA, USA) was used for Results rifampicin and the racemic mixture of gatifloxacin and a 20Â2.1 mm Betasil silica column (Thermo) for isoniazid and pyra- Twelve females and 10 males with median weight 62.5 kg zinamide. The mobile phase for gatifloxacin and rifampicin com- (range: 52–76), height 167.5 cm (range: 153–184) and age 22.5 prised a gradient from 10% to 90% acetonitrile in 0.1% formic acid years (range: 20–48) completed the study. Two participants with a 5 min run time. For isoniazid and pyrazinamide, an isocratic withdrew before receiving study treatment. elution using 80% acetonitrile in 0.1% formic acid was used. The Adverse events (frequency) included nausea or vomiting (7), flow rate was 0.3 mL/min and the injection volume was 5 mL. headache (5), dyspepsia (3), loose stools (3), skin tingling (3), Moxifloxacin served as internal standard for gatifloxacin, rifapentine flushing (2), rash at cannula or dressing site (3), generalized rash for rifampicin and sulfamethoxazole for isoniazid and pyrazinamide. (2), drowsiness (2), myalgia (2), altered taste or smell (2), faint- Selected reaction monitoring transitions of [M-H]þ precursor ions to product ions were gatifloxacin m/z 376.2–261.3; moxifloxacin m/z ness (2), fever (1) and lower back pain (1). They were mild and 402.1–261.4; rifampicin m/z 823.5–791.4; rifapentine m/z 877.2– self-limiting; none necessitated treatment interruption. Fifteen 845.3; isoniazid m/z 138.0–121.2; pyrazinamide m/z 124.1–81.1 (44%), 13 (38%) and 6 (18%) of the adverse events related or and sulfamethoxazole m/z 254.0–92.2. Plasma protein was precipi- possibly related to the study treatments were associated, respect- tated with 3 vol of acetonitrile containing the internal standard. ively, with the FDC alone, gatifloxacin and the FDC together Samples were vortexed and centrifuged for 5 min at 750 g. and gatifloxacin alone. Supernatant (5 mL) was injected into the column. Standard curves Absorption of gatifloxacin was delayed when the products were linear in the ranges 0.1–30 mg/L for rifampicin, 0.1–15 mg/L were given together, with a median Tmax of 2.25 h [interquartile for gatifloxacin and isoniazid and 0.2–70 mg/L for pyrazinamide. range (IQR): 1.39, 3.50] versus 1.5 h (IQR: 0.88, 2.13) Quality control samples covering the ranges were included with (P ¼ 0.037). Cmax of gatifloxacin was not affected (Table 1); each run. Inter- and intra-day coefficients of variation were below however, t1/2 was prolonged [median 7.17 h (IQR: 6.24, 8.09) 10%. The lower limit of quantification was set at 0.2 mg/L for pyra- versus 6.74 h (IQR: 5.77, 8.13); P ¼ 0.023], resulting in higher zinamide and 0.1 mg/L for rifampicin, gatifloxacin and isoniazid. AUC0–1 values (Table 1 and Figure 1) with FDC Drug concentrations below the validated ranges were treated administration.